IMPACT Guideline

IMPACT Third Edition (Version 3.0) 1

Reducing bacterial resistance with IMPACT –

Interhospital Multi-disciplinary Programme on AntimicrobialChemoTherapy

This guideline is available for download at:

HKU Centre of Infection

http://www.hku.hk/hkucoi/impact.pdf

DH Centre for Health Protection

http://www.chp.gov.hk/files/pdf/reducing_bacterial_resistance_with_impact.pdf

HA intranet

http://ha.home/ho/ps/impact.pdf


Editors: PL Ho and SSY Wong

Third Edition 2005

Version 3.0

Second edition: 2001 (ver 2.0), 2002 (ver 2.1), 2003 (ver 2.2)

First edition: 1999

All rights reserved. No part of this publication may be reproduced, stored in a retrieved system, or transmitted, in any form or by any

means, electronic, mechanical, photocopying, and recording or otherwise, without the prior approval from IMPACT

We seek to improve the quality of this document. If you have comments or suggestion on this draft, please email to

[email protected] or [email protected]

NOTICE

This publication contains information relating to general principles of medical care, which should not be

construed as specific instructions for individual patients. Manufacturers' product information and package inserts

should be reviewed for the latest information, including contraindications, dosages and precautions. The editors, the

working group and publisher are not responsible for errors or omissions or for any consequences from the application of the

information in this document and make no warranty, express or implied, with respect to the currency, accuracy, or completeness of the

contents of the publication. Application of this information in a particular situation remains the professional responsibility of the

health care professionals. Readers are reminded that some products may not be available in their instutues.


IMPACT Working Group

Co-chairpersons Dr. Raymond Wai Hung, YUNG

Head, Infection Control Branch, Centre for Health Protection, Department of Health

Dr. Dominic Ngai Chong, TSANG

Consultant Microbiologist, Department of Clinical Pathology Queen Elizabeth Hospital

Members (alphabetical order)

Dr. S Anandaciva Consultant Department of Anaesthesiology and

Intensive Care Unit Tuen Mun Hospital

Dr. Kin Sang, CHAN Chief of Service Department of Pulmonary Medicine Haven of Hope Hospital

Dr. Wai Ming, CHAN Consultant Intensive Care Unit Queen Mary Hospital

Dr. Sik To, LAI Consultant Department of Medicine Princess Margaret Hospital

Dr. Wai Man, LAI Chief of Service Department of Microbiology Prince of Wales Hospital

Dr. Patrick CK, LI Chief of Service Department of Medicine Queen Elizabeth Hospital

Dr. Wei Kwang, LUK Senior Medical Officer Department of Clinical Pathology Tseung Kwan O Hospital


Dr. Tak Keung, NG Consultant Microbiologist Department of Clinical Pathology Princess Margaret Hospital

Dr. Tak Lun, QUE Consultant Microbiologist Department of Clinical Pathology Tuen Mun Hospital

Dr. Loletta KY, SO Senior Medical Officer Department of Medicine Pamela Youde Nethersole Eastern

Hospital

Dr. Wing Kin, TO Senior Medical Officer Department of Clinical Pathology Yan Chai Hospital

Dr. Kwan Keung, WONG Chief of Service Department of Medicine

North District Hospital

Dr. Sai Hung, YEUNG Consultant Department of Orthopaedic Surgery Pamela Youde Nethersole Eastern

Hospital

Dr. Wai Chun, YIP Chief of Service Department of Surgery Kwong Wah Hospital

Mr. Pak Wai, LEE Chief Pharmacist Hospital Authority Head Office


Academic advisors

Professor Robert MT, CHAN Professor of Infectious Diseases Department of Medicine University of British Columbia Vancouver, Canada

Dr. Pak Leung, HO Associate Professor and Honorary Consultant

Division of Infectious Diseases, Department of Microbiology & Centre of Infection

The University of Hong Kong

Professor Margaret IP Professor Department of Microbiology Chinese University of Hong Kong

Professor Allan R. RONALD Distinguished Professor Emeritus (Internal Medicine,Medical Microbiology and Community Health Sciences)

University of Manitoba Canada

Professor Kenneth WT, TSANG Professor and Honorary Consultant Department of Medicine Queen Mary Hospital

Professor Kwok Yung, YUEN Chair Professor in Infectious Diseases Division of Infectious Diseases,

Department of Microbiology & Centre of Infection

The University of Hong Kong


Secretaries

Dr. Cindy WS, TSE Associate Consultant

Department of Clinical Pathology

Kwong Wah Hospital

Dr. Alan KL, WU Medical Officer

Department of Clinical Pathology

Pamela Youde Nethersole Eastern Hospital

Dr. Tak Chiu, WU Associate Consultant

Department of Medicine

Queen Elizabeth Hospital


ContentsList of tables ......................................................................................9Foreword .........................................................................................10Preface.............................................................................................11

Part I: Antibiotic resistance- local scenario ..................................12

Methicillin-resistant Staphylococcus aureus......................................16Vancomycin-resistant enterococci .....................................................17ESBL-producing Enterobacteriaceae .................................................17Enterobacter spp. .............................................................................19

Part II: Antimicrobial stewardship programme .............................21

Antimicrobial stewardship program: summary .................................22Classification of therapy...................................................................34

Part III: Guidelines for selected antimicrobials use ......................37

Vancomycin.....................................................................................38Quinupristin/dalfopristin and linezolid ............................................43Ceftazidime......................................................................................45Imipienem/meropenem/ertapenem..................................................48Once daily aminoglycosides..............................................................50Summary of selected antifungal agents ............................................54

Part IV: Recommendation for the empirical therapy of common

infections .......................................................................................59

Musculoskeletal infections ...............................................................60Skin and soft tissue infections .........................................................61Central nervous system infections....................................................62Intra-abdominal and GI system infections ........................................63Cardiovascular infections.................................................................64Gynaecological infections .................................................................65Head and neck infections .................................................................65Urinary tract infections ....................................................................65Respiratory tract infections ..............................................................66Guidelines on the use and choice of antibiotics in severe acute pancreatitis .....................................................................................71Management of community-acquired pneumonia .............................74General considerations and principles..............................................74


Part V: Guidelines for known pathogen therapy ...........................81

Part VI: Guidelines for surgical prophylaxis..................................88

Antibiotic prophylaxis in clean operations ........................................90Antibiotic prophylaxis in clean-contaminated operations ..................92Antibiotic prophylaxis in contaminated-infected operations ..............94

Part VII: Cost and recommended dosage of commonly-used

antimicrobial agents ......................................................................95

Preparation and recommended dosing regimens for antibiotics.........96Cost comparison of selected IV antibiotics ......................................100Cost comparison of systemic antifungal agents...............................102Dosage of antimicrobial agents for CNS infections ..........................103Intra-peritoneal antibiotic dosing recommendations for patients with CAPD peritonitis ............................................................................104

Reference List ................................................................................105Abbreviations.................................................................................123


List of tables

Table 1. Top ten isolates from clinical specimens in 2004 (data from a

regional hospital in Hong Kong). .......................................... 14

Table 2. Intrinsic and associated resistance to antimicrobial agents

among five nosocomial pathogens. ....................................... 15

Table 3. Methods to implement antimicrobial control......................... 28

Table 4. Potential barriers to reaching the strategic goals .................. 29

Table 5. Summary of published data on antimicrobial strategies as an

intervention to reduce ESBL resistance................................ 33

Table 6. Strategies for optimization of antimicrobial therapy.............. 36

Table 7. Dosage table for vancomycin................................................ 41

Table 8. Calculation of vancomycin dose for morbidly obese patient... 42

Table 9. Comparison of linezolid and quinupristin/dalfopristin.......... 44

Table 10. Hartford Hospital once-daily aminoglycoside normogram for

gentamicin and tobramycin ................................................. 53

Table 11. General patterns of antifungal susceptibility ...................... 54

Table 12. Comparison of susceptibility of selected fungi to the azoles 55

Table 13. Mechanisms of antifungal action........................................ 56

Table 14. Comparison of selected pharmacokinetic parameters for the

azoles and caspofungin ...................................................... 57

Table 15. A suggested scheme for systemic antifungal agents ............ 58

Table 16. Criteria for severity assessment of acute pancreatitis ......... 72

Table 17. Prophylactic use of antibiotic in acute pancreatitis ............. 73

Table 18. Comparative activities of commonly used beta-lactams

against Streptococcus pneumoniae with different levels of

penicillin susceptibility....................................................... 80


Foreword

Antibiotics are one of the essential armaments for management of infections. Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. It is becoming a global problem. Prevention of the emergence of resistance and the spread of resistant microorganisms will reduce these adverse effects and their attendant costs. Promoting appropriate use of antibiotic has shown to be an effective means to control antimicrobial resistance.

In Hong Kong, our long-term battle against antibiotic resistance continues and antimicrobial guideline is an essential tool to promote rational use of antimicrobial agents with better application of existing knowledge and adherence to good practice.

The IMPACT was developed in 1999 as a first step towards better control of the growing problem of antimicrobial resistance in Hong Kong. Developed with a multidisciplinary approach with inputs from different specialties and institutions, the IMPACT took into account the local data on prevalence of different pathogens and antimicrobial resistance patterns.

Now into its third edition, the IMPACT has incorporated constructive comments from clinicians and other colleagues as part of an on-going effort to keep abreast of new antibiotics, changing resistance patterns and literature. This specifically developed guideline for practitioners in Hong Kong provides evidence-based principles focused on situations in which antimicrobial therapy could be curtailed without compromising patient care.

The third edition of the IMPACT is a timely update to coincide with the launching of the Antibiotic Stewardship Programme by the Hospital Authority which includes optimal selection, dose and duration of treatment, as well as control of antibiotic use. The IMPACT constitutes an essential element along with other key elements of education, user-feedback, regular updates, clinical audits and process evaluation in this comprehensive Programme.

I thank the many individuals and organizations who have contributed to the compilation of IMPACT and look forward to your continued support and partnership in our Antibiotic Stewardship Programme.

Dr Cheung Wai-lun DirectorProfessional Services and Operations Hospital Authority


Preface

The “IMPACT” programme is a collaborative effort by recognized authorities in the areas of clinical microbiology and infection, infectious diseases, public health medicine, hospital epidemiology, intensive care medicine, respirology, surgery, orthopaedics and traumatology, and clinical pharmacology. The IMPACT working group recognizes the challenges from drug-resistant organisms and believes that the adverse impact of antimicrobial resistance could be reduced through a better and more judicial use of the existing agents. The document is intended to be of interest and value to colleagues who practise in institutional settings and prescribe or evaluate antimicrobial agents.

This new edition updates and revises all the information in the previous edition. The document is now organized into eight parts. Part 1 and II covers the background information. Part III provides guidelines on the use of six classes of antibiotics. They are discussed separately because they represent new agents (linezolid, quinupristin-dalfopristin), agents in which usage has a strong link to development of multidrug-resistant organisms (glycopeptides, ceftazidime, and carbapenems) or that the dosing and monitoring are complicated (aminoglycosides). Several new sections have been added: antimicrobial stewardship programme, severe acute pancreatitis, antifungal agents, and antibiotic dosing for CAPD peritonitis. The font size and the print-out size have been increased to enhance readability. A full list of tables and a quick reference are added to facilitate the use of this book.

The editors are grateful to the contributions by our experts in the working group. The secretaries are skillful and meticulous in their attention to the compilation of the document. On behalf of the working group, we thank the Infection Control Branch of the Centre for Health Protection for providing administrative support, the Chief Pharmacist Office in the Hospital Authority for the generous support in printing the hard copies and all colleagues who have provided us with their valuable opinions in the preparation of this document.

PL Ho SSY Wong November 2005

Part I: Antibiotic resistance – local scenario


Part I: Antibiotic resistance- local scenario



Background: the problem of antimicrobial resistance in Hong Kong

1. The emergence of resistance has threatened the successful treatment of patient with infections (1-5).

2. Antimicrobial resistance increases drug costs, length of stay and adversely affects patient’s outcome (6).

3. Resistance to all classes of antibiotics has developed to various extents among the common and important nosocomial pathogens (Tables 1 and 2).

Part

I: A

ntibio

tic r

esis

tance –

local scenario

IMPA

CT T

hir

d E

dit

ion

(V

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Table

1.T

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en

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tes f

rom

cli

nic

al

specim

en

s i

n 2

004 (data

fro

m a

regio

nal

hospit

al

in H

on

g

Kon

g).

Blo

od

R

esp

irato

ry s

pec

imen

s U

rin

e

n=

1801

n=

366

n=

6303

n=

1669

n=

9201

n=

232

Org

an

ism

Non-

ICU

/HD

U

ran

k (

%)

ICU

ran

k

(%)

Org

an

ism

Non-

ICU

/HD

U

ran

k (

%)

ICU

ran

k

(%)

Org

an

ism

Non-

ICU

/HD

U

ran

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%)

ICU

ran

k

(%)

E.

coli

1

(2

4%

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(1

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(8

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E.

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1 (

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1 (

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3 (

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K. pneu

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5 (

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-K

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4 (

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4 (

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4 (

4%

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4 (

8%

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(3

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S.

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reu

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(7

%)

6 (

5%

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. p

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(4

%)

-P

rote

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spec

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5 (

5%

) 6

(3

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En

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6 (

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(Perc

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of is

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han

30)



Table 2. Intrinsic and associated resistance to antimicrobial agents among five nosocomial pathogens.

BACTERIAINTRINSIC

RESISTANCEASSOCIATEDRESISTANCE

MRSA All beta-lactams, beta-lactam/beta-lactamaseinhibitor combinations

Common: erythromycin, clindamycin,aminoglycosides,cotrimoxazole,fluoroquinolones

VRE All cephalosporins, cotrimoxazole,clindamycin,aminoglycosides

Common: ampicillin, imipenem, meropenem, vancomycin, high level aminoglycosideresistance

ESBL-producingEnterobacteriaceae(CTX-M, SHV-, TEM-derived)

All cephalosporins including fourth generationcephalosporin (7), all penicillins, aztreonam

Common:fluoroquinolones,gentamicin,cotrimoxazole

Derepressed AmpC-type mutant among E. cloacae, C. freundii, S.marcescens

First, second and third generationcephalosporins, most beta-lactam/beta-lactamase inhibitor combinations, cefoxitin

Common:fluoroquinolones,gentamicin,cotrimoxazole

A. baumannii Ampicillin, first and second generation cephalosporins

Third generation cephalosporins,fluoroquinolones,aminoglycosides, (imipenem, meropenem) (8)



Methicillin-resistant Staphylococcus aureus

On the basis of the patient history and epidemiological analysis, Methicillin-Resistant Staphylococcus aureus (MRSA) may be categorized into healthcare-associated or community-associated.

Healthcare-associated MRSA (HA-MRSA)

This type of MRSA is endemic in the local healthcare environment including hospitals, extended care facilities and old age homes since the mid-1980s (3;4;9). The HA-MRSA tends to be isolated in patients who are hospitalized for more than 48 hours. Since MRSA carriage may persist for many months after a previous acquisition, HA-MRSA also include those isolates that are found at admission (or within 48 hours) from patients who possess risk factors for their carriage including hospitalization in the previous 1 year, recent surgery, old age home residence, renal dialysis and exposure to invasive devices and employment in a healthcare institute (10;11).

In Hong Kong, 30-50% of all hospital S. aureus isolates are currently resistant to methicillin. The proportion of MRSA increased to 70-80% among isolates from intensive care units (ICU). In 1999, a study involving ICUs in 11 public hospitals showed 12% of the patients were MRSA carriers at ICU admission and that new acquisition of MRSA occurred in about 12% of the patients who were non-carriers initially (12).

Most HA-MRSA also encode a battery of other resistance genes, theyare thus multiresistant to drugs in other antibiotic classes including aminoglycosides, macrolides, fluoroquinolones and clindamycin (3;12).

Community-associated MRSA (CA-MRSA)

1. Patients infected with CA-MRSA do not have the usual risk factors associated with HA-MRSA. In overseas countries, CA-MRSA were found to be more common among certain populations: children with chronic skin condition, prisoners, military personnel, aboriginals, injection drug users, the homeless and contact sports athletes (13-16); but such associations have not been observed among the CA-MRSA cases in Hong Kong.



2. This organism often remains susceptible to antibiotic classes other than beta-lactams, including clindamycin, aminoglycosides, tetracyclines and fluoroquinolones.

3. The genotypes of CA-MRSA are different from the local nosocomial strains. Most CA-MRSA strains in Hong Kong represent members in clonal cluster 30, similar to the situation in the Southwest Pacific region (17).

4. CA-MRSA possesses novel types of methicillin-resistance cassette elements: type SCCmec IV or V, which are rare among the HA-MRSA strains.

5. CA-MRSA is more likely to encode the virulence factor, Panton-Valentine leukocidin (PVL) toxin, which is associated with skin/soft tissue infections and severe necrotizing pneumonia (18).

Vancomycin-resistant enterococci

VRE here refers to E. faecium and E. faecalis with resistance to glycopeptides (vancomycin MIC 8 g/mL or teicoplanin MIC 16g/mL). The incidence of VRE in Hong Kong is low at present. The first

isolate of VRE (E. faecium) in Hong Kong was imported in 1997. In the subsequent 3 years, a few sporadic cases were identified in five hospitals including a small cluster recently in TMH. By the end of March 2001, about 10 cases of VRE have been detected, including both vancomycin-resistant E. faecium (vanA and vanB) and E. faecalis (vanA) (19). In a multicentre surveillance of 1600 consecutive patients hospitalized in >10 ICUs in 1999, the prevalence was found to be <0.1%.

ESBL-producing Enterobacteriaceae

1. Extended-Spectrum Beta-Lactamases (ESBLs) are any bacterial enzymes that are capable of inactivation of third generation cephalosporins. The term is most commonly used to refer to a group of bacterial enzymes that are derived from the classical beta-lactamases TEM-1, TEM-2 and SHV-1. In recent years, the “CTX-M” type of ESBL is also emerging in several Asian countries including China and Hong Kong SAR (20-22).



2. ESBL may lead to therapeutic failures despite apparent susceptiblity to some third generation cephalosporins in conventional antibiotic sensitivity testing methods. The ESBLs confer variable levels of resistance to cefotaxime, ceftazidime, other broad-spectrum cephalosporins, and to monobactams such as aztreonam, but had no detectable activity against the carbapenems (such as imipenem, ertapenem and meropenem).

3. If antibiotic therapy is indicated (colonization do not need any treatment other than infection control), serious infections by ESBL-producers should be regarded as clinically resistant to all the cephalosporins (including cefepime).

4. The ESBLs are usually encoded on genes in plasmids and because of the ready transmissibility of the responsible plasmids, dissemination of the resistance genes to other micro-organisms occur readily. Since genes encoding resistance to multiple antibiotics are often present in the same plasmid, co-transfer of multiple resistance to non-beta-lactam drugs, such as aminoglycosides, cotrimoxazole, chloramphenicol, and tetracycline is common.

