Antibiotics Prescription Pediatrics

8/2/2019 Antibiotics Prescription Pediatrics

1/25

Use of this content is subject to the Terms and Conditions

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

Copyright 2008 Churchil l Livingstone, An Imprint of Elsevier

Section B Anti-Infective Therapy

CHAPTER 289 Principles of Anti-Infective Therapy

John S. Bradley,

Sarah S. Long

When a child develops signs and symptoms consistent with a bacterial infection, the clinician must first

decide if the child's illness is caused by an infection or other inflammatory process, and subsequently,

whether an infection is likely to be caused by a microorganism that is susceptible to antibiotic therapy.

Furthermore, for the child who may benefit from antimicrobial therapy, the clinician must select an agent

that is the safest and most effective at curing the child's infection. Inappropriate antibiotic therapy given to

a child with a viral infection exposes the child needlessly to the toxicities inherent in the antibiotic, adds to

the selective pressure driving antibiotic resistance in bacteria, creates unnecessary costs to the medical

system and may divert the focus of attention from the most appropriate evaluation and therapy for thechild's actual infection.

The selection of optimal antibiotic therapy for presumed bacterial infection is based on deduction of

balance, benefits, and risks of specific therapy for each child.

SELECTING OPTIMAL ANTIMICROBIAL THERAPY

A number of questions must be addressed sequentially in order to choose optimal empiric and definitive

antimicrobial therapy. They revolve around identifying potential or presumed pathogens and considering

the relative merits of antimicrobial agents for specific pathogens and circumstances ( Box 289-1 ). The

clinician should follow the steps outlined below.

BOX 289-1

Questions Pertinent to Choosing Antimicrobial Therapy Appropriately

1. What is the clinical syndrome/site of infection? Pathogens are predictable by site

2. Does the child have normal defense mechanisms (in which case causative agents are

predictable) or are they impaired by underlying conditions, trauma, surgery, or a medical

device (in which case causative agents are less reliably predictable)?

3. What is the child's age? Pathogens are predictable by age

4. What clinical specimen(s) should be obtained to guide empirical/definitive therapy?

5. Which antimicrobial agents have activity against the pathogens considered, and what is the

current range of susceptibilities for each antibiotic against these pathogens in the

practitioner's hospital or clinic?

6. What special pharmacokinetic and pharmacodynamic properties of a therapeutic agent are

important regarding the site of the infection host?

7. For any given infection site, what percent of children require effective antimicrobial therapy

with agents first selected for treatment? Bacterial meningitis requires 100%, whereas 75% may

B - Anti-Infective Therapy from Long: Principles a... http://www.mdconsult.com/das/book/body/19324

de 25 05-04-2010 2


2/25

be acceptable for impetigo

8. What empiric therapy and what definitive therapy would be optimal? Agents with a broad

spectrum of activity may be appropriate for empiric therapy, whereas those with a narrow

spectrum of activity are preferred for definitive therapy

9. What special considerations exist regarding drug allergy, drug interaction, route of

administration, cost, alteration of flora, or selective pressure in an environment?

Step 1: Predict the Infect ing Organism

The first step in predicting the pathogen is to define the patient's site(s) of infection or the organ systems

involved. Bacteria are tropic for tissues locally following invasion; certain species have a proclivity for

causing certain infections. Examples are Neisseria meningitidis, group B streptococcus, and Streptococcus

pneumoniae for meningitis; S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis for acute

otitis media; and Staphylococcus aureus and Streptococcus pyogenes for cellulitis, osteomyelitis, and

pyogenic arthritis. On the other hand, certain pathogens can almost be dismissed in some circumstances

when the site of infection is identified. Examples are S. aureus and Streptococcus pyogenes for meningitis

and S. pneumoniae and Staphylococcus aureus for urinary tract infection.

Step 2: Consider Host Defense Mechanisms

The second question is whether the host is healthy, with intact immunity and normal integumental barriers

to infection. If so, the causative pathogens are predictable. If the child has an underlying condition such as

a defect in granulocyte number or function, or a B- or T-lymphocyte immunologic defect, whether

congenital or acquired, nonpathogenic bacteria from both the host and the environment can cause

infection. For an immune-competent child with trauma to skin or mucous membranes, a recent surgical

procedure, or an indwelling medical device, a variety of relatively nonpathogenic commensals can also be

causative pathogens, mandating therapy with an antibiotic or antibiotics that provide activity against a

much broader range of organisms.