5. At present, the prevalence of ESBLs among Enterobacteriaceae isolated in many tertiary hospitals around the world is over 10-15%. In Hong Kong, a survey of four hospitals in 1997/98 (1200 non-duplicate clinical isolates) revealed rates of 6-23% for Klebsiella pneumoniae and 9 -14% for E. coli. (23).

6. Numerous outbreaks due to ESBL-producing bacteria have been reported. Known risk factors for colonization and/or infection with organisms harbouring these enzymes include admission to an intensive care unit, recent surgery, instrumentation, prolonged hospital stay and antibiotic exposure, especially exposure to third generation cephalosporins.

7. Incidence of ESBLs can decrease after changes in antibiotic policy (mainly reducing the use of third generation cephalosporins) and enforcement of barrier precautions (Table 5).

8. Most CTX-M, TEM- and SHV-derived ESBLs are susceptible to inhibition by the beta-lactamase inhibitors and theoretically beta-lactam/beta-lactamase inhibitor combinations should be active against these isolates. It must be remembered that production of ESBL doesn't preclude other mechanisms of resistance. In a recent survey, it was found that 40-70% of the ESBL-producing



Enterobacteriaceae were resistant to amoxicillin-clavulanate,ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam and cefoperazone-sulbactam (20).

Enterobacter spp.

1. De-repression of AmpC beta-lactamase occurs most frequently among Enterobacter spp. De-repressed mutants are resistant to all the first, second and third generation cephalosporins.

2. AmpC-mediated resistance usually cannot be reversed by the currently available beta-lactamase inhibitors. Hence, most de-repressed mutants are also resistant to ampicillin-sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam, ticarcillin-clavulanate, and cefoperazone-sulbactam.

3. It should be noted that resistance may develop in 20-40% of serious Enterobacter infections during treatment with a second or third generation cephalosporin (refer to Part V for treatment recommendations).

4. In Hong Kong, a recent study found AmpC de-repression in 23% of all Enterobacter spp. (21). It was also found that ESBL of the CTX-M type may be emerging in some Enterobacter spp., such as E. hormaechei. Therefore, laboratories should pay attention to speciation of Enterobacter and be alert to the possibility of ESBL production in this genus.

Multidrug-resistant Pseudomonas aeruginosa

1. Pseudomonas aeruginosa, a saprophyte widely distributed in nature and moist habitats (e.g. sinks, respiratory equipment, antiseptic or detergent solutions found in hospitals), is being increasingly recognized as a nosocomial pathogen, especially among critically ill or immunocompromised patients. Cross transmission or acquisition among patients likely occurs through hands of healthcare workers, or via contaminated fomites.

2. Under increasing antibiotic selection pressure, P. aeruginosa could acquire increasing drug resistance, leading to emergence of multi-drug-resistant phenotype (MRPA). By definition, MRPA isolates exhibit beta-lactam multiresistance (piperacillin, piperacillin-



tazobactam, ceftazidime, cefepime, carbapenems), along with resistance to aminoglycosides and quinolones (24-26); underlying mechanisms include enhanced production and dissemination of novel beta-lactamases, decreased outer membrane permeability, and presence of drug efflux pumps (27;28).

3. During the past 10 years, there have been numerous reported outbreaks of MRPA worldwide (29-33). According to the recent global SENTRY surveillance conducted in 1997-1999, the rates of MRPA (defined as being resistant to piperacillin, ceftazidime, imipenem, and gentamicin) occurrence were as follows: Latin America, 8.2%; Europe, 4.7%; United States, 1.2%; Asia Pacific, 1.6%; and Canada, 0.9% (34). More recent reports indicate that the overall prevalence of MRPA continues to be on the rise, especially in tertiary care institutions (35;36). The exact prevalence of MRPA in Hong Kong is currently not known.

4. In patients suffering from chronic chest conditions (e.g. cystic fibrosis), MRPA infection occurs after chronic airway colonization (37); other patients appear to acquire the infection after hospitalization. MRPA is predominantly isolated from respiratory samples (35;38). Risk factors for nosocomial MRPA acquisition and infection included: old age; severe underlying disease and / or being bedridden (39); having maxillary sinusitis; high lung injury score and / or need for prolonged mechanical ventilation (40;41); various forms of instrumentation (e.g. urinary catheters and nasogastric feeding tubes (39;39), long dwelling central venous catheters (41). Prolonged use of antipseudomonal antibiotics such as beta-lactams, carbapenems, and fluoroquinolones is also important risk factor (38-41).

5. Treatment of MRPA infections is extremely difficult (42;43), because MRPA can be resistant to all the currently available anti-pseudomonal antibiotics, and may necessitate the use of unlicensed and potentially toxic drugs such as colistin and polymyxin B, or experimental combinations (44-46). Unfortunately, the new antibiotics (such as glycylcyclines and ketolides) in the pipeline are not active against MRPA. In view of this, MRPA infected or colonized patients should be nursed in single rooms whenever feasible and that all attending staff should practise hand hygiene for every patient contact and other necessary standard and contact precautions.

Part II: Antimicrobial stewardship programme





Antimicrobial stewardship program: summary

The present summary is based on an article in the Hong Kong Medical Journal (47).

Antimicrobial drug resistance is now an important public health threat because it endangers our ability to effectively treat infections. A multi-faceted approach involving the continuous application of a package of interventions should be implemented at regional and international levels. In healthcare settings, the recommended measures include infection prevention, effective diagnosis and early treatment, using antimicrobials wisely and breaking the chain of transmission (Centers for Disease Control and Prevention, 2003). In the local settings, studies have found that there are rooms for optimization of antimicrobial prescriptions in the hospitals. Research conducted in the recent years further indicates that improvement in the pattern of prescriptions is feasible and can be implemented by means of antimicrobial stewardship programme (ASP) in a safe, scientific and professional manner. As antibiotic-resistant bacteria become more widespread, such initiatives will be assuming increasingly important roles. Therefore, the Scientific Committee on Infection Control in the Centre for Health Protection recently come up with a document on “Optimizing antimicrobial prescriptions in hospitals by antimicrobial stewardship programme in Hong Kong: consensus statement”. The present text summarizes the document under six broad questions:

1. What is the definition for optimal antimicrobial use?

Optimal antimicrobial use (prudent prescribing) has been defined as “the cost-effective use of antimicrobials which maximizes their clinical therapeutic effect, while minimizing both drug-related toxicity and the development of antimicrobial resistance” (48;49). This implies usage in the most appropriate way for the treatment or prevention of human infectious diseases, having regard to the diagnosis, evidence of clinical effectiveness, likely benefits, safety, cost, and propensity for the emergence of resistance. Therefore, optimal antibiotic use means both “less” use (i.e. less unnecessary use), and “appropriate” use (i.e. not only the right antibiotic but also the right dose, route and duration to effect a cure while minimizing side effects and development of resistance according to the up-to-date knowledge).



2. What is the rationale for optimizing antimicrobial use?

There are growing concerns about antimicrobial resistance. As antimicrobial resistance increases, many previously time-honored, first-line therapies are rapidly losing their efficacies and are becoming obsolete (49). Antimicrobial resistance adds substantially to our already rising healthcare costs, prolongs periods during which individuals are infectious, increases morbidity, increases length of hospital stay, and even mortality.

In developed countries, studies have found that 30-40% of hospitalized patients were treated with antimicrobial agents. When antimicrobial usage was studied, there are large variations in the pattern of usage (50;51) and half of the usage could be classified as suboptimal using recommended quality indicators (52;53). It is clear that suboptimal use not only adversely affects patient outcome (54;55), but also increases the risk of developing antimicrobial resistance (52;53;56;57).

Currently, the issue of antimicrobial resistance is complicated further by an insecure supply of new agents (58-60) and a dwindling number of companies investing in antimicrobial agents (61). Despite the dramatic rise of antimicrobial resistance in the past five years, only two new classes of antibiotics were approved since 2000: oxazolidinones (linezolid) and the cyclic lipopeptides (daptomycin). In 2004, there are few novel antibacterial agents in the pipeline. Thus, improving the use of existing antibiotics by all clinicians is imperative.

3. What is antimicrobial stewardship programme? Who are the advocacies? (Table 3)

The term antimicrobial stewardship is defined as the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance (62). In practice, this involves prescribing antimicrobial therapy only when it is beneficial to the patient, targeting therapy to the desired pathogens and using the appropriate drug, dose, and duration. Thus, ASP should not be viewed simply as reduced use or a strategy for cost containment. Instead, by minimizing exposure to drugs, performing dose adjustments, reducing redundant therapy and targeting therapy to



the likely pathogens, such activities can be viewed as a strategy to enhance patient safety.

ASP involves a multidisciplinary, programmatic, prospective, interventional approach to optimizing the use of antimicrobial agents. The multidisciplinary team typically includes clinical microbiologists, infectious diseases specialists, infection control practitioners, and clinical pharmacists. Having members from other medical specialties, such as surgery and paediatrics, is also recommended. Multiple approaches have been employed to enforce hospital policies to limit or control antimicrobial use (Table 3). Under the auspice of ASP, several behavioural methods have been used successfully to effect changes, including problem-based education, consensus guidelines, peer review, concurrent review, data feedback, computer-based reminders, financial incentives, and the use of opinion leaders (63;64).

Many professional societies and public health guardians including the World Health Organization, Infectious Diseases Society of America (IDSA), Alliance for the Prudent Use of Antibiotics (APUA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH) are supportive of programmes that promote optimal antimicrobial use (65;66). A few have even gone a step forward with action plans (48;65-67).

4. Is there evidence that ASP is beneficial? How did people document the benefits of the programme? Is there any evidence that it leads to better and more optimal antibiotic use in the hospital setting?

Most studies found this strategy effective in reducing the usage of targeted antibiotics and in controlling antimicrobial expenditures. In terms of its impact on antimicrobial resistance, programmatic interventions in hospitals have yielded mixed results (68;69). The reason for this is that the factors promoting resistance are complex and multiple. It is clear that strong relationship exists between certain antibiotic classes and multi-drug resistant pathogens such as vancomycin with VRE; third generation cephalosporins with ESBL; and fluoroquinolones with MRSA and MRPA. At an institutional level, programmes designed to limit utilization of agents that exert greater effect on the above were successful in reducing the specific resistance rates.



Measurement and monitoring is an essential part of the programme.After an initial implementation of a restricted formulary and antimicrobial approval system as part of an antimicrobial control programme, the team should meet regularly to review and update the formulary, assess its effectiveness, provide and coordinate ongoing physician education, and analyze antimicrobial utilization data within the hospital. The programme should be dynamic, and continually reassessed, adding new components or deleting unsuccessful components over time.

To allow for accurate intra- and inter-institutional comparison, confounding differences in expenditure related to acquisition costs and variations in the amount of individual antibiotic used for individual patients should be corrected by appropriate standardization using the defined daily dose (DDD) and rates calculated in terms of DDD per 1,000 admissions and DDD per 1,000 bed-days.

5. Is this the right time for Hong Kong to introduce ASP? Are we too early, or are we too late, and why?

In Hong Kong, few would dispute the threat from antimicrobial resistance and the needless expenditures associated with excessive antimicrobial use (70). Recent surveys show that suboptimal antimicrobial prescriptions may be commonplace in our hospitals (71), and that they could be improved. In the two university hospitals, one prospective study in 2003 found that 76% of antibiotic prescriptions for patients hospitalized for exacerbation of chronic obstructive pulmonary disease were unjustified according to the prevailing Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (71). In 2004, real-time audit of “big gun” antibiotics in two hospitals have revealed that 20-25% of the prescriptions were not justified or suboptimal. The most common problems include treatment of colonization, narrower and equally effective alternative or less toxic alternatives not being used and inappropriate duration (Seto WH, personal communication). In another prospective study of antibiotic combinations over a six-month period, it was found that one of the agents was redundant in 80% of 200 prescription episodes (71).

More actions are required in areas where the antimicrobial resistance problem is most serious. In Hong Kong, there is evidence that antibiotic resistance in some important nosocomial pathogens



is worse than in many other parts of the world (72). In the United States, a “Public health action plan to combat antimicrobial resistance-action plan” was developed in 1999. In the United Kingdom, significant progress has been made in optimizing the clinical use of antimicrobials since 2000 in terms of governmental directives, strategy and action plan (67;73). Recently, similar initiatives have been launched in Taiwan and South Korea at a national level. It is, therefore, definitely not premature to introduce such a “universal” and “continuous” programme to the public hospitals in Hong Kong.

Many studies have found that optimization of antibiotics in hospitals was feasible, safe and effective. A diversity of approaches have been reported and the experience accumulated so far indicates a multi-faceted “stewardship” and “immediate concurrent feedback” approach has clear advantages (62;74-81).

6. What are the disadvantages for having ASP? What problems have been reported? Are there any arguments against having ASP in the literature? Is there a role for an alternative mechanism? (Table 4)

ASP involves proactive monitoring and feedbacks. One alternative approach is “no control” (i.e. only by passive means). Such an approach relies heavily on the distribution of national guidelines. As discussed in detail in an international workshop, such a strategy has not worked in the past (82). Guidelines are seldom studied thoroughly by clinicians, and even if they are read, they rarely are incorporated into everyday practice. On the other hand, there are barriers and concerns to ASP that need to be addressed (Table 4). The perception of “threatened physician autonomy” can be a significant impediment to the effort. Previous studies and local experiences have indicated that this is often an “emotional” response that can be resolved by immediate concurrent feedback, consensus building, involvement of institutional opinion leaders, and attention to process measures (83-85). In fact, similar programmes have been launched successfully in some Hospital Authority hospitals for the other drugs, including the statins, calcium channel blockers and acid suppressive agents.

Another impediment is the incorrect perception that antimicrobial stewardship programmes are solely cost-driven and that patient safety may be at risk. In this regard, recent



reports have emphasized the inclusion of quality indicators such as time to reception of appropriate empirical antibiotics. Other suggested indicators include: (a) clinical outcomes of bacteraemia due to Gram-negative organisms (86), (b) mortality for all patients, for those treated with antimicrobials, and for those suffering from infections, (c) duration of hospital stay for all patients and for those treated with antimicrobial drugs, and (d) re-hospitalization rate within 30 days after discharge for all patients and those treated with antimicrobial drugs (81). As in any quality improvement programme, a financial incentive is important to secure support by the hospital management. This is no exception for antimicrobial stewardship programme. Good leadership and effective communications are essential to keep members, prescribers and patients to the appropriate focus. This could be enhanced by having a multidisciplinary steering committee, and by regular use of data feedback on the patterns of usages, patient outcomes, and antimicrobial resistance data. In principle, member in the committee should have a strong sense of commitment and cooperation. The composition of the multidisciplinary steering committee may be unique to each institute.

Conclusion

Considering the broader perspective, working targets are needed and the programmes should be regularly evaluated. For a start, each hospital will need to form a steering group and to lay down the institutional priorities. In the literature, programme models are available for optimizing the uses of aminoglycosides, vancomycin, broad-spectrum antibiotics, antibiotic combinations, and for switching therapy from intravenous to oral. It is clear that a multi-faceted approach incorporating immediate concurrent feedback is most likely to be successful. In order to safeguard health care quality, the use of quality indicators and timely feedback of data are essential. Our fight against antimicrobial resistance is going to continue. Hence, a major challenge will be how to keep the programmes viable and sustainable within our system in the longer terms.



Table 3. Methods to implement antimicrobial control 1. Written hospital guidelines.

2. Educational efforts aimed at changing prescribing practices of

physicians.

3. Providing consultation from clinical microbiologist/infectious

diseases specialist.

4. Restriction of hospital formulary through the Drug and

Therapeutics Committee.

5. Utilization review with guidelines for rational and appropriate

usage.

6. Ongoing monitoring and analysis of antimicrobial agents

usage.

7. Ongoing surveillance of antimicrobial susceptibility.

8. Monitoring adherence to advice on choice of antimicrobial

agents.

9. Usage feedback to physicians.



Table 4. Potential barriers to reaching the strategic goals Barrier Countermeasures and improvement

strategies

Ownership and accountability

1. Lack of ownership and

accountability for recognizing and

reporting trends.

2. Failure to integrate work of

laboratory, infection control,

medical, nursing, and intensive

care-unit staffs.

1. Designate responsibility and

accountability for the process.

2. Set up a multi-disciplinary team to

develop a collaborative system and

monitor results.

Staff knowledge and practice

1. Lack of time for the laboratory

and/or infection control staff to

generate and analyze data.

2. Lack of time for healthcare

providers to examine and discuss

data and inconsistent or

erroneous interpretation of data

by staff.

1. Ensure adequacy of laboratory and

infection-control staffing and prioritize

activities of staff so that data can be

generated and analyzed.

2. Report data in an easy-to read/interpret

format and, when appropriate, include

data interpretation in the report.

Physician attitudes

1. Lack of trust in the hospital

administration

1. Use a data-driven approach to cultivate

trust; e.g. communicate regularly with

physicians about trends in antimicrobial

usage, cost, and resistance; feedback to

individual physicians their performance

results.

Expertise

1. Lack of expertise in biostatistics

(e.g. presenting trends and

analyzing data).

1. Ensure availability of consultants,

especially when designing analytic

strategy and interpreting trend data.

Reference (82)



State-of-the art: Limiting antimicrobial resistance

1. US surveys: 22-65% usage of antibiotics in the hospitals is inappropriate.

2. Outbreaks of multi-resistant bacteria, including those that persist despite apparently adequate infection control measures, can be limited effectively by antibiotic programme directed at judicious use of antibiotics.

3. While restriction of an individual antibiotic (such as cefotaxime or ceftazidime) has been reported to be useful in controlling outbreaks of drug-resistant bacteria, the general consensus is that the main focus should be directed at the rational use of all classes of antibiotics rather than merely restricting the use of individual drugs (6;86-96).

Over-prescription of third generation cephalosporins and vancomycin

Experience from several overseas centres suggests that over-prescription of third generation cephalosporins and glycopeptides are closely associated with the selection and dissemination of ESBL-producing Enterobacteriaceae, de-repressed AmpC-type mutant among Enterobacter cloacae, Citrobacter freundii, Serretia marcescens, MRSA, and VRE.

1. Cephalosporin use has been identified as a risk factor for enterococcal colonization and superinfection, as well as for antibiotic-associated diarrhea, the main reason for oral vancomycin (97;98).

2. Significant risk factors for colonization or infection with VRE were prior antibiotic use (p=0.04), the previous use of third-generation cephalosporins (p=0.03), and the previous use of parenteral vancomycin (p=0.002). This data was obtained from 7 hospitals including primary and tertiary care facilities (200-700 beds) (99).