Step 3: Consider the Age of the Child

Infectious agents causing specific organ infections in immunocompetent hosts are predictable in many

circumstances based on the age of the child and age-specific exposures. Examples are limitation of

meningitis due to group B streptococci, Escherichia coli, and Listeria to the first 90 days of life.

Developmental maturity of the immune system provides improved recognition of polysaccharide-

encapsulated pathogens such as Streptococcus pneumoniae orH. influenzae type b as infants approach

the th ird year of life. Group childcare exposures in young infants are linked to the carriage of, and infection

by, antibiotic-resistant strains ofS. pneumoniae, requiring the practitioner to increase the antibiotic

spectrum of selected agents in order to achieve the same level of treatment success as that achieved for a

child not in group childcare. School-related exposure to S. pyogenes is associated with increased

age-specific attack rates of infection, which is low in young infants. Likewise, adolescent exposure to

sexually transmitted disease pathogens increases the potential causes of pyogenic arthritis such as

Neisseria gonorrhoeae.

Step 4: Perform Diagnostic Tests

Every effort should be made to prove the etiology of the infection and obtain an isolate for susceptibility

testing. The Gram stain is perhaps the simplest, least expensive, and most useful of the rapid tests

because it provides clues to the pathogen (e.g., swab in neonatal conjunctivitis), pathogenesis (e.g.,

aspirate in polymicrobial lung abscess), or interpretation of culture results (e.g., tracheal secretions in

pneumonia). Although Gram stain result of a tissue sample may lead to the inclusion of additional empiric

therapy, it should not necessarily lead to exclusion of antibiotics customarily used in the empiric treatment

of that infection. In meningitis, the finding of gram-negative diplococci visualized on Gram stain of

cerebrospinal fluid (CSF), suggesting N. meningitidis, should not exclude the possibility ofH. influenzae


2 de 25 05-04-2010 2


3/25

type b, or ofS. pneumoniae. An error in processing or interpreting the Gram stain must not lead to

ineffective therapy of bacterial meningitis. Similarly, a Gram stain that demonstrates gram-positive cocci in

clusters from endotracheal secretions in a neutropenic child with pneumonia should lead to the addition of

agents active against staphylococci, not the elimination of agents active against Pseudomonas

aeruginosa.

Molecular techniques are emerging from research applications and are being used more frequently in

clinical laboratories for the diagnosis of bacterial infections. Polymerase chain reaction is used to identify

bacteria, viruses, and other microorganisms in a variety of specimens, and probes are used to identifyorganisms recovered in culture (see Chapter 286 , Laboratory Diagnosis of Infection Due to Bacteria,

Fungi, Parasites, and Rickettsiae, and Chapter 287 , Laboratory Diagnosis of Infection due to Viruses,

Chlamydia, and Mycoplasma). Advantages are obvious, but standardization and lack of an isolate for

susceptibility testing are problems. [1]

Step 5: Consider Antibiotic Susceptibilities of Suspected Pathogens

Bacteria have a wide range of antibiotic resistance patterns (see Chapter 290 , Mechanisms of Antibiotic

Resistance). Organisms can have single or multiple different mechanisms of resistance against a single

antibiotic. Resistance mechanisms include ways: to keep the antibiotic out of the organism (cell wall

changes or efflux pumps); inactivation of antibiotics enzymatically; alterations of the target binding site of

the antibiotic; of these mechanisms. Organisms can have resistance mechanisms against antibiotics of a

single class or many different classes. They can express resistance constitutively, or only on exposure toan antibiotic (inducible resistance). Some pathogens can have genetic dysregulation leading to the

constitutive hyperproduction of resistance factors such as beta-lactamases. With such vast biologic

variability in resistance mechanisms and efficient transmission of resistance genes between organisms, it is

understandable tha t a single organism such as E. colican manifest different patterns of antibiotic

resistance in different populations within the same region, between regions of a country, and between

countries of the world. In a single community, the E. colicausing a urinary tract infection likely has a very

different resistance pattern in the child who was previously healthy and unexposed to antibiotics versus the

patient with relapsed leukemia who has had a prolonged hospitalization in an Oncology Unit in a tertiary

care pediatric hospital versus the prematurely born infant in an intensive care unit. The resistance patterns

ofE. colifrom cities in the United States differ from those in Buenos Aires and Hong Kong due to local

differences in antibiotic pressure and the types of transmissible resistance factors present in each location.

Regardless of which population is under study, however, a range of susceptibilities is always present: some

organisms are relatively more susceptible and others more resistant to specific agents. The hospitalantibiogram is a widely available tool that allows the clinician to assess the current local resistance pattern

for each pathogen and each antibiotic. These antibiograms are updated annually, as the resistance

patterns can change substantially within a 12-month period. The probability that the antibiotic selected for

empiric therapy will be effective against the p resumed pathogen is directly related to the proportion of

susceptible pathogens infecting patients in that location.

Step 6: Consider Pharmacokinetic/Pharmacodynamic Properties of Drugs

The route of administration, the absorption, the tissue distribution of antibiotic at the site of infection, and

the drug elimination characteristics are all critical pieces of information to guide the selection of both drug

and drug dosage in antimicrobial therapy (see Chapter 291 , PharmacokineticPharmacodynamic Basis of

Optimal Antibiotic Dosing). Eradication of pa thogens causing infection requires the appropriate antibiotic

exposure in the infected tissues. [2] For many agents, particularly those that have been investigated

recently, published data describe the average concentrations and variability of concentrations achieved at

specific tissue sites over time. Unfortunately, for many older antibiotics this important information is often

unavailable.

To understand best how effective an antibiotic will be in achieving a microbiologic cure using otitis media

and amoxicillin treatment as an example, information is required on the average and range of

concentrations achievable in the middle-ear fluid following administration of a specific Food and Drug

Administration (FDA)-approved dosage of amoxicillin, as well as the characteristics of amoxicillin e limination

from this particular body site over time. These data provide a measure of exposure of the amoxicillin to


3 de 25 05-04-2010 2


4/25

bacteria in the middle-ear fluid (MEF). Based on the amoxicillin exposure required to achieve a

microbiologic cure (presence of amoxicillin in MEF for at least 30-40% of each dosing interval), the

proportion of children given that specific dosage who would likely respond or fail treatment is predictable.

For different classes of antibiotics, different types of drug exposure may be required for bacterial

eradication. [3]

In the treatment of meningitis, adequate antibiotic concentrations in the CSF are critical for cure. The

concentration of aminoglycoside antibiotics in the CSF following intravenous infusion is likely inadequate as

single antibiotic therapy to treat meningitis caused by gram-negative pathogens, despite the fact that CSFconcentrations are roughly 20% of those achievable in serum (see Chapter 292 , Antimicrobial Agents). In

contrast, although CSF concentration of penicillin is only 5% of tha t achievable in serum, the high serum

concentration leads to adequate CSF concentration if the pathogen has exquisite susceptibility to

penicillin. Within the range of predictable tissue penetration of antimicrobial agents there is considerable

variability among children receiving the same dose of drug. For example, antibiotic concentrations in the

middle-ear space can be inadequate in a low but predictable percentage of children given the same mg/kg

oral dosage. However, unlike acute otitis media, the clinician (and thus, dosing recommendations) cannot

risk inadequate dosing for even one child with meningitis. The inherent variability among children of serum

and site-of-infection tissue concentrations of an tibiotics are relevant to other infections, such as pyogenic

arthritis, pyomyositis, cellulitis, pneumonia. Clearly, one single dosage of an antibiotic may not be

appropriate and effective for all susceptible pathogens causing infection at a ll tissue sites.

The absorption, distribution, and elimination of drugs are variable in children by age and developmentalchanges. [4] [5] The volume of distribution of antibiotics varies profoundly during the first few years of life,

being greater in the neonate than in the infant. Drug elimination based on organ function generally

increases during the first several weeks of life, peaks in infancy, and approaches adult values during

adolescence. Many antibiotics require different dosages during these stages of life in order to achieve the

most appropriate antibiotic exposure to maximize efficacy and minimize toxicity (see Chapter 292 ,

Antimicrobial Agents) ( Table 289-1 ).