3. In the Cornell University Medical College, New York, it was found that the duration of hospitalization, intrahospital transfer between floors, use of antimicrobials (i.e. vancomycin and third generation cephalosporins), and duration of vancomycin use ( 7



days) were independently associated with VRE infection or colonization (100).

4. Ten weeks after the introduction of cefotaxime, resistant Enterobacter cloacae could be isolated from stool cultures in an increasing proportion of patients and septicaemia developed in 6 cases (101).

5. In 6 US hospitals, previous administration of third-generation cephalosporins was more likely to be associated with multi-resistant Enterobacter isolates in an initial positive blood culture (69%) than was administration of antibiotics (20%) that did not include a third-generation cephalosporins (p<0.001) (102).

6. Resistance to third generation cephalosporins among Enterobacter spp, Citrobacter freundii, Morganella morganii,Serratia marcescens and Providencia spp. has become widespread both locally within hospitals and nationally. This trend has been shown to correlate closely with the extent of usage of some third generation cephalosporins (1;103).

Decreased antibiotic resistance after changes in antibiotic use

No simple answer exists on the control of multi-drug resistant bacteria. The traditional approach slanted heavily on infection control measures, which are obviously important but can be difficult to implement. When audited, compliance with hand hygiene measures has been consistently low (<40%) (104). Outbreaks of multi-drug resistant bacteria have continued despite apparent adherence to “standard” hygienic measures. In recent years, there has been renewed interest on the strategic use of antibiotics as a measure for prevention or control of antimicrobial resistance (94). In fact, several studies have demonstrated that strategic use of antibiotics (so far, only class restriction of the cephalosporins have been evaluated to a significant extent) can lead to:

1. Less multi-resistant de-repressed AmpC-type Enterobacter spp. An outbreak of infections by multi-resistant Enterobacter spp. disappeared after use of cefotaxime was discontinued in the unit.

2. Less ESBL-producing Enterobacteriaceae. Literature on antimicrobial strategies as an intervention to reduce ESBL-producing K. pneumoniae was summarized in Table 5. In a case-



control study, the use of beta-lactam/beta-lactamase inhibitor combination was shown to be a protective factor (105).

3. Less vancomycin-resistant enterococci. Two studies reported on the successful control of VRE outbreaks by changing antibiotic usage (92;106). In one medical centre (92) , the antibiotic formulary was altered by restricting the use of cefotaxime and vancomycin and adding beta-lactamase inhibitors to replace third-generation cephalosporins. After 6 months, the average monthly use of cefotaxime, ceftazidime, vancomycin, and clindamycin had decreased by 84%, 55%, 34% and 80% respectively (p<0.02). The point prevalence of faecal colonization with VRE decreased from 47-15% (p<0.001). In another haematologic unit (106), acquisition of VRE paralleled the use of ceftazidime as empirical therapy for neutropenic fever. Phase 1: ceftazidime as empirical therapy, VRE carriage rate was 57%. Phase 2: piperacillin-tazobactam replaced ceftazidime as empirical therapy, VRE carriage decreased to 8%. Phase 3: ceftazidime re-introduced as empirical therapy, VRE carriage increased to 36%. Those who are interested in the experimental data that might explained this observed relation between VRE, cephalosporins and BLBLI should refer to a recent review by Rice et al (107).

Part

II: A

ntim

icro

bia

l ste

ward

ship

pro

gra

mm

e

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 33

Table

5.

Sum

mary

of

publi

sh

ed data

on

an

tim

icro

bia

l str

ate

gie

s as an

in

terv

en

tion

to

re

duce

ESB

L r

esis

tan

ce.

Year

peri

od (R

ef)

Sett

ing (ty

pe o

f stu

dy)

Inte

rven

tion

/re

su

lt

Ou

tcom

e

Oth

er

observ

ati

on

s

1994

99 (108)

Epid

em

ic r

ise in

ES

BL in

K.

pn

eu

mon

iae fro

m 6

-28%

wit

hin

1

year

in a

medic

al cen

tre

(in

terv

en

tion

stu

dy)

Min

imiz

e u

se o

f ceft

azi

dim

e

(mark

ed a

nd s

usta

ined

);addit

ion

of pip

era

cillin

-ta

zobacta

m t

o form

ula

ry (u

sage

)

ES

BL r

ate

rem

ain

<10%

next

4 y

ears

1993

98 (109)

Spre

ad o

f V

RE

in

on

e in

sti

tute

con

tin

ued d

espit

e in

fecti

on

con

trol

measu

res (in

terv

en

tion

stu

dy).

Use o

f B

LB

LI

em

ph

asiz

ed a

nd t

he

use o

f 3G

Cs, van

com

ycin

an

d

clin

dam

ycin

restr

icte

d; addit

ion

of

am

pic

illin

-su

lbacta

m a

nd

pip

era

cillin

-tazo

bacta

m t

o

form

ula

ry.

Mean

in

cid

en

ce o

f C

RK

P b

y 3

4%

C

efo

taxim

e-r

esis

tan

t A

cin

eto

ba

cte

r b

y

>100%

1989

90 (110)

Ou

tbre

ak o

f C

RK

P in

on

e m

edic

al

cen

tre. U

se o

f ceft

azi

dim

e

600%

in

th

e 2

years

befo

re o

utb

reak

(in

terv

en

tion

stu

dy).

Ceft

azi

dim

e w

as r

epla

ced b

y

imip

en

em

. C

RK

P fro

m >

30%

to

<10%

1993

95 (111)

A c

lon

al ou

tbre

ak o

f E

SB

L-

pro

du

cin

g K

. pn

eu

mon

iae in

an

IC

U

(in

terv

en

tion

stu

dy).

Restr

icti

on

of 3G

C (u

sage

by

87%

aft

er

inte

rven

tion

).

ES

BL c

arr

iage

fro

m

33 t

o 4

0%

to 0

%.

1995

96 (112)

An

ou

tbre

ak o

f E

SB

L-p

rodu

cin

g K

. p

neu

mon

iae in

a h

ospit

al sin

ce

1990 (in

terv

en

tion

stu

dy).

Cla

ss r

estr

icti

on

of ceph

alo

spori

ns

(usage

by 8

0%

aft

er

inte

rven

tion

). U

sage r

epla

ced b

y

imip

en

em

.

CR

KP E

SB

L

by

44%

.

Imip

en

em

-resis

tan

t P

. a

eru

gin

osa

b

y

69%

1996 (113)

Clo

nal ou

tbre

ak o

f C

RK

P in

hospit

al

A. Poly

clo

nal ou

tbre

ak o

f C

RK

P in

h

ospit

al B

(in

terv

en

tion

stu

dy).

Ph

ysic

ian

edu

cati

on

on

associa

tion

of

ceft

azi

dim

e u

se

an

d C

RK

P. U

se o

f ceft

azi

dim

e

by 7

1%

(h

ospit

al A

) an

d 2

7%

(h

ospit

al B

).

Hospit

al A

: C

RK

P

from

22 t

o 1

5%

. H

ospit

al B

: C

RK

P

from

10 t

o 5

%.

% K

P r

esis

tan

t to

B

LB

LI

als

o

(36 t

o

19%

in

A a

nd 2

2 t

o

14%

in

B)

3G

C, th

ird g

en

era

tion

ceph

alo

spori

ns; B

LB

LI,

beta

-lacta

m/beta

-lacta

mase in

hib

itor;

CR

KP, ceft

azi

dim

e-r

esis

tan

t K

. pn

eu

mon

iae.



Classification of therapy

Empirical therapy

In the clinical situation of “empirical use”, the antimicrobial(s) is/are used as initial therapy directed to eradicate the most likely pathogens. Before initiation of antimicrobials, appropriate specimens for stains and culture of microorganisms should be obtained. Results of identification and susceptibility of microorganisms are likely to be available in the following 48 to 72 hours. The use of broad-spectrum antibiotics or combination therapy is usually necessary to cover the different organisms capable of causing an infection. In general, the use of agents in this situation should not extend beyond the time required to obtain results of cultures and susceptibility.

Choice of agent(s): based upon adequate coverage of the potential pathogens of the potential infection sites and the anticipated antimicrobial susceptibility patterns of the bacterial isolates. Recommendations of empirical therapy for some common infections are outlined in Part IV.

Known-pathogen therapy

In the clinical situation of known pathogen use, the antimicrobial(s) is /are used when the microbiology laboratory has identified the micro-organism causing the infection and the susceptibility pattern is known. If during empirical use, the patient is started on combination therapy or broad spectrum antibiotics, the antimicrobial spectrum should be narrowed to cover the micro-organisms identified as the aetiologic agent. Streamlining from broad-spectrum to specific, narrow spectrum antimicrobials helps to avoid colonization with resistant organisms and superinfections. In the absence of allergy or other contraindications, the agent (appropriate for the site and type of infection) with the narrowest spectrum in a group or a list of candidate drugs should be used.

It should be noted that the skin and mucous membrane surface of the hospitalized patient are often colonised with nosocomial bacteria (such as MRSA, E. coli, Klebsiella spp, etc.), systemic antimicrobial therapy (both IV and PO) should not be administered in an attempt to eradicate these micro-organisms.



Switch therapy-conversion from IV to PO

In the clinical situation of switch therapy use, PO antimicrobials replace IV usage for completion of therapy. IV is almost always employed in serious infections to ensure maximal serum/tissue levels. With few exceptions such as meningitis, infective endocarditis, the majority of patients with infections do not require completion of the antimicrobial course with IV therapy. The following criteria have been developed for transition from IV to PO antimicrobial (114;115):

1. Patient with no clinical indication for IV therapy.

2. Patient is afebrile for at least 8 hours.

3. The WBC count is normalizing (falling towards or <10x109/L).

4. Signs & symptoms related to infection are improving.

5. Patient is not neutropenic (neutrophil count >2 x109/L).

6. Patient is able to take drugs by mouth (non-NPO).

7. Patient with no continuous nasogastric suctioning.

8. Patient with no severe nausea or vomiting, diarrhea, gastrointestinal obstruction, motility disorder.

9. Patient with no malabsorption syndrome.

10. Patient with no pancreatitis or active gastrointestinal bleeding or other conditions that contraindicated to the use of oral medications.



Table 6. Strategies for optimization of antimicrobial therapy

Stages in the management of infection Strategies for optimization

Empirical therapy (ET) Document the presence of infection Likely pathogens? Likely susceptibility pattern Community- or hospital-acquired infection?Monotherapy or combination therapy?

EducationCollection and analysis of local dataPocket reference guide

When culture and susceptibility results are available

Known-pathogen therapy (KPT) Narrowest spectrum according to laboratory results Follow guidelines on the judicious use of ceftazidime, imipenem/ertapenem/ meropenem, vancomycin/teicoplanin/ linezolid

Cascade reporting of sensitivity Daily review of prescription of “big gun” antibiotics by ASP team.Daily reporting of deviations from guidelines to clinical microbiologist/ID physician ASP team to give daily immediate concurrent feedback (ICF) to prescribers.

Switch therapy (116;117) A switch from intravenous to oral therapy Criteria for switch therapy Clinical diagnosis compatible with oral therapyPatient has functioning gastrointestinal tractPatient is afebrile (for >24h) Signs and symptoms related to infection are improving or resolved The WBC count is normalizing

Daily review of patients on IV “big gun” antibiotics by ASP teamDaily recommendation for “switching” by ASP team

Stop therapy Type of infection Clinical responses Follow-up culture results where appropriate

Education

Part III: Selected Antimicrobial agents


Part III: Guidelines for selected antimicrobials use



Vancomycin

Situations in which the use of vancomycin/teicoplanin is appropriate (6;83)

1. Treatment of serious infections caused by beta-lactam resistant Gram-positive bacteria (e.g. MRSA, coagulase-negative staphylococci).

2. Treatment of infections caused by Gram-positive bacteria in patients who have serious allergies to beta-lactam antimicrobial agents (e.g. anaphylactic reaction, Stevens-Johnson syndrome).

3. When Clostridium difficile colitis fails to respond to metronidazole therapy or is severe and life-threatening.

4. As prophylaxis for endocarditis following certain procedures in-patients at high risk for endocarditis; according to recommendation from the American Heart Association. (e.g. as prophylaxis for genitourinary or gastrointestinal procedures in moderate or high-risk patients allergic to ampicillin/amoxicillin).

5. As prophylaxis for major surgical procedures involving the implantation of prosthetic material or devices in known carriers of MRSA. For elective procedures, daily washing of skin and hair with a suitable antiseptic soap (e.g. 4% chlorhexidine liquid soap) and topical treatment of the anterior nares with nasal mupirocin ointment (for 5 days) are recommended before the procedures. Vancomycin may be less effective in preventing surgical wound infection due to methicillin-sensitive staphylococci (118).

Situations in which the use of vancomycin/teicoplanin are not advised

1. Treatment of MRSA nasal carriage or colonization at other sites such as the isolation of MRSA from

Surface swab of superficial wounds

Surface swab of chronic ulcers

Surface swab of pressure ulcers

2. Routine surgical prophylaxis other than in a patient who has serious allergy to beta-lactam antimicrobial agents.

3. Routine empirical antimicrobial therapy for neutropenic fever (except as recommended by the IDSA 2002 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever).



4. Treatment in response to a single blood culture positive for coagulase-negative staphylococci, if other blood cultures taken during the same time frame are negative.

5. Continued empirical use of presumed infections in patients whose cultures (blood, joint fluid, peritoneal fluid, pus, etc), are negative for beta-lactam-resistant Gram-positive bacteria (e.g. MRSA).

6. Systemic or local (e.g. antibiotic lock) prophylaxis against infection (or colonization) of indwelling (central or peripheral) intravascular catheters.

7. As routine prophylaxis, before insertion of Hickman/Brovac catheter or Tenckhoff catheter.

8. As part of the regimen for selective digestive tract decontamination.

9. Primary treatment of Clostridium difficile colitis, except when it is severe and life-threatening.

10. Routine prophylaxis for patients on continuous ambulatory peritoneal dialysis or haemodialysis.

11. Treatment (e.g. chosen for dosing convenience) of infection caused by beta-lactam-sensitive Gram-positive bacteria in patients who have renal failure.

12. Use of vancomycin solution for topical application (e.g. to burn wound, ulcers) or irrigation (e.g. of T-tube, drains).

Vancomycin dosage in special situations and therapeutic drug monitoring

1. In adults, the standard recommended dose of vancomycin is 30 mg/kg/day (IV 1 g q12h or IV 0.5 g q6h in a normal 70 kg person).

2. Therapeutic drug monitoring (TDM)

Vancomycin exhibits time-dependent killing. Efficacy can usually be assumed if the trough concentration is sufficiently above the MIC of the infecting organism (i.e. best if vancomycin levels at site of infection are maintained above MIC throughout the dose interval). MIC of most susceptible organisms (e.g. MRSA) ranges 1-2 g/mL.

Routine TDM is not indicated in most patients because vancomycin pharmacokinetics are sufficiently predictable that safe and effective vancomycin dosage regimens (giving trough



levels 5-10 g/mL and peak levels <40 mg/mL) can be constructed on the basis of patient's age, weight and estimated renal function.

Indications for TDM

(a) Renal impairment (rapid change/unstable renal function making it difficult to estimate dose)

(b) ICU patients co-treated with dopamine and/or dobutamine (119)

(c) Severe burn (120)

(d) Morbid obesity (121)

(e) Spinal cord injury (122)

When TDM is indicated, check only trough level. There is no solid data to support the widely referenced trough range of 5-10 g/mL and accordingly, serum concentrations have been selected somewhat arbitrarily, based on pharmacology, retrospective studies, case reports and personal opinions. Due to the poor penetration of vancomycin to certain lung tissues, the 2005 ATS guideline recommend trough levels of 15 20 g/mL for treatment of MRSA hospital-acquired pneumonia (123). Current literature does not support peak concentration measurement (124).

3. Dosage table/nomogram in patients with impaired renal function (Table 7)

An initial single dose of 15 mg/kg should be given to achieve prompt therapeutic serum concentration. Subsequent daily maintenance dose is to be determined according to dosage table/nomogram.

The dosage table/nomogram is not valid for functionally anephric patients on dialysis. For such patients, the dose required to maintain stable concentrations is 1.9 mg/kg/day (~130 mg/day for a 70 kg person).

For patients with marked renal impairment, it may be more convenient to give maintenance doses of 0.25 g to 1 g every 3-7 days.



Table 7. Dosage table for vancomycin

Creatinine clearance ( mL/min) Vancomycin dose (mg/24 h)

100 1,545

90 1,390

80 1,235

70 1,080

60 925

50 770

40 620

30 465

20 310

10 155

Adapted from vancomycin package insert July 2004 .

4. Vancomycin in morbidly obese patients (121;125) (Table 8)

Serum clearance of vancomycin in morbidly obese patients was 2.3-2.5 times higher than that observed in non-obese subjects (121;126).

In a study of 24 morbidly obese patients, the mean (±SD) vancomycin dose required to achieve steady state peak 25-35 g/mL and trough 5-10 g/mL were 1.9 g (±0.5 g) q8h.



Table 8. Calculation of vancomycin dosage for morbidly obese patient

Steps Calculation

Scenario: Female/30yr, body weight 200 kg, height 1.8 m, serum creatinine 80 mol/L

Determine if the patient is morbidly obese

TBW/IBW ratio:

0.8 1.25 = normal

>1.25 1.9 = obese

>1.9 = morbid obesity

200/70.7 = 2.8

Determine dose of vancomycin

30 mg/kg TBW/day 6 g per day if normal renal function. (administer as IV 2 g q8h; infuse each 2 g dose over at least 2 h)

Estimate creatinine clearance (CrCl)

Cockcroft-Gault formula not accurate in morbidly obese patients. The Salazar-Corcoranequation appears to give the least biased estimate of CrCl

Monitor trough level Target trough at 5-10 g/mL

Adjust dosing interval according to trough level

Equations:

1. Ideal body weight (IBW)

IBW for male = 50 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet)

IBW for female = 45.5kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet)

2. Salazar-Corcoran equation (for estimate of creatinine clearance in morbidly obese patients):

Male patient, calculate CrCl as follows:

(137 age in years) (TBW in kg 0.285) + (12.1 height in meter)

0.58 serum creatinine in mol/L

Female patient, calculate CrCl as follows:

(146 age in years) (TBW in kg 0.287) + (9.74 height in meter)

0.68 serum creatinine in mol/L

a TBW, total body weight



Quinupristin/dalfopristin and linezolid

1. Indications for linezolid (Zyvox) or quinupristin/dalfopristin (Synercid):

a. Infections by vancomycin-resistant enterococci (VRE) or S.aureus with reduced susceptibility to vancomycin (e.g. VISA)

b. Infections by methicillin-resistant Staphylococcus aureus in the case of vancomycin failure (e.g. unexplained breakthrough bacteraemia) and/or serious allergy. In these complicated circumstances, the opinion of a specialist (microbiologist or ID physician) should be sought.