TABLE 289-1 -- Pharmacodynamic Antibacterial Effect of Antimicrobial Agents by Primary Bacterial

Target and by Antibiotic Class

Primary

Target [a] Antibacterial Class Pharmacodynamics [b]Intracellular

activity [c]

Cell wall -Lactams Bactericidal Not generally

effective

Penicillins Time-dependent

Cephalosporins PAE only against gram-positive organisms

Monobactams

Carbapenems Carbapenems PAE aga inst g ram-positive and

gram-negative organisms

Glycopeptides

Vancomycin

Teicoplanin [d]

Cell

membrane

Lipopeptides Bactericidal Not known

Daptomycin Concentration-dependent Long PAE

(daptomycin)

Polymyxins PAE (polymyxins)


4 de 25 05-04-2010 2


5/25

Primary

Target [a] Antibacterial Class Pharmacodynamics [b]Intracellular

activity [c]

Polymyxin B

Colistin

Ribosome Macrolides, azalides,

ketolides

Bacteriostatic or -cidal (Ketalides) Time- and

concentration-dependent Long PAE

Yes

Tetracyclines,

glycylcyclines

Bacteriostatic

Time-dependent

Long PAE

Yes

Lincosamides

(clindamycin)

Bactericidal or -static

Time-dependent

PAE

Yes

Aminoglycosides Bactericidal

Concentration-dependent

PAE

Not effective

generally

Oxazolidinones Bacteriostatic (except against Streptococcus

pneumoniae)


PAE

Not effective

generally

Rifamycins Bactericidal

Long

PAE

Yes

Quinolones Bactericidal


Long

PAE

Yes

Streptogramins Bactericidal (except against Enterococcus.faecium)


PAE

Yes

Nucleic acid Metronidazole Bactericidal


PAE

Yes

Sulfamethoxazole-

trimethoprim

Bactericidal


Yes

References forTable 289-1 : 72-102.

PAE, postantibiotic effect, or the observation of delay in regrowth of organisms following removal of

antibiotic from the media.

a The primary antibiotic target within the bacterial pathogen.

b The type of pharmacodynamic relationship that best describes antibiotic-mediated inhibitory or bactericidal activity.


5 de 25 05-04-2010 2


6/25

c The ab ility to treat intracellula r pathogens, based on the penetration of antibiotic into the host cell by passive diffusion or by active

uptake.

d Not marketed in the United S tates.

The pharmacodynamic properties of an antibiotic describe how exposure of the antibiotic to the pathogen

leads to a bacteriostatic or bactericidal effect and are important in designing an antibiotic dosing regimen

(see Chapter 291 , PharmacokineticPharmacodynamic Basis of Optimal Antibiotic Dosing).

Aminoglycosides kill bacteria in a concentration-dependent fashion. Therefore, it is desirable to achieve the

highest concentrations possible at the site of infection. Unfortunately, the maximum safe serum

concentration is limited by risk of toxicity. For other antibiotic classes, such as the penicillins, achieving

tissue concentration above the minimum inhibitory concentration (MIC) for that pathogen for 30-40% of the

dosing interval is associated with microbiologic and clinical cure. For this class of antibiotic, a higher

concentration of penicillin at the infected tissue site is not associated with more rapid sterilization of tissues

or better clinical outcome, although higher serum concentrations would likely be safe.

The postantibiotic effect is also considered in dosing of antibiotics (see Table 289-1 ). For the

aminoglycosides, the postantibiotic effect is profound, i.e., an extended period of time lapses after the

antibiotic concentration drops below the MIC before regrowth occurs of organisms that remain viable after

initial antibiotic exposure. On the other hand, exposure to other antibiotics (e.g., most macrolides) inhibits

growth only until the antibiotic concentration drops below the MIC. Differences probably reflect molecular

mechanisms of antibiotic activity by target site (e.g., ribosome or cell wall), the avidity of antibiotic binding to

the target site, the rate of elimination of the antibiotic from the target site, and whether the damage to the

target site structure is reversible or irreversible.

Although growth of a populat ion of organisms can generally be inhib ited at a certain antibiotic

concentration (the MIC), as defined by standard laboratory techniques, antibiotic dosages that lead to less

frequent emergence of resistance can be better defined using h igher inocula than those employed in

standard clinical assays. Mechanisms of resistance include spontaneous nucleic acid mutations leading to

amino acid changes that result in less avid target site binding. These single-step mutations often may lead

to a slightly higher MIC for the mutant. The antibiotic concentration required to inhibit the single-step

mutation may or may not be achievable in infected tissues. Second-step mutations in viable organisms

during continual exposure to an antibiotic can lead to more profound changes in the MIC, rendering the

organisms fully resistant at the highest tissue concentrations attainable. It is often possible to identify the

concentration o f antibiotic required to prevent the selection of viable single-step mutants, the mutantprevention concentration (MPC), which is often two- or threefold higher than the standard MIC. [6] [7] If the

higher dosage required for the MPC can be achieved in tissues without undue toxicity, the risk of selecting

antibiotic-resistant strains that can subsequently affect that child or his/her contacts may be reduced.

Step 7: Consider Target Attainment

In treating any child, the practitioner must assess the seriousness of the infection, and the risk of injury or

death if the an tibiotic is not effective. For infections that a re bothersome (e.g., impetigo), but not

life-threatening, achieving a cure rate of 70% to 80% with a safe and inexpensive antibiotic is often

acceptable, especially if use of an a lternative agent to achieve a 98% success rate has excessive risk of

toxicity or high cost. For other infections that cause a degree of suffering or risk of organ damage (e.g.,

pyelonephritis or acute otitis media), the cure rate of 80% to 90% is often desirable. For serious,

life-threatening infections (e.g., bacterial meningitis or septicemia in a neutropenic child), a cure of 100%must be achieved. [3] No formal list of approved cure rates, also called target attainments, exists.

Accepted target attainment may diffe r between d iseases, physicians, families, and societ ies. Collaborative

understanding of the range of targeted cure rate is applicable to each child with any infection, from the

premature infant with urosepsis, to the child with congenital heart disease and endocarditis, to the child

with scoliosis and a device-associated infection. Setting targets can help clarify decision-making regarding

relative merits, risks, and costs of management.

Step 8: Separate Empiric and Definitive Therapeutic Decisions


6 de 25 05-04-2010 2


7/25

Empiric therapy is selected based on the presumed pathogens at the site of infection, the local resistance

patterns of the presumed pathogens as outlined above, and the desired cure rates selected by the

clinician. In general, the sicker child demands treatment dosages and antibacterial activity associated with

a higher rate of cure. Therefore, antibiotics with appropriately broad antibacterial activity at the highest

tolerated dosage are selected for empiric therapy. Data suggest that adequate empiric therapy compared

with inadequate empiric therapy for seriously ill adults is associated with decreased mortality and shorter

hospital stays. [8] [9] [10] For the seriously ill child, knowledge of the local resistance patterns for suspected

pathogens should lead to selection of antibiotics with a likely achievable cure rate of greater than 95%.

Less critically ill children may not require broad-spectrum agents as empiric therapy, particularly if cultureresults can provide information within 48 to 72 hours on the most appropriate narrow-spectrum antimicrobial

therapy, and the risks of delayed appropriate therapy are acceptable to the clinician and the family.

Combination therapy is frequently given to ensure the appropriate antimicrobial activity against potential

pathogens. Combination of vancomycin plus a third-generation cephalosporin is used for empiric treatment

of community-acquired meningitis, as Streptococcus pneumoniae with decreased susceptibility to -lactam

agents is a concern. Empiric therapy for meningitis in the first 2 months of life consists of ampicillin plus an

aminoglycoside or third-generation cephalosporin because the possible causative agents include Listeria

monocytogenes, group B streptococcus, and Escherichia coli. Long-established combination therapies or

broad-spectrum monotherapy is currently recommended for febrile neutropenic patients to ensure activity

against Pseudomonas aeruginosa, enteric gram-negative bacilli, and Staphylococcus aureus. [11] Because

particular organisms are indigenous to a center, because differences exist in underlying diseases,

treatments and host factors in children, and because different nosocomial pathogens are prevalent inchildren's centers versus adults' centers, caution is urged against simple adoption of strategies reported to

be efficacious in adults.