2. Most VRE (n=11) identified in Hong Kong so far are susceptible to linezolid (both E. faecalis and E. faecium) at 4 g/mL and quinupristin/dalfopristin (E. faecium only, at 1 g/mL) (19).



Table 9. Comparison of linezolid and quinupristin/dalfopristin Linezolid Quinupristin/dalfopristin

FDAapproval/year

Yes/2000 Yes/1999 (for serious infections associated with vancomycin-resistant E. faecium)

Registration in Hong Kong

Yes No

Formulary IV/PO. Bioavailbility of PO linezolid is ~100%.

Only IV

Usual dose IV/PO 600 mg q12h IV 7.5 mg/kg q8h (infuse over 1 h in D5)

Central venous catheter for administration

No Yes

Activity vs. VRE both vancomycin-resistant E. faecalis and E. faecium

Only vancomycin resistant E.

faecium a

Effect on cytochrome P450

Nil (No effect on 1A2, 2C9, 2C19, 2D6, 2E1, 3A4)

Inhibit 3A4 isoenzyme strongly, hence interactions with midazolam, nifedipine, astemizole, terfenadine, cyclosporin (must monitor level), tacrolimus

Monoamineoxidase (MAO) inhibition

Yes (a weak, reversible, nonselective MAO inhibitor), hence potential for interactions with adrenergic and serotonergic drugs.

Nil (No effect on MAO).

Side effects Thrombocytopenia (related to duration of treatment; incidence 0.3-10%; need monitoring if treated for >7d)

Phlebitis (high incidence if administered via peripheral vein); arthralgia/myalgia (dose related; incidence 1.3-33%)

Generalcompatibility

Compatible with both D5 and saline.

Form precipitate with saline. DO NOT flush with saline or heparin after quinupristin/ dalfopristin administration.

Renalimpairment

No adjustment in dose required in pt. with renal impairment. Give dose after HD.

No adjustment in dose required in pt. with renal impairment or undergoing dialysis.

Data from package insert of Zyvox and Synercid.

a All E. faecalis isolate (including vancomycin-resistant E. faecalis) are intrinsically resistant to quinupristin/dalfopristin.



Ceftazidime

Indications for using ceftazidime (Fortum) (127)

1. Empirical therapy of neutropenic fever, either as monotherapy or in combination with an aminoglycoside (128).

2. Therapy of infection by Burkholderia pseudomallei infection (melioidosis).

Probable case (compatible chest X-ray plus a melioidosis titre of 1/640) or definite case (isolation of B. pseudomallei).

3. Known pathogen therapy of documented infection by susceptible Pseudomonas aeruginosaa, such as:

(a) Bacteraemia with isolation of Pseudomonas aeruginosa fromblood culture.

(b) Deep-seated infection with isolation of Pseudomonas aeruginosa from normally sterile body site or fluid (CSF,

peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc) a.

(c) Nosocomial pneumonia, as defined by CDC guidelines (appendix), with isolation of Pseudomonas aeruginosa in a significant quantity, from a suitably obtained, good quality

respiratory tract specimenb.

Footnotes

a For serious P. aeruginosa infection, an anti-pseudomonal beta-lactam should be given in combination with an aminoglycoside such as gentamicin given once daily for the initial 3 to 5 days to achieve synergistic killing. For susceptible isolates; anti-pseudomonal beta-lactams in decreasing order of preference: piperacillin or piperacillin-tazobactam or ticarcillin-clavulanate > cefoperazone or cefoperazone-sulbactam or cefepime or ceftazidime > imipenem or meropenem.

b Colonization of the respiratory tract by P. aeruginosa, especially in mechanically ventilated patients is common. Antimicrobial therapy of colonization is not indicated. Isolation of P. aeruginosa at the indicated quantity and specimen type is suggestive of infection rather than colonization (in descending order of clinical significance):

1. 102-103CFU/mL or moderate/heavy growth for protected specimen brush.

2. 103-104 CFU/mL or moderate/heavy growth for bronchoalveolar lavage.

3. Moderate/heavy growth for tracheal/endotracheal aspirate specimens with ++ to +++ white cells and absent/scanty epithelial cells.

4. Expectorated sputum (as defined by the American Society for Microbiology) with >25 WBC/low power field and <10 epithelial cells/low power field.



Situations/conditions in which ceftazidime is not advised

1. Treatment of colonization by Pseudomonas aeruginosa such as the isolation of these organisms from




2. Empirical or continued treatment of suspected or confirmed infection by S. pneumoniae including bacteraemia, pneumonia and meningitis.

Infection outside the central nervous system by both penicillin-susceptible and penicillin-non-susceptible (MIC <4 g/mL), the drugs of choice are penicillin G (standard or high dose) or amoxicillin or cefotaxime or ceftriaxone (refer to known-pathogen therapy chart).

3. Empirical or continued treatment of infection by Enterobacteriaceae such as E. coli and Klebsiella spp. susceptible to other antimicrobial agents.

For susceptible isolates the beta-lactam of choice in descending order of preference are as follows: ampicillin or amoxicillin > ampicillin-sulbactam or amoxicillin-clavulanate > cefuroxime > ceftriaxone or cefotaxime.

4. Empirical therapy of community-acquired pneumonia, including patients hospitalized in the ICU for serious pneumonia and patients with structural disease of the lung (adapted from Infectious Disease Society of America 1998).

Other agents with activity vs. P. aeruginosa and S. pneumoniae preferred because ceftazidime (while active vs. P. aeruginosa) is not useful vs. penicillin-non-susceptible S. pneumoniae.

5. Empirical or continued treatment of anaerobic or mixed infection in the head and neck, biliary, pancreatic, gastrointestinal, peritoneal, pelvic or peritoneal regions.

Ceftazidime has virtually no activity against most of the medically important anaerobes.

6. Empirical or continued treatment of patients with colonization or infection by Enterobacteriaceae such as E. coli, Klebsiella spp. and Enterobacter spp. known to produce ESBL.

Applies irrespective of whether ceftazidime was tested or not and also irrespective of the apparent in vitro susceptibility of the isolate to ceftazidime.



7. Empirical or continued treatment of infection by S. aureus (both MSSA and MRSA).

8. Empirical or continued treatment of infection by all enterococci such as E. faecalis and E. faecium.

9. Empirical treatment for community-acquired meningitis.



Imipienem/meropenem/ertapenem

Indications for using imipenem/meropenem/ertapenem

1. Therapy of infections attributed to ESBL-producing bacteria (such as E. coli or Klebsiella spp. ) such as:

Bacteraemia with isolation of ESBL-producing bacteria from blood culture.

Deep-seated infection with isolation of ESBL-producing bacteria from normally sterile body site or fluid (CSF, peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc).

Nosocomial pneumonia, as defined by CDC guidelines, with isolation of ESBL-producing bacteria in a significant quantity, from a suitably obtained, good quality respiratory tract specimensa

2. Empirical therapy of neutropenic fever in high risk patients. (As Ertapenem has no anti-pseudomonal activity, it should not be used as empirical therapy for neutropenic fevers or for treatment of presumed/confirmed infections by the non-fermenters such as Pseudomonas aeruginosa and Acinetobacter.)

Footnotes

a Colonization of the respiratory tract by ESBL-producing bacteria, especially in mechanically ventilated patients is common. Antimicrobial therapy of colonization is not indicated. Isolation of ESBL-producing bacteria at the indicated quantity and specimen type is suggestive of infection rather than colonization (in descending order of clinical significance):

1. 102-103 CFU/mL or moderate/heavy growth for protected specimen brush.

2. 103-104 CFU/mL or moderate/heavy growth for bronchoalveolar lavage.

3. Moderate/heavy growth for tracheal/endotracheal aspirate specimens with ++ to +++ white cells and absent/scanty epithelial cells.

4. Expectorated sputum (as defined by the American Society for Microbiology)

with >25 WBC/low power field and <10 epithelial cells/low power field.



Situations/conditions in which imipenem/meropenem/ertapenem is not advised

1. Treatment of colonization by ESBL-producing bacteria such as the isolation of these organisms from.




2. Empirical therapy of most community-acquired infections including pneumonia, appendicitis, cholecystitis, cholangitis, primary peritonitis, peritonitis secondary to perforation of stomach, duodenum or colon, skin/soft tissue infections, etc.

3. As known-pathogen therapy for infections caused by organisms susceptible to other beta-lactams.



Once daily aminoglycosides

1. Once daily aminoglycoside (ODA) dosing is as effective as multiple-daily dosing in most clinical settings. The former dosing probably results in a lower risk of nephrotoxicity than the latter. With ODA, any differences in the relative nephrotoxicity of the aminoglycosides are likely to be small. Nonetheless, there is considerable confusion on the dose and how to monitor serum aminoglycoside levels when using ODA dosing.

2. Dosing to be based on actual body weight unless the patient is morbidly obese (i.e. 20% over ideal body weight, IBW).

Aminoglycoside dosing weight for morbidly obsess patient

= ideal body weight + 0.4 (actual body weight - IBW).

Formula for calculation of ideal body weight is as follows:

Ideal body weight for male = 50 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet)

Ideal body weight for female = 45.5 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet)

3. For patient with impaired renal function, give the first dose according to body weight as above. Subsequent frequency of administration (of the same dose) to be based on the estimated creatinine clearance of the patient according to the following table.

Cockcroft-Gault formula

To estimate creatinine clearance, calculate as follows

Creatine clearance for male patient (mL/min) = (140-age) x 1.2 x ideal body weight (kg) /serum creatinine ( mol/L)

(Female: 0.85 above value)

(Unit conversion for serum creatinine: mg/dL x 88.4 = mol/L)



CrCl (mL/min)

Initial dosing interval a

60 q24h

40-60 q36h

20-40 q48h

<20 Follow serial levels to determine time of

next dose (level <1 g/mL)

a At present, the dosage of aminoglycoside to use in a ODA strategy has not been clearly determined. Dosages for gentamicin, tobramycin and netilmicin have ranged from 3 to 7 mg/kg, and amikacin dosages have ranged from 11 to 30 mg/kg. On the basis of local experiences and a recent consensus meeting, the following doses are recommended for initial therapy in local Chinese: for gentamicin and tobramycin, 3.5 mg/kg; netilmicin, 4.4 mg/kg and amikacin, 15 mg/kg (129).

4. Therapeutic drug monitoring (TDM) (130-132)

Routine TDM not indicated in patients under the following conditions:

(a) Receiving 24-h dosing regimen,

(b) Without concurrently administered nephrotoxic drugs (e.g. vancomycin, amphotericin B, cyclosporin),

(c) Without exposure to contrast media,

(d) Not quadriplegic or amputee,

(e) Not in the ICU,

(f) Younger than age 60 yr

(g) Duration of planned therapy less than 5 to 7 days.



If Therapeutic drug monitoring is indicated (e.g. due to impaired renal function), check level and interpret the result as follows:

a) For once daily (extended-interval) dosing, obtain a single blood sample after the first dose between 6-14 h after the start of the infusion. Do not check pre- and post-dose.

b) Write down the time in number of hours after last dose in request form (e.g. 8 h post-dose). This is essential for result interpretation.

c) When result becomes available, plot the value on the Hartford normogram (Table 10) and work out the appropriate dosing interval by the following table. With this method, the size of each dose need not be reduced.

Post-dose level Dosing interval

Level falls in the area designated q24h

Dose at an interval of every 24h





Level on the line Choose the longer interval

Level off the normogram at the given time

Stop the scheduled therapy, obtain serial levels to determine the appropriate time of the next dose



Table 10. Hartford Hospital once-daily aminoglycoside normogram for gentamicin and tobramycin

The Hartford normogram has not been validated in the following category of patients: paediatrics, pregnancy, burns (>20%), ascites, dialysis, Enterococcal endocarditis (51).

Part

III:

Sele

cte

d A

ntim

icro

bia

l agents

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 54

Su

mm

ary

of sele

cte

d a

nti

fun

gal agen

tsT

able

11.

Gen

era

l patt

ern

s o

f an

tifu

ngal

suscepti

bil

ity

Flu

con

azo

le

Itra

con

azo

le5-F

lucyto

sin

eA

mph

ote

ricin

B

Vori

con

azo

leC

aspofu

ngin

C.

alb

ican

s

S

S

S

S

S

S

(MIC

0.5

g/m

L)

C.

trop

icalis

SS

SS

SS

C.

gla

bra

ta

S-D

D t

o R

S

-DD

to R

S

S

-I

S

S

C. kru

sei

RS

-DD

to R

I-

RS

-IS

SC

. lu

sit

an

iae

S

S

S

S-R

S

S

(M

IC 0

.5

g/m

L)

C. p

ara

psilosis

S

SS

SS

less a

cti

ve

C.

gu

ille

rmon

dii

S

S

S

S

S

less a

cti

ve

MIC

2

g/m

L)

Cry

pto

coccu

s

neofo

rma

ns

SS

SS

SR

(M

IC 3

2

g/m

L)

Tri

ch

osp

oro

n

S

S

?

I S

R

F

usari

um

R

Som

e s

pp.

R in

vit

ro

?I

to R

+

R in

vit

ro

(mean

MIC

60-

70

g/m

L)

Pseu

dallesch

eri

a

?

+

?

- ?

S (m

ean

MIC

1.3

g/m

L)

Asp

eri

gillu

s

–+

++

++

(mean

MIC

0.4

g/m

L)

++ (m

ean

MIC

0.1

-0.1

5g/m

L)

Mu

cor

R

R

NA

+

R

R

S,

su

scepti

ble

; S

-DD

, su

scepti

bilit

y is d

ose-d

epen

den

t; R

, re

sis

tan

t



Table 12. Comparison of susceptibility of selected fungi to the azoles Organism (no. of isolates tested) (133-135)

Range( g/mL)

MIC that can inhibit 50% of all

tested isolates ( g/mL)

MIC that can inhibit 90% of all

tested isolates ( g/mL)

C. glabrata (n=217) Fluconazole 0.25 128 16 64 Itraconazole 0.06 8 1 4 Voriconazole 0.03 8 0.5 2

C. krusei (n=33)Fluconazole 8 128 64 64 Itraconazole 0.12 2 1 2 Voriconazole 0.06 4 0.5 1

Fluconazole-resistant C. albicans (n=12)Fluconazole 64 128 >128 >128 Itraconazole 1 8 >8 >8 Voriconazole 0.25 8 >8 >8

A. fumigatus (n=284) Amphotericin B 0.125 1 0.25 0.5Itraconazole 0.125 4 0.5 1Voriconazole 0.125 2 0.25 0.5

Amphotericin-resistant A. fumagitus (n=15) Itraconazole 0.25 0.5 0.25 0.5 Voriconazole 0.25 1 0.25 1

Itraconazole-resistant A.fumigatus (n=15) Amphotericin B 0.25 1 0.5 0.5 Voriconazole 0.25 1 0.5 1



Table 13. Mechanisms of antifungal action.

Primary mode of action

Target

Azoles: (fluconazole, itraconazole,voriconazole)

Inhibit ergosterol biosynthesis

Fungal cytochrome P-450 dependent 14 -steroldemethylase

Caspofungin Inhibit fungal cell wall glucan synthesis

Fungal -1,3-glucansynthase

Amphotericin B Bind to and make fungal cell membrane ‘leaky’

Fungal cell membrane

Part

III:

Sele

cte

d A

ntim

icro

bia

l agents

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 57

Table

14.

Com

pari

son

of

sele

cte

d p

harm

acokin

eti

c p

ara

mete

rs f

or

the a

zole

s a

nd c

aspofu

ngin

Flu

oconazole

It

racon

azole

V

ori

con

azole

Caspofu

ngin

T

rade n

am

e

Dif

lucan

Spora

nox

Vfe

nd

Cancid

as

Ora

lbio

availabilit

y

>80%

C

apsu

le:

30-5

5%

S

olu

tion

: 60-8

0%

90%

O

nly

IV

Cm

ax

10.2

0.2

-0.4

mg/L a

fter

2-4

h o

f 200 m

g o

ral

2 m

g/L a

fter

250 o

ral

10 m

g/L e

nd in

fusio

n

Tim

e t

o C

max

(hr.

)2-4

4-5

1-2

-

CS

Fpen

etr

ati

on

50-9

4%

<1%

20-5

0%

U

nkn

ow

n (V

ery

low

)

Pla

sm

a h

alf-l

ife

(hr.

)22-3

5

24-4

2

6-2

4

9-1

1 (te

rmin

al h

alf-l

ife 4

0-5

0

hou

rs)

Tis

su

e

dis

trib

uti

on

W

idely

dis

trib

ute

d in

m

ost

tissu

es

inclu

din

g C

SF

.

Levels

in

body f

luid

s/C

SF

lo

w;

con

cen

trati

on

s in

lu

ng,

liver

& b

on

e 2

-3 t

imes >

seru

m.

Hig

h c

on

cen

trati

on

in

str

atu

m c

orn

eu

m d

ue t

o

dru

g s

ecre

tion

in

sebu

m.

Wid

ely

dis

trib

ute

d in

to b

ody

tissu

es &

flu

id in

clu

din

g b

rain

&

CS

F

Wid

ely

dis

trib

ute

d;

hig

hest

con

cen

trati

on

in

liv

er.

Pri

ncip

al ro

ute

of

elim

inati

on

R

en

al

Hepati

c

Hepati

c

Hepati

c

Acti

ve d

rug in

u

rin

e (%

) 80

<1

2%

1%

Dosage

Ora

l or

i.v. 50-

400 m

g/day

depen

din

g o

n

indic

ati

on

s

200-4

00m

g/day

[In

life-t

hre

ate

nin

g

sit

uati

on

s,

a loadin

g d

ose

sh

ou

ld b

e u

sed w

heth

er

giv

en

ora

l capsu

le o

r IV

, e.g

. 200m

g P

O t

ds f

or

firs

t 3 d

ays]

Adu

lt,

ora

l, 2

00-4

00 m

g 1

2-

hou

rly f

or

24 h

, th

en

, 100-2

00

mg 1

2-h

ou

rly;

i.v.

6m

g/kg 1

2 h

ou

rly f

or

24 h

, th

en

4 m

g/kg 1

2 h

ou

rly

i.v.

infu

sio

n o

f 70 m

g loadin

g,

then

50 m

g d

aily

Ren

al

insu

ffic

ien

cy

Redu

ce d

ose;

rem

oved b

y

haem

odia

lysis

Usu

al dose.

At

CFR

<10

ml/

min

, som

e r

ecom

men

d

decre

ase d

ose 5

0%

No d

ose a

dju

stm

en

t n

eed w

ith

ora

l vori

con

azo

le.

Avoid

iv

vori

con

azo

le in

ren

al fa

ilu

re.

No d

ose a

dju

stm

en

t n

eeded.