Once the pathogen is identified, a narrow-spectrum agent can frequently provide the same degree of

bacterial eradication and clinical efficacy with decreased toxicity, decreased selective pressure, and

decreased cost. For example, initial therapy with a carbapenem agent for ventilator-associated pneumonia

can be narrowed to cefotaxime if the pathogen isolated is a susceptible Klebsiella species rather than

Pseudomonas aeruginosa. A postoperative wound infection treated with vancomycin and cefotaxime can

be narrowed to ampicillin if a susceptible E. coli, rather than methicillin-resistant Staphylococcus aureus

(MRSA) orEnterobacterspecies, is isolated. For an outpatient with a cutaneous abscess presumed to be

caused by S. aureus, empiric clindamycin can be replaced with an oral first-generation cephalosporin or

beta-lactamase-stable penicillin if the organism is not MRSA. In this way, the lifespan of clindamycin as an

antistaphylococcal agent may be p rolonged by decreasing exposure.

Definitive, convalescent outpatient therapy of serious infections initially treated in the hospital can be

acceptable if the risks of complications of the infection are negligible, the parents and child can adhere to

well defined management plans and can return to hospital quickly for any infection- or therapy-related

problem. Situations exist in which either convalescent oral therapy or convalescent parenteral therapy is

preferred. High-dose beta-lactam therapy orally for bone and joint infections is one of the best evaluated

step-down therapies of invasive infection. [12] Outpatient parenteral convalescent therapy (intravenous or

intramuscular) of serious bacterial infections is sometimes chosen when adherence to oral antibiotic

therapy is a concern, or vomiting or diarrhea could affect absorption of drug given o rally. Although

antibiotics that can be administered once daily such as ceftriaxone are advantageous, specific

susceptibility of the pathogen and non protein-bound antibiotic concentrations at the tissue site also must

be considered. An agent with narrow or better targeted activity that requires multiple daily administrations,

or multiple agents, has been administered successfully in outpatients. [13]

Step 9: Special Considerations

Considerations of drug allergy for a particular agent, agents of the same type, or agents in the same class

impact selection. The degree and type of drug reaction should be obtained. The history of a morbilliform

rash in a child 4 days after commencing amoxicillin therapy does not carry the same risk of a serious drug

reaction as the history of hives and airway obstruction following the first dose of amoxicillin. Cost

considerations have become a greater issue as health insurers and governmental agencies develop


7 de 25 05-04-2010 2


8/25

antibiotic formularies that contain approved, less costly antibiotics with a narrow spectrum of activity. The

antibiotic resistance pattern of the suspected pathogen provides guidance for the likelihood of cure using

a particular agent. As antibiotic resistance in a community increases and failures with older, less active

agents increase proportionately, formularies must be reassessed. An acceptable risk of fa ilure needs to be

determined by the treating physicians and medical advisors to the health plan formularies to allow families

to achieve acceptable cure rates and continue to have confidence in their healthcare providers.

ANTIMICROBIAL SUSCEPTIBILITY TESTING AND INTERPRETATION

The primary purpose of performing antimicrobial susceptibility testing on clinical isolates is to guide

individual therapeutic decisions and amass collective data to apply when a pathogen is predicted but not

proved. A detailed discussion of susceptibility testing is presented in Chapter 286 , Laboratory Diagnosis of

Infection Due to Bacteria, Fungi, Parasites, and Rickettsiae. Susceptibility testing is routinely unnecessary

for only a few bacteria, which might include organisms that are predictably susceptible to penicillins, for

example, Streptococcus pyogenes and other -hemolytic streptococci, anaerobic streptococci, clostridia,

Eikenella corrodens, and Pasteurella multocida. Testing is important for the vast majority of clinical isolates

as they can display one or more mechanisms of antibiotic resistance or different susceptibility patterns in

different regions of the world or in different patient populations. A comparison of the antibiograms from

cultured pathogens can provide guidance for interpretation of the clinical relevance of two or more isolates

from an individual patient (e.g., coagu lase-negative staphylococci as a true pathogen vs. contaiminant) or

in preliminary assessment of a nosocomial outbreak (e.g., gram-negative bacilli) prior to the use of more

sophisticated molecular techniques to differentiate pathogens within a species.