Not

rem

oved b

y h

em

odia

lysis

Hepati

c

insu

ffic

ien

cy

- avoid

? a

void

R

edu

ce d

ose t

o 3

5 m

g d

aily (aft

er

the 7

0 m

g loadin

g d

ose) in

m

odera

te (C

hild-P

ugh

score

7-9

).

No d

ata

on

usage in

pati

en

t w

ith

severe

hepati

c f

ailu

re

Part

III:

Sele

cte

d A

ntim

icro

bia

l agents

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 58

Table

15.

A s

uggeste

d s

ch

em

e f

or

syste

mic

an

tifu

ngal

agen

ts

Fir

st-

Lin

eA

ltern

ati

ve

Com

men

ts

INV

ASIV

E C

AN

DID

IASIS

Neu

tropen

ic o

r cri

tically

ill

Am

ph

ote

ricin

B

Flu

con

azo

le o

r caspofu

ngin

(if

into

lera

nt

of

am

ph

ote

ricin

B)

Con

sid

er

agen

t oth

er

than

caspofu

ngin

for

seri

ou

s in

fecti

on

du

e t

o C

. gu

illierm

on

dii &

C.

para

psilosis

(136)

Sta

ble

an

d

non

neu

tropen

icFlu

con

azo

le

Am

ph

ote

ricin

B

Evid

en

ce is m

ain

ly f

or

C.

alb

ican

s.

It a

lso w

ork

s f

or

C.

para

psilosis

an

dC

. tr

op

icalis

INV

ASIV

E A

SPE

RG

ILLO

SIS

Vori

con

azo

le(d

ocu

men

ted in

vasiv

e

asperg

illo

sis

)

Am

ph

ote

ricin

B (1-1

.5

mg/kg) or

caspofu

ngin

for

docu

men

ted n

on

-fu

mig

atu

s

asperg

illo

sis

.

Effic

acy o

f vori

con

azo

le is c

lear

for

A. fu

mig

atu

s. In

th

e c

ase o

f n

on

-fu

mig

atu

s a

sp

erg

illu

s,

treatm

en

t re

spon

se r

equ

ires

con

firm

ati

on

wit

h a

larg

er

data

set

(137).

Note

: Th

e d

iagn

osis

an

d t

reatm

en

t of

syste

mic

fu

ngal in

fecti

on

is c

om

plicate

d.

Th

e n

ew

er

an

ti-f

un

gal agen

ts (e.g

. it

racon

azo

le,

vori

con

azo

le,

caspofu

ngin

) sh

ou

ld b

e u

sed a

t th

e s

pecific

advic

e o

f a s

pecia

list.

Part IV: Empirical therapy


Part IV: Recommendation for the empirical therapy of common infections

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 60

Usual

org

an

ism

s

Pre

ferr

ed r

egim

en

sA

ltern

ati

ves

Specia

l con

sid

era

tion

s /

[u

sual

dura

tion

of

treatm

en

t]

Musculo

skele

tal

infe

cti

on

sSepti

c a

rth

riti

s,

adu

ltS

. au

reu

s;

Str

ep

tococci,

N.

gon

orr

hoea

e

IV c

loxacillin

+

am

pic

illin

IV c

efa

zolin

U

rgen

t dia

gn

osti

c t

appin

g

for

gra

m s

tain

to g

uid

e

thera

py.

If s

mear

reveal G

ram

-n

egati

ve c

occi or

bacilli:

ceft

riaxon

e o

r cefo

taxim

e t

o

repla

ce c

loxacillin

..

Facto

rs s

uggest

N.

gon

orr

hoea

e e

tiolo

gy:

sexu

ally a

cti

ve

teen

ager/

adu

lt r

ash

..

Oste

om

yeli

tis,

haem

ato

gen

ous,

adu

lt

S.

au

reu

sIV

clo

xacillin

IV c

efa

zolin

Occasio

nally

Salm

on

ella

spp..

Oft

en

vert

ebra

l.

IVD

U:

S.

au

reu

s (vert

ebra

l);

P.

aeru

gin

osa (ri

bs,

ste

rnocla

vic

ula

r jo

int)

.

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 61

Dia

beti

c f

oot

infe

cti

on

(a) Pre

vio

usly

u

ntr

eate

d,

no

oste

om

yeliti

s

S.

au

reu

s,

beta

-h

aem

oly

tic

Str

ep

tococci

Am

pic

illin

-su

lbacta

m (138) or

am

oxic

illin

-cla

vu

lan

ate

Clin

dam

ycin

or

ceph

ale

xin

[14 d

ays]

(b) C

hro

nic

, re

cu

rren

t, lim

b

thre

ate

nin

g

Poly

mic

robia

l:aero

bes +

an

aero

bes

PO

levofloxacin

/

cip

rofloxacin

+ P

O

clin

dam

ycin

or

am

pic

illin

-su

lbacta

m (138)

Tic

arc

illin

-cla

vu

lan

ate

or

pip

era

cillin

-ta

zobacta

m

Cu

ltu

res f

rom

ulc

ers

u

nre

liable

.E

arl

y r

adic

al debri

dem

en

t to

obta

in t

issu

e f

or

cu

ltu

re;

to

exclu

de n

erc

oti

zin

g f

asciiti

s

an

d f

or

cu

re.

Abilit

y t

o in

sert

pro

be t

o b

on

e

su

ggest

con

com

itan

t oste

om

yeliti

s.

Skin

an

d s

oft

tis

sue

infe

cti

on

sE

rysip

ela

s o

r cell

uli

tis

Gro

ups A

, B

, C

, G

S

trep

tococci (

S.

au

reu

s)

(IV

pen

icillin

or

IV

am

pic

illin

or

PO

am

oxic

illin

) + I

V/PO

clo

xacillin

Ceph

ale

xin

or

am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m

Necro

tizin

g f

ascii

tis

(139)

Im

media

te s

urg

ical

inte

rven

tion

essen

tial.

1.

Follow

ing

exposu

re t

o

fresh

wate

r;seaw

ate

r or

seafo

od

Aero

mon

as

hyd

roph

ilia

,A

.cavia

e;

Vib

rio

vu

lnif

icu

s

IV f

luoro

qu

inolo

ne +

IV

am

oxic

illin

-cla

vu

lan

ate

U

rgen

t con

su

lt c

lin

ical

mic

robio

logis

t.

2.

Follow

ing c

uts

an

d

abra

sio

n;

recen

t ch

icken

pox;

IVD

U;

healt

hy a

du

lts

Gro

up A

S

trep

tococcu

sIV

pen

icillin

G +

IV

clin

dam

ycin

Add h

igh

dose I

VIG

(1

2 g

/kg

for

1 d

ose) fo

r str

epto

coccal

toxic

sh

ock s

yn

dro

me (140)

a

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 62

3.

Follow

ing in

tra-

abdom

inal;

gyn

aecolo

gic

al or

peri

neal su

rgery

Poly

mic

robia

l:E

nte

rob

acte

riacea,

str

ep

tococci,

an

aero

bes

IV a

moxic

illin

-cla

vu

lan

ate

+ I

V

flu

oro

qu

inolo

ne

Bit

e w

ound

(an

imal

or

hu

man

) (1

41)

Str

ep

tococci,

S.

au

reu

s,

an

aero

bes,

Paste

ure

lla

m

ult

ocid

a (cat)

, C

ap

nocy

top

haga

spp.

(dog),

Eik

en

ella s

pp.

(hu

man

)

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m

Pen

icillin

V o

r am

pic

illin

+

clo

xacillin

Ris

k o

f in

fecti

on

aft

er

cat

bit

e =

80%

. M

on

oth

era

py w

ith

pen

icillin

, clo

xacillin

or

firs

t gen

era

tion

ceph

alo

spori

n

inadequ

ate

.

Cen

tral

nerv

ous

syste

m i

nfe

cti

on

s

Bra

in a

bscess

Usu

ally

poly

mic

robia

l w

ith

aero

bes a

nd

an

aero

bes

Ceft

riaxon

e +

m

etr

on

idazo

leC

efo

taxim

e +

m

etr

on

idazo

leU

rgen

t con

su

lt

neu

rosu

rgic

al.

Exclu

de p

rim

ary

focu

s in

m

iddle

ear,

masto

id,

para

nasal sin

uses,

den

tal

an

d lu

ng.

Men

ingit

is

(142;1

43)

S.

su

is,

S.

pn

eu

mon

iae,

N.

men

ingit

ides,

gro

up B

S

trep

tococcu

s

Ceft

riaxon

e o

r cefo

taxim

eM

ero

pen

em

If im

pair

ed c

ellu

lar

imm

un

ity e

.g.

hig

h d

ose

ste

roid

, add a

mpic

illin

to

cover

Lis

teri

a s

pp..

If

rapid

test

(e.g

. G

ram

sm

ear,

an

tigen

dete

cti

on

) or

oth

er

clu

es s

uggest

S.

pn

eu

mon

iae,

add

van

com

ycin

un

til sen

sit

ivit

y

data

available

. For

pen

-R S

. pn

eu

mon

iae (M

IC

2), 7

7%

an

d 5

% a

re r

especti

vely

in

term

edia

te a

nd r

esis

tan

t to

Ceft

riaxon

e (56;1

44).

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 63

Intr

a-a

bdom

inal

an

d

GI

syste

m i

nfe

cti

on

s

Secon

dary

peri

ton

itis

(PPU

, oth

er

bow

el

perf

ora

tion

, ru

ptu

red

appen

dic

itis

,div

ert

icu

liti

s)

En

tero

bacte

riacea,

B. fr

agilis

, oth

er

an

aero

bes,

En

tero

cocci

Cefu

roxim

e +

m

etr

on

idazo

le +

(g

en

tam

icin

or

neti

lmic

in)

(Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m) +

(gen

tam

icin

or

neti

lmic

in)

Su

rgic

al in

terv

en

tion

essen

tial.

BL/B

LI

cover

an

aero

bes

inclu

din

g B

. fr

agilis

.

Ch

ola

ngit

is,

ch

ole

cysti

tis o

r oth

er

bil

iary

sepsis

En

tero

bacte

riacea,

En

tero

cocci,

Bacte

roid

es

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m (

an

am

inogly

cosid

e)

Tic

arc

illin

-cla

vu

lan

ate

or

(cefu

roxim

e +

m

etr

on

idazo

le)

Adequ

ate

bilia

ry d

rain

age

essen

tial.

BL/B

LIs

coverm

ost

En

tero

bacte

riaceae,

en

tero

cocci an

d a

naero

bes.

Liv

er

abscess

(com

mu

nit

y-a

cqu

ired)

En

tero

bacte

riacea,

Bacte

roid

es,

en

tero

cocci,

En

tam

oeb

a

his

toly

tica

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m +

m

etr

on

idazo

le (fo

r E

.h

isto

lyti

ca)

Cefu

roxim

e +

m

etr

on

idazo

leFor

all c

ases:

sero

logy f

or

E.

his

toly

tica.

CT g

uid

ed o

r open

dra

inage

for

larg

e a

bscess.

Mil

d t

o m

odera

te

gastr

oen

teri

tis

Food

pois

on

ing (B

. cere

us,

S.

au

reu

s,

C.

perf

rin

gen

s),

Salm

on

ella

sp

p.,

E

. coli,

Cam

py

lob

acte

r sp

p.,

Aero

mon

as

spp.

Rou

tin

e a

nti

bio

tic

thera

py n

ot

recom

men

ded

Flu

id a

nd e

lectr

oly

tes

repla

cem

en

t.

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 64

Modera

te t

o s

evere

gastr

oen

teri

tis

(pre

su

me b

acte

rial)in

pers

on

s w

ith

im

mu

nosu

ppre

siv

edis

ease (e.g

. fo

r H

IV

+ve;

hig

h d

ose s

tero

id

wh

en

labora

tory

re

su

lts n

ot

available

)

Salm

on

ella s

pp,

Cam

py

lob

acte

rspp.

Flu

oro

qu

inolo

ne

Flu

oro

qu

inolo

ne r

esis

tan

ce

am

on

gC

am

pylo

bacte

rin

cre

asin

g.

If s

ym

pto

ms n

ot

impro

vin

g o

r w

ors

en

ing w

hen

dia

gn

osis

of

cam

pylo

bacte

r gastr

oen

teri

tis is m

ade;

sto

p

flu

oro

qu

inolo

ne a

nd p

rescri

be

a c

ou

rse o

f ora

l m

acro

lide f

or

5-7

days.

Severe

gastr

oen

teri

tis

(labora

tory

resu

lts

not

available

)

6 u

nfo

rmed

sto

ol

/d

ay

, fe

ver

38

.5C

; te

nesm

us;

blo

od

or

faecal

WB

C +

ve

Flu

oro

qu

inolo

ne

A

dd m

etr

on

idazo

le if

severe

gastr

oen

teri

tis a

fter

recen

t an

tibio

tic t

hera

py;

repla

ce

flu

id a

nd e

lectr

oly

tes;

avoid

an

tim

oti

lity

agen

ts.

Card

iovascula

rin

fecti

on

sSubacute

in

fecti

ve

en

docard

itis

(C

RH

D,

degen

era

tive o

r con

gen

ital valv

ula

r dis

eases) (1

45;1

46)

S.

vir

idan

s,

HA

CE

K,

En

tero

cocci

IV A

mpic

illin

2 g

q4h

+ g

en

tam

icin

1

mg/kg q

8h

O

bta

in a

t le

ast

3 s

ets

of

blo

od

cu

ltu

res b

y 3

diffe

ren

t ven

epu

nctu

re o

ver

24 h

(la

bel

“? I

E”

in labora

tory

form

); t

hen

sta

rt I

V a

nti

bio

tics (147).

Acute

in

fecti

ve

en

docard

itis

(IV

DU

) (1

45;1

46)

S.

au

reu

s

IV C

loxacillin

2 g

q4h

+ g

en

tam

icin

1

mg/kg q

8h

for

the

firs

t 5 d

ays

IV C

efa

zolin

2 g

q8h

Usu

ally t

ricu

spid

valv

e

infe

cti

on

meta

sta

tic lu

ng

abscesses.

Blo

od c

ult

ure

q30m

in

3

sets

(la

bel “?

IE

” in

la

bora

tory

form

); t

hen

sta

rt

IV a

nti

bio

tics im

media

tely

(1

47).

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 65

Gyn

aecolo

gic

al

infe

cti

on

s

Pelv

ic i

nfl

am

mato

ry

dis

ease

(or

upper

gen

ital tr

act

infe

cti

on

)(1

48)

N.

gon

orr

hoeae,

C.

trach

om

ati

s,

En

tero

bacte

riacea,

an

aero

bes

IV a

moxic

illin

-cla

vu

lan

ate

or

cefo

xit

in 1

-2 g

q6h

+ d

oxycyclin

e

IV C

lin

dam

ycin

600

900 m

g q

8h

+ g

en

tam

icin

Covera

ge o

f an

aero

bes

import

an

t in

tu

bo-o

vari

an

abscess,

co-e

xis

tin

g b

acte

rial

vagin

osis

, H

IV +

ve (149).

Bre

ast

abscess

Usu

ally S

. au

reu

s

( a

naero

bes in

n

on

-pu

erp

era

labscess)

IV/PO

clo

xacillin

(+

PO

metr

on

idazo

le if

an

aero

bes lik

ely

)

Cefa

zolin

or

am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m

I &

D e

ssen

tial; s

en

d p

us f

or

Gra

m s

mear

an

d c

ult

ure

.

Head a

nd n

eck

infe

cti

on

sO

don

togen

ic o

r n

eck i

nfe

cti

on

O

ral an

aero

bes

(IV

Pen

icillin

+ P

O

metr

on

idazo

le) or

IV/PO

clin

dam

ycin

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

mU

rin

ary

tra

ct

infe

cti

on

s

Cysti

tis

E.

coli;

S.

sap

rop

hy

ticu

s,

gro

up

B

Str

ep

tococcu

s

PO

Nit

rofu

ran

toin

or

cotr

imoxazo

leb

PO

Ceph

ale

xin

or

am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-

su

lbacta

mc

En

cou

rage f

luid

in

take

Acute

pyelo

neph

riti

sE

nte

rob

acte

riacea,

En

tero

coccu

s,

(Pseu

dom

on

as in

cath

ete

r-re

late

d,

obstr

ucti

on

,tr

an

spla

nt)

IV A

moxic

illin

-cla

vu

lan

ate

or

IV

am

pic

illin

-su

lbacta

m o

r PO

/IV

flu

oro

qu

inolo

ne

(Tic

arc

illin

-cla

vu

lan

ate

or

pip

era

cillin

-ta

zobacta

m if

su

spect

P.

aeru

gin

osa) or

ceft

riaxon

e 1

2g

q24h

Blo

od c

ult

ure

an

d M

SU

cu

ltu

res,

need t

o r

ule

ou

t obstr

ucti

ve u

ropath

y.

IV u

nti

l afe

bri

le 2

448h

, th

en

com

ple

te 1

4 d

ays c

ou

rse w

ith

ora

l dru

gs.

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 66

Respir

ato

ry t

ract

infe

cti

on

s

Acute

bacte

rial

exacerb

ati

on o

f C

OPD

(A

EC

B) (1

50-

152)

Appro

pri

ate

use o

f an

tibio

tics in

AE

CB

is

impera

tive t

o h

elp

con

trol th

e e

merg

en

ce

of

mu

ltid

rug r

esis

tan

t org

an

ism

s

Respir

ato

ryvir

uses,

S.

pn

eu

mon

iae,

H.

infl

uen

zae,

M.

ca

tarr

halis

d

IV/PO

am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m

Cefo

taxim

e o

r a

new

an

ti-G

ram

posit

ive

flu

oro

qu

inolo

nee

for

mu

lti-

resis

tan

tS

.p

neu

mon

iae w

ith

pen

icillin

MIC

>2

g/m

L)

Late

st

AA

CP/A

CP-A

SIM

re

com

men

dati

on

: an

tibio

tic

is o

nly

in

dic

ate

d w

hen

all 3

card

inal sym

pto

ms a

re

pre

sen

t: s

pu

tum

pu

rule

nce,

spu

tum

volu

me,

dyspn

oea.

Pen

icillin

-in

term

edia

te/re

sis

tan

tS

.

pn

eu

mon

iae (M

IC 0

.12

g/m

L) can

be t

reate

d b

y

hig

h d

ose P

O a

moxic

illin

or

IV p

en

icillin

G (h

igh

dose

Am

oxic

illin

-cla

vu

lan

ate

if

co-i

nfe

cti

on

by a

mpic

illin

-re

sis

tan

tH

. in

flu

en

zae)

(152)

Acute

bacte

rial

exacerb

ati

on o

r pneum

onia

in

pati

en

t w

ith

bro

nch

iecta

sis

P.

aeru

gin

osa

(most)

PO

Levofloxacin

/

cip

rofloxacin

or

IV

ticarc

illin

-cla

vu

lan

ate

or

pip

era

cillin

-ta

zobacta

m a

n

am

inogly

cosid

e

For

P.

aeru

gin

osa,

flu

oro

qu

inolo

ne s

hou

ld b

e

giv

en

at

hig

h d

ose (e.g

. Levofloxacin

PO

500-7

50 m

g

qd;

cip

rofloxacin

500-7

50m

g

bd)(153;1

54)

Aspir

ati

on

pneum

onia

Ora

l an

aero

bes:

Bacte

roid

es,

Pep

tostr

ep

tococci,

Fu

sob

acte

riu

m,

S.

mille

ri

(IV

Pen

icillin

G +

PO

m

etr

on

idazo

le) or

PO

clin

dam

ycin

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 67

Com

mun

ity-

acquir

ed p

neum

on

ia

(CA

P)

1.

CA

P,

not

hospit

alize

dS

. p

neu

mon

iae,

H.

infl

uen

zae,

M.

pn

eu

mon

iae,

C.

pn

eu

mon

iae,

C.

psit

taci (in

flu

en

za

A,

M.

tub

erc

ulo

sis

)

PO

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m a

m

acro

lide

or

PO

am

oxic

illin

+ a

n

ew

er

macro

lide

M

eta

-an

aly

sis

of

127 s

tudie

s

(n=33148):

S.

pn

eu

mon

iae

(73%

);H

. in

flu

en

zae (14%

); S

.a

ure

us (3%

); G

ram

-negati

ve

rods (2%

). I

n H

on

g K

on

g,

macro

lide/aza

lide,

tetr

acyclin

e

or

co-t

rim

oxazo

le s

hou

ld n

ot

be u

sed a

lon

e f

or

em

pir

ic

treatm

en

t of

CA

P.Locally,

50

70%

pen

-S a

nd p

en

-R S

.p

neu

mon

iae isola

tes (both

com

mu

nit

y a

nd h

ospit

al

isola

tes) are

mu

ltip

ly r

esis

tan

t to

th

ese a

gen

ts (5;1

55;1

56)

2.

CA

P,

hospit

alize

d

in g

en

era

l w

ard

(1

57)

As a

bove

IV/PO

Am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m a

macro

lidesf

Cefo

taxim

e o

r ceft

riaxon

e a

macro

lidesf

Modifyin

g f

acto

rs:

bro

nch

iecta

sis

: eit

her

(tic

arc

illin

-cla

vu

lan

ate

or

pip

era

cillin

-tazo

bacta

m o

r cefe

pim

e) + a

macro

lide;

or

flu

oro

qu

inolo

ne +

an

am

inogly

cosid

e

3.

CA

P,

hospit

alize

d

in I

CU

for

seri

ou

s

pn

eu

mon

ia

As a

bove +

E

nte

rob

acte

riaceae

IV P

ipera

cillin

-ta

zobacta

m o

r cefo

taxim

e o

r ceft

riaxon

e +

a

macro

lide

Cefe

pim

e +

a

macro

lide

Tic

arc

illin

-cla

vu

lan

ate

an

d

ceft

azi

dim

e a

re n

ot

usefu

l vs

pen

icillin

-non

-su

scepti

ble

S.

pn

eu

mon

iae

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 68

Hospit

al-

acquir

ed

pneum

onia

(H

AP)

HA

P,

on

set

<4 d

ays

aft

er

adm

issio

n +

no

pre

vio

us a

nti

bio

tics

(158)

S.

pn

eu

mon

iae,

H.

infl

uen

zae, M

.ca

tarr

halis,

S.

au

reu

s

IV/PO

Am

pic

illin

-su

lbacta

m o

r am

oxic

illin

-cla

vu

lan

ate

Cefu

roxim

e if

pati

en

t is

pen

icillin

-allerg

y(n

on

-type I

h

ypers

en

sit

ivit

y)

HA

P,

on

set

4 d

ays

aft

er

adm

issio

n +

had

an

tibio

tics r

ecen

tly,

OR

on

set

5 d

ays

aft

er

adm

issio

n O

R

mech

an

ical

ven

tila

tion

(158)

MR

SA

;P

.a

eru

gin

osa,

Acin

eto

ba

cte

r,K

lebsie

lla s

pp.,

E

nte

rob

acte

r spp.

IV T

icarc

illin

-cla

vu

lan

ate

or

pip

era

cillin

-ta

zobacta

m a

n

am

inogly

cosid

e

Cefo

pera

zon

e-

su

lbacta

m o

r cefe

pim

e a

n

am

inogly

cosid

e

Refe

r als

o t

o g

uid

elin

e o

n

use o

f van

com

ycin

.

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 69

Footn

ote

a C

lassif

icati

on

an

d d

efi

nit

ion

of

gro

up A

str

epto

coccal

toxic

shock s

yn

dro

me (159)

Defi

nit

e c

ase =

cri

teri

a I

A +

IIA

+ I

IB;

pro

bab

le c

ase =

cri

teri

a I

B +

IIA

+ I

I B

Cri

teri

a I

A:

Isola

tion

of

gro

up A

str

epto

cocci

(Str

ep

tococcu

s p

yogen

es)

from

a n

orm

ally ste

rile

sit

e (e

.g.,

blo

od,

cere

bro

spin

al, p

leu

ral, o

r peri

ton

eal flu

id,

tissu

e b

iopsy,

su

rgic

al w

ou

nd).

Cri

teri

a I

B:

Isola

tion

of

gro

up A

str

epto

cocci

(Str

ep

tococcu

s p

yogen

es)

from

a n

on

ste

rile

sit

e (

e.g

., t

hro

at,

spu

tum

, vagin

a,

su

perf

icia

l skin

lesio

n).

Cri

teri

a I

IA:

Hypote

nsio

n,

systo

lic b

lood p

ressu

re

90 m

m H

g in

adu

lts o

r <5th

perc

en

tile

for

age in

ch

ildre

n,

an

d;

Cri

teri

a I

IB:

2 o

f th

e f

ollow

ing s

ign

s:

(a)

Ren

al

impair

men

t: c

reati

nin

e

177 µ

mol/

L f

or

adu

lts o

r >2

th

e u

pper

lim

it o

f n

orm

al

for

age.

In

pati

en

ts w

ith

pre

-exis

tin

g r

en

al dis

ease,

a

2-f

old

ele

vati

on

over

the b

aselin

e level.

(b)

Coagu

lopath

y:

pla

tele

ts

100,0

00/m

m3 or

DIC

defin

ed by pro

lon

ged clo

ttin

g ti

mes,

low

fibri

nogen

le

vel, a

nd t

he p

resen

ce o

f fibri

n d

egra

dati

on

pro

du

cts

.

(c)

Liv

er

involv

em

en

t: a

lan

ine a

min

otr

an

sfe

rase (

ALT), a

spara

te a

min

otr

an

sfe

rase (

AS

T), o

r to

tal

bilir

ubin

le

vels

>2

th

e u

pper

lim

it of

norm

al

for

age.

In pati

en

ts w

ith

pre

-exis

tin

g liver

dis

ease a

2-f

old

ele

vati

on

over

the b

aselin

e level.

(d)

Adu

lt re

spir

ato

ry dis

tress syn

dro

me defin

ed by acu

te on

set

of

diffu

se pu

lmon

ary

in

filt

rate

s an

d

hypoxaem

ia i

n t

he a

bsen

ce o

f card

iac f

ailu

re,

or

evid

en

ce o

f diffu

se c

apilla

ry l

eak m

an

ifeste

d b

y a

cu

te

on

set

of

gen

era

lize

d o

edem

a,

or

ple

ura

l or

peri

ton

eal effu

sio

ns w

ith

hypoalb

um

inaem

ia.

(e)

A g

en

era

lize

d e

ryth

em

ato

us m

acu

lar

rash

th

at

may d

esqu

am

ate

.

(f)

Soft

tis

su

e n

ecro

sis

, in

clu

din

g n

ecro

tizi

ng f

asciiti

s o

r m

yosit

is,

or

gan

gre

ne.

b A

void

in

pati

en

t w

ith

G6PD

deficie

ncy.

c T

hese a

gen

ts p

refe

rred in

pati

en

t w

ith

recen

t an

tim

icro

bia

l th

era

py.

Part

IV

: E

mpir

ical th

era

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 70

d

Str

ati

ficati

on

sch

em

es

have

been

pro

posed

to

allow

th

e

ph

ysic

ian

to

id

en

tify

h

igh

ri

sk

pati

en

ts

for

targ

ete

d

an

tim

icro

bia

l ch

em

oth

era

py.

On

e s

uch

sch

em

e is a

s f

ollow

s:

Gro

up

Cri

teri

aPath

ogens

1.

Acu

te t

rach

eobro

nch

itis

N

o u

nderl

yin

g s

tru

ctu

ral dis

ease

Usu

ally v

iral

2.

Sim

ple

ch

ron

ic b

ron

ch

itis

FE

V1>50%

, s

pu

tum

volu

me +

pu

rule

nce

H.

infl

uen

zae,

M.

ca

tarr

halis,

S.

pn

eu

mon

iae

3.

Com

plicate

d c

hro

nic

bro

nch

itis

As f

or

gro

up 2

+

1 o

f FE

V1<50%

, advan

ced a

ge,

sig

nific

an

t co-m

orb

idit

y

H.

infl

uen

zae,

M.

ca

tarr

halis,

S.

pn

eu

mon

iae

4.

Ch

ron

ic b

ron

ch

ial in

fecti

on

A

s f

or

gro

up 3

+ c

on

tin

uou

s s

pu

tum

th

rou

gh

ou

t year

Above +

En

tero

bacte

riaceae,

P.

aeru

gin

osa

eC

au

tion

requ

ired a

s u

niq

ue g

rou

ps o

f C

OPD

pati

en

ts a

ppears

to b

e t

he m

ain

reserv

oir

of

levofloxacin

-resis

tan

t S

.

pn

eu

mon

iae (

32). S

ubopti

mal

dose o

f le

vofloxacin

has b

een

associa

ted w

ith

levofloxacin

-resis

tan

t S

. p

neu

mon

iae (

32).

Ofloxacin

an

d c

ipro

floxacin

sh

ou

ld n

ot

be u

sed f

or

treatm

en

t of

pn

eu

mococcal

infe

cti

on

. Levofloxacin

is t

he L

-isom

er

of

the r

acem

ate

, ofloxacin

. Th

e M

ICs o

f m

ost

pn

eu

mococci

in H

on

g K

on

g a

re c

lose t

o t

he b

reakpoin

t of

levofloxacin

. In

pati

en

ts

wit

h

acu

te

pu

rule

nt

exacerb

ati

on

of

ch

ron

ic

bro

nch

itis

, fa

ilu

res

appeare

d

to

be

com

mon

in

th

ose

wit

h

pn

eu

mococci (failu

res in

65%

, 13/20) (1

6). T

he r

ecom

men

ded d

ose f

or

levofloxacin

is 5

00 m

g Q

D t

hat

for

moxiflo

xacin

is

400 m

g Q

D.

Opin

ion

fro

m c

lin

ical m

icro

bio

logis

t su

ggeste

d if

use o

f flu

oro

qu

inolo

ne is c

on

tem

pla

ted.

fIV

or

PO

ery

thro

mycin

pre

ferr

ed.

Alt

ern

ati

ves

for

pati

en

ts

into

lera

nt

of

ery

thro

mycin

are

cla

rith

rom

ycin

an

d

azi

thro

mycin

.



Guidelines on the use and choice of antibiotics in severe acute pancreatitis

1. Criteria for severity assessment of acute pancreatitis (Table 16).Most acute pancreatitis is mild. Severe acute pancreatitis (SAP) occurs in about 5-13% of all patients. SAP is commonly defined as having any of the following 4 criteria: (a) organ failure; (b) local complication such as necrosis, pseudocyst, or abscess; (c) Ranson score 3; or (d) at least 8 of the APACHE II criteria (160). Of all markers available, CRP is the single most useful parameter in predicting the severity of acute pancreatitis (161).

2. Infection risk. Pancreatic or peripancreatic infection occurs in 30-40% patients who have >30% pancreatic necrosis in CT staging. Infection usually occurs at least 10 days after the onset of SAP. In patients with severe acute pancreatitis, the data suggests that prophylactic antibiotic reduce infection and mortality (162-166).

3. Choice of antibiotics (Table 17): the agents should be able to penetrate into pancreatic tissue. Good pancreatic tissue concentrations have been documented for cefotaxime, piperacillin, imipenem and metronidazole (167). In terms of activity, it seems reasonable to provide coverage for the enteric Gram-negative bacilli and anaerobes. Carbepenem group of antibiotic should be reserved for the most severe form of disease (i.e. SAP with highly suspected or documented pancreatic necrosis)

4. Duration of prophylactic antibiotics: 5 to 14 days depending on disease severity and patient progress (162-169). Excessive and prolonged antibiotic use in this setting is known to cause fungal super-infection and emergence of antibiotic-resistant bacteria, and should be avoided (170;171).

5. Work-up. Consider CT or USS guided-FNA of necrotic area for culture if secondary pancreatic infection is suspected and if fever or leukocytosis persist or develops beyond 7-10 days.



Table 16. Criteria for severity assessment of acute pancreatitis Box 1. RANSON’S CRITERIA Box 2. ORGAN FAILURE

One point for each of: At admission

Age > 55 yr WBC >16,000/ LGlucose >11.1 mmol/L (>200 mg/dL)LDH >350 IU/L AST >250 IU/L

During initial 48 hours Haematocrit decrease >10% BUN increase >1.8 mmol/L (>5 mg/dL) Calcium <2 mmol/L (<8 mg/dL)PaO2 <60 mm Hg Base deficit >4 mEq/L Fluid sequestration >6 L

CVS: shock (SBP <90mmHg or mean arterial pressure <70mmHg or inotropic support)Resp: PaO2 <60 mmHg or ventilator dependent Renal: Urea >7.4 mmol/L or Creatinine >250 mol/L or requiring renal replacement Gastrointestinal: bleeding >500mL in 24 hours



Table 17. Prophylactic use of antibiotic in acute pancreatitis

Acute pancreatitis

MildSevere

(Box 1 & 2)

Moderately severe

Only Ranson 3

but no organ failure and

CRP <150 mg/L

Very severe

Organ failure;

CRP 150 mg/L;

CT proven pancreatic necrosis

Options

1. Cefuroxime +

metronidazole

2. Cefotaxime +

metronidazole

3. Piperacillin-

tazobactam

Options

Carbapenem



Management of community-acquired pneumonia General considerations and principles

1. A number of guidelines on the management of community-acquired pneumonia (CAP) were released or updated recently. While these guidelines were drawn on the basis of the same set of literature, patient stratification and specific suggestions still vary quite a bit (157;172;173).

2. All agreed that S. pneumoniae is the most common pathogen in CAP including those without an identifiable etiology. Hence, the choice of agents for empirical therapy should consider the regional data on prevalence and risk factors for drug-resistant S. pneumoniae (DRSP).

3. Appropriate antimicrobial therapy should be initiated within 8 hours of hospitalization. Prior studies indicated that compliance with this recommendation is associated with a significant reduction in mortality (174).

4. Factors to be considered in choosing empirical therapy for CAP:

(a) Place of therapy (outpatient, inpatient ward, or intensive care unit).

(b) Role of atypical pathogens (e.g. Chlamydia pneumoniae,Mycoplasma pneumoniae and Legionella spp.) is increasingly being recognized. ATS guidelines even suggested that all patients should be treated for the possibility of atypical pathogen infections (173).

(c) Presence of modifying factors including risk factors for DRSP (e.g. age >65 yr., beta-lactam therapy within past 3 months, alcoholism, multiple medical comorbidities, exposure to a child in a day care centre), enteric Gram- negatives (residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbidities, recent antibiotic therapy), and P. aeruginosa (e.g. bronchiectasis).

5. Several antibiotics active against P. aeruginosa, including cefepime, imipenem, meropenem, piperacillin, and piperacillin-tazobactam are also highly active against DRSP. They can be used for patients having specific risk factors for P. aeruginosa.

6. If a macrolide is relied upon for coverage of H. influenzae, the newer macrolides (e.g. clarithromycin or azithromycin) should be used instead of erythromycin.



7. For most patients, appropriately chosen initial antibiotic therapy should not be changed in the first 72 h, unless there is marked clinical deterioration.

8. Most patients with CAP will have an adequate clinical response within 72 h. After the patient has met appropriate criteria, switch from iv to oral therapy can be made.



Management of community-acquired pneumonia in the era of pneumococcal resistance: conclusions from the CDC working group

1. The current CLSI (NCCLS) categories for defining susceptibility concentrations (i.e. penicillin G: sensitive for 0.06 g/mL;intermediate for 0.1-1 g/mL and resistant for 2 g/mL) are not clinically useful for treatment of patients with pneumococcal pneumonia. Comparative studies of adults and children have reported that pneumonia due to penicillin-nonsusceptible pneumococci (most had MIC >0.1-1 g/mL) does not influence the outcome of pneumonia treatment (175;176). At higher level of resistance (penicillin MIC 2-4 g/mL), recent evidence suggests that risk of mortality or suppurative complications were increased (177;178). In one study (179), the observed increase in mortality was confined to patients with pneumococcal isolates with penicillin MIC of 4 g/mL.

2. For S. pneumoniae causing pneumonia (but not otitis media and meningitis), the following revised categorization was suggested: 1 g/mL, sensitive; 2 g/mL, intermediate; 4 g/mL resistant.

By modifying the breakpoints, it is hope that there will be decreased use of broad-spectrum antimicrobial therapy in favour of more narrow-spectrum therapy. Patients with pneumococcal pneumonia caused by strains with penicillin MIC 1 g/mL can be treated appropriately with optimal dosage of IV penicillin and selected other PO/IV beta-lactams. Comparative anti-pneumococcal activities of commonly used beta-lactams is shown in Table 18.

3. Vancomycin is not routinely indicated for treatment of CAP or for pneumonia caused by DRSP.

4. The CDC working group does not advocate the use of newer fluoroquinolones for first line treatment of CAP. The reasons are:

(a) Most penicillin-nonsusceptible S. pneumoniae pneumonia can be appropriately treated with a beta-lactam with good anti-pneumococcal activity at optimal dosage.

(b) Concerns that resistance among pneumococci will rapidly emerge after widespread use of this class of antibiotics.

(c) Their activity against pneumococci with high level penicillin resistance (MIC 4 g/mL) makes it important that they be reserved for selected patients with CAP.

5. Indications for use of fluoroquinolones in CAP



(a) Adults for whom one of the first line regimen has already failed.

(b) Allergic to alternative agents.

(c) Documented infection due to pneumococci with high level penicillin resistance (penicillin MIC 4 g/mL).



Regional considerations for S. pneumoniae

(4;5;56;96;144;155;180-182)

1. In Hong Kong, reduced susceptibility to penicillin and resistance to macrolides were high in both hospital (56;155) and community settings (180;181) (50-70% and >70%, respectively).