Interpretation of Susceptibility Test Results

An assortment of routine susceptibility tests can be performed, including the disk diffusion (BauerKirby)

test, an antibiotic strip gradient-diffusion method (E-test), agar dilution with a mechanized inoculator, broth

macrodilution or microdilution (with or without the use of an instrument or a growth indicator), and the short-

incubation automated instrument method. [14] [15] Results are usually provided as a measure of the

inhibition of growth of a defined inoculum of organisms following incubation in the presence of defined

concentrations of an antibiotic. The two most common methods employed to assess susceptibility are the

minimum concentration of antibiotic required for inhibition of growth in micrograms/mL (MIC), and the

measured diameter in millimeters of inhibition of growth around an antibiotic-containing disk in the

BauerKirby disk diffusion technique. The MIC value provides an operational definition of a strain's intrinsic

antibiotic susceptibility, generally incorporating the additive effects of multiple mechanisms of resistance, if

present. Standardizing these susceptibility techniques and interpretation has largely been the task of the

Clinical and Laboratory Standards Institute (CLSI, formerly National Committee on Clinical Laboratory

Standards, or NCCLS). This nonprofit organization is comprised of participants from the pharmaceutical

industry, the testing device manufacturers, the CDC, the FDA, and academic institutions.

Interpretation and clinical application of MIC values are required. [16] Misunderstanding of the absolute

values of the MICs can lead to errors in antibiotic management. Examples of misinterpretation could be

that ampicillin and gentamicin MICs of 4 g/mL forE. colidenote equivalence, or that the vancomycin MIC

of 1 g/mL and the ampicillin MIC of 2 g/mL forEnterococcus denote the superiority of vancomycin. The

variables of the former were discussed in the landmark report by Ericsson & Sherris, [17] which formed the

basis for the categoric interpretations recommended by Bauer and colleagues [18] and the CLSI. [19]

The interpretation of the susceptitibility test results is provided by the laboratory report as S (sensitive), I

(intermediate), or R (resistant). A report of S suggests that treatment with standard FDA-approved

dosages could be expected to lead to clinical success if tissue concentration of drug at the infected site

mimics the serum concentration. A report of I suggests that some clinical failures can be expected at

standard dosages due to decreased susceptibility of the pathogen to that antibiotic. A report of R

suggests that a microbiologic cure is unlikely as the pa thogen is not inhibited by the antibiotic at

achievable tissue concentrations. Susceptibility testing predicts failure better than success. Categorization

is most valid when MIC values indicate a widely spaced, distinctly bimodal distribution of susceptible and

resistant strains, such as Staphylococcus aureus for penicillin and Escherichia colifor ampicillin. The MIC

values at which an organism is considered S, I, or R are called the breakpoints. [16] The uniformity imposed


8 de 25 05-04-2010 2


9/25

by arbitrary breakpoints for interpretation is frequently not microbiologically sound, such as in the

continuum of MIC values of penicillin forStreptococcus pneumoniae or MIC values of aminoglycosides for

P. aeruginosa. [20] The interpretion of the clinical relevance of MICs is based on: (1) the susceptibility of

isolates in a large population (range and mode of distribution, such as unimodal, bimodal, skewed); (2) the

clinical pharmacology of the drug (protein binding, volume of distribution, tissue concentations); and (3)

clinical and microbiologic efficacy derived from prospective animal models and clinical investigations.

At the time an antibiotic is f irst approved for use by the FDA, MIC interpretative b reakpoints are assigned to

the antibiotic for various pathogens (sometimes at specific tissue sites). As organisms develop newmechanisms for resistance, the interpretation of the susceptibility test results (the breakpoints) for a

particular organism and a particular antibiotic can change. For example, when ceftriaxone was first

approved for use in children, S. pneumoniae was considered susceptible if the MIC value was 8 g/mL.

Pneumococci then developed a novel mechanism of resistance, alterations in the penicillin-binding site on

the cell-wall-synthesizing transpeptidase enzymes. Beginning in 1990, microbiologic failures in the

treatment of meningitis occurred in children infected by organisms with ceftriaxone MIC of 2 g/mL. The

breakpoints were subsequently changed so that on ly organisms with MIC 0.5 g/mL were considered

susceptible. However, with the knowledge that ceftriaxone concentrations in tissues other than the CSF

are higher, prospective data were collected that documented clinical and microbiologic success of

ceftriaxone for noncentral nervous system infections in which the MIC forStreptococcus pneumoniae was

2.0 g/mL. Subsequently, two breakpoints for ceftriaxone were proposed: a lower breakpoint of 0.5

g/mL for central nervous system infection, and a h igher breakpoint of 1.0 g/mL for noncentral nervous

system infections.