2. Erythromycin resistant isolates are also resistant to the newer macrolides/azalides such as clarithromycin and azithromycin (183).

3. Globally, resistance to fluoroquinolones among the pneumococci is low (<1-2%). Hong Kong is one of the rare exceptions in which fluoroquinolone resistance (levofloxacin MIC 8 g/mL) is rapidly emerging among the S. pneumoniae (56). The findings of two recent multi-hospital studies were summarized below. Similar findings have been reported from several recent international surveillance studies (e.g. Alexander project). In local strains of S.pneumoniae, fluoroquinolone resistance is associated with resistance to penicillin and is a result of double mutations in both targets (parC and gyrA) (156).

Percentage resistant to levofloxacin (MIC 8 g/mL)

Year Penicillin-sensitive

Penicillin-resistant

Overall Ref.

1998 0% 9.2% 5.5% (155)

2000 0% 28.4% 13.3% (56)

4. In view of the above, adherence to the CDC guidelines on the use of the fluoroquinolones seems appropriate. Moreover, tuberculosis is prevalent in Hong Kong and was reported to account for ~10% of CAP in the elderly. Excess use of fluoroquinolones in CAP may lead to: (1) delay in diagnosis of tuberculosis; (2) increased fluororoquinolone resistance among Mycobacterium tuberculosis (184;185). Hence, this class of agents is not recommended as first line (or routine) therapy in Hong Kong for CAP. In this regard, extra-care need to be exercised in using fluoroquinolones in patients with risk factors for fluoroquinolone-resistant S. pneumoniae (186):

presence of COPD;



nosocomial pneumococcal infection;

residence in old age home; and

past exposure to fluoroquinolones.

Ciprofloxacin and ofloxacin should not be used to treat pneumococcal infection. Use of a suboptimal dose of fluoroquinolone should be avoided (e.g. the dose/frequency approved by FDA for levofloxacin in CAP is 500 mg qd). Use of <500 mg and in divided doses should be avoided as these have been showed to be associated with the emergence of fluoroquinolone-resistant S. pneumoniae (156). If a respiratory fluoroquinolone is indicated, there is evidence to suggest that the more potent ones (e.g. gemifloxacin, moxifloxacin, gatifloxacin) are less likely to lead to development of resistance.

5. Penicillin G (IV) or ampicillin (PO/IV) or amoxicillin (PO/IV) are generally viewed as the beta-lactam drugs of choice for treating infections with penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae. The following beta-lactams are not recommended because of poor intrinsic activities against S.pneumoniae: penicillin V, all first generation cephalosporins, cefaclor, cefixime, ceftibuten, and loracarbef.

6. Lung infections involving strains with intermediate susceptibility to penicillin (MIC 0.1-1 g/mL) may be treated with IV penicillin G or oral amoxicillin (high dose).

7. Penicillins combined with beta-lactamase inhibitors (ampicillin-sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam) are active against beta-lactamase-producing organisms including H. influenzae, M. catarrhalis, and methicillin-sensitive S. aureus.Except in-patients with mixed infection, these drugs offer no advantage over penicillin G or amoxicillin for the treatment of S.pneumoniae pneumonia, including those due to penicillin-resistant strains because beta-lactamase is not produced by S. pneumoniae. The MIC of ampicillin, amoxicillin, piperacillin for most local strains were similar to that of penicillin. However, the MIC of ticarcillin is increased disproportionately among penicillin non-susceptible strains.

8. Amoxicillin capsules taken together with standard Augmentin (375 mg tablet) may be an acceptable alternative to high dose Augmentin (1 g preparation) in some clinical situations. An example of dosing for combinational use would be amoxicillin (Amoxil) 250 mg tds + Augmentin 375 mg tds. While they are expected to produce similar pharmacodynamic targets (T>MIC) (187), no specific pharmacokinetic studies have been conducted to demonstrate their bioequivalence.



Table 18. Comparative activities of commonly used beta-lactams against Streptococcus pneumoniae with different levels of penicillin susceptibility

Penicillin MIC

Sensitivea intermediate Resistant

0.06 g/mL 0.12 1 g/mL 2 g/mL 4 g/mL

Year/type of study (ref.)

2000/hospital (56) 39.4% 11.7% 37.8% 11.1%

2000/community (181) 41.8% 32.1% 22.7% 3.4%

Agent

Penicillin V +++ +

Penicillin G +++ +++ ++

Ampicillin PO +++ ++

Ampicillin IV +++ +++ ++

Amoxicillin PO +++ ++ +

Piperacillin +++ ++ +

Ticarcillin ++ +

Cefotaxime +++ +++ ++

Ceftriaxone +++ +++ ++

Cefepime +++ ++ +

Cefuroxime IV +++ ++ +

Cefuroxime PO +++ ++

Cefpodoxime +++ ++

Ceftazidime +++ +

Cefaclor +++

Cefixime +++

Imipenem/meropenem +++ +++

a interpreted according to current CLSI (NCCLS) recommendation (188).

Part V: Known pathogen therapy


Part V: Guidelines for known pathogen therapy

Part

V: K

now

n p

ath

ogen thera

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 82

Guid

eli

nes f

or

Know

n-P

ath

ogen T

hera

py

DR

UG

OF

CH

OIC

E

ALT

ER

NA

TIV

ES

RE

MA

RK

S

Acin

eto

ba

cte

r

ba

um

an

nii

IV

Am

pic

illin

-su

lbacta

m +

an

am

inogly

osid

e

Cefo

pera

zon

e-s

ulb

acta

m +

an

am

inogly

osid

e (m

ixed in

fecti

on

w

ith

P.

aeru

gin

osa)

Flu

oro

qu

inolo

ne +

an

am

inogly

osid

e (if a

llerg

ic t

o

pen

icillin

)

Su

lbacta

m is h

igh

ly a

cti

ve

again

st

Acin

eto

bacte

r,

gen

tam

icin

added t

o p

reven

t re

sis

tan

ce a

nd f

or

syn

erg

y.

Th

e e

ntr

y s

ite f

or

at

least

50%

of

the A

cin

eto

bacte

r bacte

raem

ia in

ou

r h

ospit

als

is

in

fecte

d in

travascu

lar

cath

ete

r. R

em

oval of

the

cath

ete

r a

sh

ort

cou

rse o

f an

tibio

tic is u

su

ally

adequ

ate

tre

atm

en

t.

Com

bin

ati

on

th

era

py

recom

men

ded f

or

all s

eri

ou

s

infe

cti

on

except

for

un

com

plicate

d c

ath

ete

r-re

late

d b

acte

raem

ia.

Clo

str

idiu

md

iffi

cil

ePO

metr

on

idazo

le

PO

van

com

ycin

(if m

etr

on

idazo

le

fails a

s d

ocu

men

ted

mic

robio

logic

ally)

Clin

ical eff

icacy:

metr

on

idazo

le =

PO

van

com

ycin

. R

ela

pse r

ate

: m

etr

on

idazo

le =

PO

van

com

ycin

M

etr

on

idazo

le r

em

ain

s t

he

dru

g o

f ch

oic

e f

or

rela

pse.

Part

V: K

now

n p

ath

ogen thera

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 83

DR

UG

OF

CH

OIC

E

ALT

ER

NA

TIV

ES

RE

MA

RK

S

Ente

robacte

r

clo

aca

ecom

ple

x

PO

/IV

Levofloxacin

/

cip

rofloxacin

for

uri

nary

tra

ct

infe

cti

on

IV c

efe

pim

e ( ±

an

am

inogly

cosid

e)

for

severe

in

fecti

on

Carb

apen

em

(fo

r severe

in

fecti

on

an

d/or

ES

BL-

pro

du

cin

g s

train

)

Cefe

pim

e is h

igh

ly a

cti

ve in

vit

ro a

gain

st

alm

ost

all

En

tero

ba

cte

r is

ola

tes.

Em

erg

en

ce o

f A

mp

Cdere

pre

ssed m

uta

nts

em

erg

e

in 2

0-4

0%

of

infe

cti

on

s

treate

d w

ith

th

e s

econ

d o

r th

ird g

en

era

tion

ceph

alo

spori

ns.

Use o

f th

ese

agen

ts (even

in

com

bin

ati

on

s) fo

r seri

ou

s

infe

cti

on

s (oth

er

than

UTI)

is

not

recom

men

ded.

On

e s

tudy in

Hon

g K

on

g

fou

nd h

igh

pre

vale

nce o

f E

SB

L p

rodu

cti

on

am

on

g E

.h

orm

aech

ei (a

mem

ber

of

the

E.

clo

aca

e c

om

ple

x) (2

1)

E c

oli

(E

SB

L -ve)

PO

/IV

am

pic

illin

-su

lbacta

m o

r am

oxic

illin

-cla

vu

lan

ate

(add

an

am

inogly

osid

e

if r

apid

bacte

ricid

al acti

on

desir

able

on

clin

ical gro

un

ds)

Cefu

roxim

e (if r

esis

tan

t to

am

oxic

illin

-cla

vu

lan

ate

), a

dd

metr

on

idazo

le (if m

ixed

infe

cti

on

wit

h a

naero

bes lik

ely

).Pip

era

cillin

-tazo

bacta

m +

an

am

inogly

osid

e (if P

. aeru

gin

osa

or

Acin

eto

bacte

r are

co-

path

ogen

s)

Part

V: K

now

n p

ath

ogen thera

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 84

DR

UG

OF

CH

OIC

E

ALT

ER

NA

TIV

ES

RE

MA

RK

S

Ha

em

oph

ilu

sin

flu

en

za

ePO

am

oxic

illin

or

PO

/IV

am

pic

illin

-su

lbacta

m o

r am

oxic

illin

-cla

vu

lan

ate

Flu

oro

uin

olo

nes

(if

allerg

ic t

o

pen

icillin

)A

moxic

illin

-cla

vu

lan

ate

als

o

pro

vid

es g

ood c

overa

ge f

or

M.

ca

tarr

halis a

nd S

.p

neu

mon

iae.

Kle

bsie

lla

pn

eu

mon

iae

(ES

BL -ve)

PO

/IV

am

pic

illin

-su

lbacta

m o

r am

oxic

illin

-cla

vu

lan

ate

(add

an

am

inogly

osid

e

if r

apid

bacte

ricid

al acti

on

desir

able

on

clin

ical gro

un

ds)

Cefu

roxim

e (if r

esis

tan

t to

am

oxic

illin

-cla

vu

lan

ate

), a

dd

metr

on

idazo

le (if m

ixed

infe

cti

on

wit

h a

naero

bes lik

ely

).Pip

era

cillin

-tazo

bacta

m +

an

am

inogly

osid

e (if P

. aeru

gin

osa

or

Acin

eto

bacte

r are

co-

path

ogen

s)

Am

pic

illin

-su

lbacta

m less

sati

sfa

cto

ry b

ecau

se o

f poor

inh

ibit

ory

acti

vit

y o

f su

lbacta

m f

or

SH

V-1

beta

-la

cta

mase.

E.

coli

/ K

. pn

eu

mon

iae

(ES

BL +

ve)

PO

cotr

imoxazo

le

or

am

oxic

illin

-cla

vu

lan

ate

or

PO

n

itro

fura

nto

in o

r PO

levofloxacin

or

cip

rofloxacin

for

uri

nary

tra

ct

infe

cti

on

Carb

apen

em

for

bacte

raem

ia o

r oth

er

seri

ou

s

infe

cti

on

Flu

oro

qu

inolo

ne (add a

n

am

inogly

osid

e f

or

seri

ou

s

infe

cti

on

an

d a

lso if

rapid

bacte

ricid

al eff

ect

is d

esir

able

clin

ically).

Pip

era

cillin

-tazo

bacta

m +

an

am

inogly

osid

e

Carb

apen

em

has b

een

sh

ow

n t

o b

e e

ffecti

ve

clin

ically a

nd is c

urr

en

tly

the b

eta

-lacta

m a

gen

t of

ch

oic

e f

or

seri

ou

s in

fecti

on

by E

SB

L+ve E

. coli /

Kle

bseilla

spp.

Data

for

beta

-la

cta

m/beta

-lacta

mase

inh

ibit

or

com

bin

ati

on

s

lim

ited a

nd s

hou

ld b

e u

sed

cau

tiou

sly

.

Part

V: K

now

n p

ath

ogen thera

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 85

DR

UG

OF

CH

OIC

E

ALT

ER

NA

TIV

ES

RE

MA

RK

S

Pseudom

onas

aerugin

osa

IV P

ipera

cillin

or

ticarc

illin

-cla

vu

lan

ate

or

pip

era

cilin

-ta

zobacta

m +

an

am

inogly

osid

e

Cefo

pera

zon

e-s

ulb

acta

m +

an

am

inogly

osid

e (m

ixed in

fecti

on

w

ith

Acin

eto

bacte

r).

Levofloxacin

/cip

rofloxacin

+ a

n

am

inogly

osid

e (if a

llerg

ic t

o

pen

icillin

).

Com

bin

ati

on

th

era

py

recom

men

ded (fo

r syn

erg

ism

) fo

r all s

eri

ou

s

infe

cti

on

except

for

un

com

plicate

d c

ath

ete

r-re

late

d b

acte

raem

ia.

Pip

era

cillin

-tazo

bacta

m u

sed

inste

ad o

f ceft

azi

dim

e d

ue t

o

rapid

ris

e in

Am

pC

type a

nd

ES

BL-p

rodu

cers

in

E

nte

rob

acte

ria

cea

e.

In a

para

llel evalu

ati

on

of

7000

P.

aeru

gin

osa isola

tes,

no d

iffe

ren

ce w

as f

ou

nd in

th

e s

uscepti

bilit

y b

etw

een

pip

era

cillin

-tazo

bacta

m a

nd

pip

era

cillin

i.e

. 93.9

% v

s

93%

Part

V: K

now

n p

ath

ogen thera

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 86

DR

UG

OF

CH

OIC

E

ALT

ER

NA

TIV

ES

RE

MA

RK

S

Meth

icil

llin

-sen

sit

ive S

.aureus

PO

/IV

clo

xacillin

or

am

oxic

illin

-cla

vu

lan

ate

or

am

pic

illin

-su

lbacta

m o

r firs

t gen

era

tion

ceph

alo

spori

n

Cefa

zolin

(if a

llerg

ic t

o

pen

icillin

, bu

t lim

ited t

o t

hose

wit

h m

inor

allerg

y s

uch

as

rash

alo

ne)

Clin

dam

ycin

(if a

llerg

ic t

o

pen

icillin

)

Meth

icil

lin

-re

sis

tan

tS

.aureus

IV v

an

com

ycin

Lin

ezo

lid o

r te

icopla

nin

(if

exte

nsiv

e r

ash

, oth

er

than

red-

man

syn

dro

me d

evelo

p a

fter

van

com

ycin

)

Cotr

imoxazo

le,

fusid

ic a

cid

or

rifa

mpic

in a

re u

sefu

l adju

ncts

for

deep-s

eate

d

infe

cti

on

s (e.g

. oste

om

yeliti

s)

bu

t th

ese a

gen

ts s

hou

ld n

ot

be a

dm

inis

tere

d a

s

mon

oth

era

py.

Ste

notr

oph

o-

monas

ma

ltoph

ilia

PO

/IV

C

otr

imoxazo

le +

IV

ti

carc

illin

-cla

vu

lan

ate

Cotr

imoxazo

le +

flu

oro

qu

inolo

ne

Cotr

imoxazo

le +

tic

arc

illin

-cla

vu

lan

ate

is s

yn

erg

isti

c in

vit

ro.

Cotr

imoxazo

le is a

key

com

pon

en

t in

th

era

py.

Com

bin

ati

on

th

era

py

recom

men

ded f

or

syn

erg

y

an

d t

o p

reven

t re

sis

tan

ce.

Part

V: K

now

n p

ath

ogen thera

py

IMPA

CT T

hir

d E

dit

ion

(V

ers

ion

3.0

) 87

DR

UG

OF

CH

OIC

E

ALT

ER

NA

TIV

ES

RE

MA

RK

S

Str

epto

coccu

spn

eu

mon

iae

a

For

infe

cti

on

s

ou

tsid

e t

he c

en

tral

nerv

ou

s s

yste

m:

Pen

icillin

-sen

sit

ive:

IV

pen

icillin

G (4 t

o

8 M

U /

day,

q6h

) Pen

icillin

-in

term

edia

te:

IV

pen

icillin

G (h

igh

dose,

12 t

o 1

8

MU

/d;

q4h

)a

Pen

icillin

-re

sis

tan

t: I

V

cefo

taxim

e o

r ceft

riaxon

e

Beta

-lacta

m/beta

-lacta

mase

inh

ibit

or

com

bin

ati

on

wit

h t

he

excepti

on

of

cefo

pera

zon

e-

su

lbacta

m (fo

r m

ixed

infe

cti

on

s).

Ery

thro

mycin

or

clin

dam

ycin

(if

allerg

ic t

o p

en

icillin

).

For

pu

re p

neu

mococcal

infe

cti

on

, pen

icillin

G

inste

ad o

f am

oxic

illin

-cla

vu

lan

ate

is p

refe

rred,

sw

itch

th

ere

fore

re

com

men

ded.

>70%

resis

tan

t to

ery

thro

mycin

. C

ross-

resis

tan

ce t

o c

lin

dam

ycin

very

com

mon

. R

esis

tan

ce t

o e

ryth

rom

ycin

= r

esis

tan

ce t

o o

ther

new

er

macro

lides (cla

rith

rom

ycin

, azi

thro

mycin

,ro

xit

hro

myxin

).

a

CLS

I (N

CC

LS

) M

IC

(g/m

L)

bre

akpoin

ts

for

pen

icillin

G

: sen

sit

ive,

0.0

6;

inte

rmedia

te

0.1

2-1

; re

sis

tan

t2.

Th

ese b

reakpoin

ts w

ere

decid

ed m

ain

ly f

or

the r

ele

van

ce o

n m

en

ingit

is.

For

pn

eu

mococcal

pn

eu

mon

ia,

ph

arm

acokin

eti

c/dyn

am

ic

data

in

dic

ate

s

that

isola

tes

wit

h

MIC

of

up

to

12

g/m

L

sh

ou

ld

be

con

sid

ere

d “

sen

sit

ive”

to a

ppro

pri

ate

dose o

f pen

icillin

, am

pic

illin

an

d a

moxic

illin

.

Part VI: Surgical prophylaxis


Part VI: Guidelines for surgical prophylaxis



General principles in surgical prophylaxis

1. Duration of prophylaxis: There is wide consensus that only a single dose of intravenous antibiotic is needed for surgical prophylaxis in the great majority of cases. Published evidence showed that antibiotic prophylaxis after wound closure is unnecessary and could lead to emergence of resistant bacteria. Most studies comparing single- with multiple-dose prophylaxis have not shown benefit of additional doses (189).

2. Timing: Antibiotic should be given in a sufficient dose within 30 minutes before incision. This can be facilitated by having the anesthesiologist administer the drug in the operating room at induction. The goal is to archieve a high antibiotic level at the time of incision.

3. Antimicrobial dosing: The dose should be adequate based on the patient’s body weight. An additional dose of antibiotic should be given (intra-operatively) if the operation is still continuing after two half-lives of the initial dose, as follows:

Suggested initial dose and time to re-dose for selected antibiotics used for surgical prophylaxis

Antibiotic Standardintravenous dose

Recommendedredosing interval (hr)

Cefazolin 1 2 g 2 5 hr Cefuroxime 1.5 g 3 4Clindamycin 600 900mg 3 6Amoxycillin-clavulanate 1.2 g 2 3Ampicillin-sulbactam 1.5 g 2 3Metronidazole 500 mg 6 8Vancomycin 1 g over 60 min 6 12

References for this section (189-192)



Antibiotic prophylaxis in clean operations Type of

Operation

Indications Recommended drugs

Cardiaca Prosthetic valve Coronary artery bypassPacemaker implantOpen-heartsurgery

Cefazolin 1-2 g

Thoracica Pulmonary resectionClosed tube thoracostomy for chest trauma

Cefazolin 1-2 g; or (Amoxicillin-clavulanate 1.2 g or ampicillin-sulbactam1.5 g)

Vascular Abdominal aortic operationsProsthesis Groin incision Lower extremity amputation for ischaemia

Cefazolin 1-2 g

Neurosurgical Craniotomy V-P Shunt

Cefazolin 1 g or Cotrimoxazole 960 mg

Orthopaedic a Total joint replacementInternal fixation of fractures

Cefazolin 1-2 g (complete infusion of antibiotic before inflation of a tourniquet)

Ophthalmic Prevent post-operative endo-ophthalmitis

Multiple drops topically over 2 to 24 hours gentamicin or Tobramycin or Neomycin-gramicidin-polymyxins and



Cefazolin 100 mg subconjunctivally at the end of the procedure

a For hospitals or units with a high incidence of postoperative wound infections by MRSA or MRSE, screening for MRSA may be indicated to identify patients for additional preoperative measures such as chlorhexidine bath, 2% mupirocin nasal ointment [Bactroban Nasal] and/or the use of vancomycin as preoperative prophylaxis (see also “Guidelines for prescribing vancomycin” section)(193). b For patients allergic to cefazolin or patients with high risk of MRSA / MRSE infections, vancomycin 1 g infused over at least 1 h should be given after premedication with an antihistamine. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anaesthesia.



Antibiotic prophylaxis in clean-contaminated operations

Type of operation Indications Recommendeddrugs

Head and neck Entering oral cavity or pharynx

Cefazolin 1-2 g (Amoxicillin-clavulanate 1.2 g or ampicillin-sulbactam 1.5 g orclindamycin 600-900 mg)

Ear Placement of tympanostomy tube (to decrease incidence of purulent otorrhoea)

Gentamicin eardrop

Gastroduodenal High risk: ObstructionHaemorrhage Gastric ulcer MalignancyH2 blocker Proton pump inhibitor Morbid obesity Gastric bypass Percutaneous endoscopicgastrostomy

Cefazolin 1 g

Biliary High risk: Age more than 70 yearsAcute cholecystitis Obstructive jaundice Common bile duct stonesMorbid obesity

Cefuroxime 1.5 g



Type of operation Indications Recommendeddrugs

Colorectal Most procedures require parenteral oral prophylaxis

Parenteral

(Cefuroxime 1.5 g + metronidazole 0.5 g)

Oral

Neomycin and erythromycin base 1 g each P.O. tds the day before operation

Appendectomy Both elective and emergency procedures

Cefuroxime 1.5 g + metronidazole 0.5 g

Therapy should be continuedpostoperatively for ruptured and gangrenousappendix

Vaginal or abdominal hysterectomy

Both elective and emergency procedures

Cefazolin 1-2 g, OR

orCefuroxime 1.5 g

Urology Significant bacteriuria Treat according to culture result.



Antibiotic prophylaxis in contaminated-infected operations

Type of operation Indications Recommended drugs

Ruptured viscus For treatment of established infection

Cefuroxime 0.75 to 1.5 g q8h and metronidazole 0.5 g q8h

Traumatic wound For treatment of established infection

Cefazolin 1-2 g q8h (Ampicillin 0.5 g q6h + cloxacillin 0.5 g q6h)

Bite wound For treatment of established infection

IV/PO Amoxicillin-clavulanate or ampicillin-sulbactam

Cost and dosage


Part VII: Cost and recommended dosage of commonly-used antimicrobial agents

Cost and dosage


Preparation and recommended dosing regimens for antibiotics

Agents(generic)

Trade name Dosage form (unit cost, HK$)

Usual adult regimen (daily dose, route, dosing interval) a

Amikacin (129) Amikin 0.1 g vial ($18)

0.25 g vial ($38)

0.5 g vial ($59)

IV 15 mg/kg q24h (750 mg q24h)b or 7.5 mg/kg q12h

Amoxicillin Amoxil 250 mg cap. ($0.14)

125 mg/5 mL syr. ($0.13/mL)

PO 500 mg tds

Amoxicillin-clavulanate

Augmentin 0.6 g vial ($14.14)

1.2 g vials ($28.3)

375 mg tab ($0.90)

1 g tab ($ 2.49)

156 mg/5 mL syr. ($0.46/mL)

457 mg/5ml “BD syr” ($1.60/mL)

IV 1.2 g q8h

PO 375-750 mg tds

PO 1 g bd

PO 312 mg (10 mL) tds (syr)

PO 914 mg (10 mL) bd (syr)

Ampicillin 500 mg vial ($1.98)

250 mg cap ($0.16)

500 mg cap ($0.32)

125 mg/5 mL syrup ($0.20/mL)

IV 1 g q6h

PO 250 500 mg qid

Ampicillin-sulbactam

Unasyn 750 mg vial ($25)

375 mg tab ($5.45)

250 mg/5mL syrup ($0.93/mL)

IV 1.5 3 g q6h

PO 375 mg tds

Azithromycin Zithromax 500 mg vial ($141)

250 mg tab ($13)

200 mg/5ml syrup ($3.67/mL)

IV 500 mg qd

PO 500 mg on first day then 250 mg q24h

Cefazolin Cefamezin 1 g vial ($13) IV 1 g q8h

Cefepime Maxipime 1 g vial ($95.45)

2 g vial ($190.91)

1 2 g q12h

Cefoperazone Cefobid 2 g vial ($135) 2 g q12h

Cost and dosage


Agents(generic)



Cefoperazone+

sulbactam

Sulperazon 1 g vial ($89.50) 1-2 g q12h

Ceftazidime Fortum 1 g vial ($79.9)

2 g vial ($160.8)

1 g q8h

Cefotaxime Claforan 1 g vial ($54.6) IV 1g q6 8h (max 12 g/day)

Ceftriaxone Rocephin 0.25 g IM ($54)

1 g IM ($55)

1 g vial IV( $31.20)

IM 250 mg once

IM/IV 1 2 g/day q12 24h (max 4 g/day)

Cefuroxime Zinacef 0.75 g vial ($8.70)

1.5 g vial ($16.5)

IV 0.75 1.5 g q8h

Cefuroxime-axetil

Zinnat 125 mg tab ($3.8)

250 mg tab($7.39)

125 mg/5 mL suspension ($1.07/mL)

PO 250 500 mg bd

Cephalexin Keflex 250 cap ($0.40)

500 cap ($0.68)

250mg/5mL syrup

($0.18/ml)

PO 250 500 mg qid

Ciprofloxacin Ciproxin 200 mg vial ($155)

400 mg vial ($260)

250 mg tab ($1.77)

500 mg tab ($8.60)

IV 200 400 mg q12h

PO 500 750 mg bd

Clarithromycin Klacid 500 mg vial ($50)

250 mg tab ($7.23)

500 mg tab ($14.55)

125 mg/5 mL syrup ($1.18/mL)

IV 500 mg q12h

PO 250 500 mg bd

Cost and dosage


Agents(generic)



Clindamycin Dalacin C 150 mg/mL in 2ml vials ($17.7/mL)

150 mg cap ($2.82)

300 mg cap ($5.03)

IV 600 mg q8h (max 2.7 g/day)

PO 150 300 mg qid

Cloxacillin 500 mg vial ($2.04)

250 mg cap ($0.33)

500 mg cap ($0.44)

IV 0.5 1 g q6h (max 12 g/day)

PO 500 mg qid

Doxycycline Vibramycin 100 mg tab ($0.25) PO 200 mg qd

Erythromycin Erythrocin 500 mg vial ($30.8)

250 mg tab ($0.39)

IV 500 mg q6h

PO 250 500 mg qid

Flucloxacillin 125 mg/5 ml elixir ($0.14/mL)

PO 250 500 mg qid

Gentamicin(129)

Garamycin 20 mg/2 mL ($12)

80 mg/2 mL ($1.85)

IV 3.6 mg/kg/day q24h (180 mg q24h) b

or

1.2 mg/kg/dose q8h

Imipenem Tienam 500 mg vial ($114.5) IV 500 mg q6h

Levofloxacin Cravit 500 mg vial ($248.9)

100 mg tab ($3.81)

250 mg ($8.6)

IV 500 mg qd

PO 500 mg qd

Linezolid Zyvox 600 mg vial ($400)

600 mg tab ($360)

20 mg/mL syrup ($12/ml)

IV/PO 600 mg q12h

Meropenem 500 mg vial ($126)

1g vial ($193.4)

IV 1 g q8h

Metronidazole 500 vial ($4.50)

200 mg tab (0.17)

IV 500 mg q8h

PO 400 mg tds

Moxifloxacin Avelox 400 mg vial ($250)

400 mg tab ($14)

IV 400 mg qd

PO 400 mg qd

Cost and dosage


Agents(generic)



Netilmicin(129)

Netromycin 50 mg vial ($18.5)

300 mg vial ($33.6)

IV 4.4 mg/kg q24h (200 mg q24h) b or IV 2.2 mg/kg q12h

Penicillin G 1 MU vial ($2.80) IV 1 2 million unit q4 6h (max 24 million unit/day)

Piperacillin Pipracil 4 g vial ($56) IV 4 g q6h

Piperacillin-tazobactam

Tazocin 4.5 g vial ($108) IV 4.5 g q6 8h

Teicoplanin Targocid 200 mg vial ($314.6) IV 400 mg x 1 dose then 200 mg q24h

Ticarcillin-clavulanate

Timentin 3.2 g vial ($52) IV 3.2 g q4 6h

Tobramycin (129)

TOBR suspended

40 mg/mL 2 ml vial ($25)

IV 3.6 mg/kg q24h (180 mg q24h) b or 1.2 mg/kg q8h

Vancomycin 500 mg vial ($16.39) IV 1 g q12h or IV 500 mg q6h (i.e. 30 mg/kg/day)

PO 125 mg qid

(for refractory C. difficile colitis)

Note: Approximate cost updated as of October 2005 in the public service.a Typical dosages in a 70 kg person with normal renal function. Dosage modification may be necessary for (i) the elderly; (ii) the very obese individuals (in whom the distribution volume of water-soluble drugs may be smaller than expected from body mass); (iii) those with renal failure and/or IV) liver failure. b Dosage for a typical 50 kg person given. Once daily administration of aminoglycoside is appropriate for most infections with the possible exceptions of neutropenic fever, infective endocarditis and in the presence of severe renal failure.

Cost and dosage


Cost comparison of selected IV antibiotics Antibiotics Usual dosage Cost(HK$/day)

Aminoglycosides

IV Gentamicin* (3.5 mg/kg/day) 180 mg qd 5.55

IV Netilmicin* (4.4 mg/kg/day) 200 mg qd 67.2 IV Tobramycin* (3.5 mg/kg/day) 180 mg qd 56 IV Amikacin* (15 mg/kg/day) 750 mg Daily 97

Penicillins

IV Ampicillin 0.5 1 g q6h 8 16IV Cloxacillin 0.5 1 g q6h 8 16IV Amoxillin-clavulanate (augmentin)

1.2 g q8h 85

IV Ampicillin-sulbactam 1.5 g q8h 150 IV Ticarcillin-clavulanate 3.2 g q6h 208 IV Piperacillin 4 g q8h 168 IV Piperacillin-tazobactam 4.5 g q8h

(4.5 g q6h) 324(432)

Cephalosporins

IV Cefuroxime 750 mg q8h 26 IV Cefazolin 1 g q8h 39 IV Ceftriaxone 1 g q12h 62 IV Cefotaxime 1 g q8h 164 IV Cefoperazone-sulbactam (Sulperazon)

1 g q12h (1 g q8h)

179(268)

IV Cefepime 1 g q12h 191 IV Ceftazidime 1 g q8h 239

Carbapenems

IV Meropenem 0.5 g q8h (1 g q8h)

378(580)

IV Imipenem 500 mg q6h 458

Cost and dosage


Fluoroquinolones

IV Moxifloxacin PO Moxifloxacin

400 mg qd 400 mg qd

20514

IV LevofloxacinPO Levofloxacin

500 mg qd 500 mg qd

24917

IV Ciprofloxacin PO Ciprofloxacin

400 mg q12h 500 mg bd

52017

Macrolides

IV Clarithromycin 500 mg q12h 100 IV Azithromycin 500 mg qd 141

Others

IV Metronidazole 500 mg q8h 14 IV Vancomycin 1 g q12h 66 IV Linezolid(PO Linezolid)

600 mg q12h (600 mg q12h)

800(720)

Note: Approximate cost updated as of October 2005 in the public service. *Dosage for a typical 50 kg person

Cost and dosage


Cost comparison of systemic antifungal agents Antifungal agent Usual dosage Cost

(HK$/day)PO Itraconazole(capsule) PO Itraconazole (solution) IV Itraconazole

200 mg bd

200 mg bd

200 mg q12h

96

190

1040

PO Fluconazole IV Fluconazole

200 mg bd 200 mg q12h

249736

PO VoriconazoleIV Voriconazole

200 mg bd 200 mg q12h

6761476

IV Caspofungin Loading 70 mg Day 1 Maintenance 50 mg qd

25171950

IV Amphotercin B (1 mg/kg/day) *

50 mg qd 195

IV Liposomal amphotericin B (3 mg/kg/day) *

150 mg qd 4995

Note: Approximate cost updated as of October 2005 in the public service.

*Dosage for a typical 50 kg person

Cost and dosage


Dosage of antimicrobial agents for CNS infections

Antibiotics* Recommended doses Cost (HK$/day)

IV Cefotaxime 2 g q4h 655

IV Ceftriaxone 2 g q12h 125

IV Cefepime 2 g q8h 573

IV Meropenem 2 g q8h 1160

IV Ampicillin 2g q4h 48

IV Penicillin G 3 4 MU q4h 52-69

IV Metronidazole 500 mg q6h 18

IV Vancomycin 1 g q12h 66

PO Rifampin** 600 mg qd 3

Note: * Dosage for a typical body weight 70 kg and normal renal function.

** Rifampicin should only be used in combination with another antibiotic for meningitis by certain bacteria (e.g. multi-resistant Streptococcus pneumoniae or MRSA) with documented sensitivity in susceptibility testing.

Cost and dosage


Intra-peritoneal antibiotic dosing recommendations for patients with CAPD peritonitisAntibiotics Intermittent dosing (once daily) *

(Add drug into 1 bag/day unless otherwise specified) (194)

Aminoglycosides Amikacin 2 mg/kg Gentamicin 0.6 mg/kg Netilmicin 0.6 mg/kg Tobramycin 0.6 mg/kg

Cephalosporins Cefazolin 15 mg/kg Cefepime 1 g Cefotaxime 2 g Ceftazidime 1-1.5 g Ceftriaxone 1 g

Others Ampicillin/sulbactam 2 g q12h Imipenem 1 g q12h

* In patients with residual renal function, the drug dose should be empirically increased by 25%.

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Abbreviations


Abbreviations

3GC Third generation cephalosporins

AACP American Association of Colleges of Pharmacy

ACP-ASIM American College of Physicians- American Society of Internal Medicine

AECB Acute exacerbation of chronic bronchitis

APUA Alliance for the Prudent Use of Antibiotics

ASP Antimicrobial stewardship programme

bd Twice daily

BLBLI Beta-lactam/beta-lactamase inhibitor

CA-MRSA Community acquired methicillin resistant Staphylococcal aureus

CAP Community acquired pneumonia

cap/caps Capsule/capsules

CDC Centers for Disease Control and Prevention

CLIS Clinical and Labortory Standards Institute

COPD Chronic obstructive pulmonary disease

CRHD Chronic rheumatic heart disease

CRKP Ceftazidime-resistant Klebsiella pneumoniae

CT Computerised tomography

D5 5% dextrose solution

DDD Defined daily dose

DRSP Drug resistant Streptococcus pneumoniae

ESBL Extended-spectrum beta lactamase

ET Empirical therapy

FDA Food and Drug Administration

FNA Fine needle aspiration

HA-MRSA Healthcare associated methicillin resistant Staphylococcus aureu

HACEK Hemophilus parainfluenzae, H. aphropilus, Actinobacillus, Cardiobacterium, Eikenella,

Abbreviations


Kingella IBW Ideal body weight

IDSA Infectious Diseases Society of America

IE Infective endocarditis

IM Intramuscular

IV Intravenous

IVDA Intravenous drug abuser

KPT Known-pathogen therapy

MIC Minimal inhibitory concentration

MRPA Multiply-resistant Pseudomonas aeruginosa

MRSA Methicillin resistant Staphylococcus aureus

MSSA Methicillin sensitive Staphylococcus aureus

NCCLS National Committee for Laboratory Standards

NIH National Institues of Health

ODA Once daily aminoglycerides

PO Oral

PPU Perforated peptic ulcer

PVL Panton-Valentine leukocidin

qd Daily

qid Four times per day

syr Syrup

tab/tabs Tablet/tablets

TBW Total body weight

TDM Therapeutic drug monitoring

tds Three times per day

USS Ultrasound

VRE Vancomycin resistant Enterococcus

WHO World Health Organisation

Soft copy of this document is available at the following web links. http://www.hku.hk/hkucoi/impact.pdfhttp://www.chp.gov.hk/files/pdf/reducing_bacterial_resistance_with_impact.pdfhttp://ha.home/ho/ps/impact.pdf

Part I: Antibiotic resistance-local scenario 12

Part II: Antimicrobial stewardship programme 21

Part III: Guidelines for selected antimicrobial use 37

Part IV: Empirical therapy of common infections 59

Part V: Known-pathogen therapy 81

Part VI: Guidelines for surgical prophylaxis 88

Part VII: Cost and dosage of antimicrobial agents 95

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IMPACT Guideline

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