The process of regular review of breakpoints for important pathogens against commonly used antibiotics is

not well standardized. The clinician can never assume that an antibiotic will be effective in all clinical

situations when the MIC leads to an S interpretation in the laboratory report. Furthermore, since S only

indicates likely inhibition, the need for a bactericidal agent under certain conditions must be considered.

SITE OF INFECTION

As a rule, only free, nonprotein-bound drug is active in eradicating pathogens. For -lactam agents,

excessive concentrations of antibiotic present at the site of infection are not more efficacious in bacterial

eradication, as this class of agents displays time-dependent killing. Higher concentrations at the site of

infection may enhance killing for aminoglycosides and other concentration-dependent drugs. [21]

Subinhibitory concentrations are not always ineffective; however, morphology and adherence properties

can be altered after exposure to subinhibitory concentrations of some antibiotics, with phagocytosis and

intracellular killing enhanced by neutrophils.

Extracellular Infections

Most bacterial infections occur in interstitial tissue fluid. For such infections, serum concentrations of

antibiotics generally predict responses adequately. Antibiotics leave the vasculature and enter the

extracellular fluid (ECF) via passive diffusion. When the ratio of the surface area of vascular tissue to the

site or volume of infection (SAV/V) is high (e.g., in cellulitis, pneumonia, pyelonephritis), antibiotic

concentrations at that site are predicted by p rinciples of passive diffusion. This is not the case when the

volume of infection exceeds the surface a rea of the vasculature (e.g., abscess, fibrin clot, cardiac

vegetation, skin blister, or tissue cage animal model). Passive diffusion principles alone also cannot be

used to predict the ECF concentration of certain antibiotics at sites with active transport (e.g., urine or bile)

or with a barrier to capillary permeability (e.g., into the ocular aqueous humor and CSF). The ability ofantibiotics to pass through membranes by nonionic diffusion is related to lipid solubility. Lipid-soluble

agents such as rifampin, chloramphenicol, trimethoprim, and isoniazid penetrate membranes and cross the

bloodbrain barrier better than do the more highly ionized aminoglycosides. For meningitis, relatively large

dosages of third-generation cephalosporins, penicillin G, ampicillin, or vancomycin are required in order to

achieve adequate concentrations in the CSF. Additionally, active transport out of the ECF, including the

CSF, can also result in reduced concentrations of certain antibiotics such as -lactam agents.

Table 292-1 delineates the distribution characteristics of the major classes of antibiotics. Clinical evidence


9 de 25 05-04-2010 2


10/25

has indicated the inferiority of antibiotics used for the treatment of infection at sequestered tissue sites

where penetration is poor (e.g., brain, eye, bone), and logical preference exists for the use of antibiotics

known to accumulate at the site of infection (e.g., urine, bile). The vegetations of endocarditis, devitalized

tissue, and bones are areas in which the penetration of most agents may be poor; high-dose and

prolonged parenteral therapy is usually required, and surgical debridement is sometimes adjunctive or

necessary therapy. The pharmacology of the drug can o ffer particular advantages. Agents eliminated by

glomerular filtration, renal tubular secretion, or both accumulate in urine. Quinolones, a few -lactam

agents (such as ampicillin, ceftriaxone and especially cefoperazone), and doxycycline are actively

transported into bile, whereas first-generation cephalosporins and aminoglycosides diffuse passively.Clindamycin and the fluoroquinolones achieve excellent concentration in bone.

The primary effects of the protein binding of antibiotics are slowing of excretion by glomerular filtration and

a reduction in the volume of distribution. Although only free drug passes through capillary walls and fibrin

clots, intercompartmental and pathogen end-target dynamic changes in binding, reversibility, and complex

interactions at the tissue site probably account for the complexities in interpretation of clinical efficacy as a

result of the degree of protein binding. Only free drug is considered capable of antibiotic activity. [22] Most

examples of the poor activity of highly protein-bound drugs involve staphylococci. Multiple biologic factors

affect the extent of protein binding: antibiotic concentration, the nature and concentration o f protein, pH,

lipid solubility, competition with other drugs or biologic components (e.g., bilirubin or fatty acids), and

disease states such as uremia. In general, the p lasma protein binding of aminoglycosides and quinolones

is low, whereas binding is low to very high for -lactam agents. A high degree of protein binding precludes

the use of sulfa drugs, ceftriaxone, and nafcillin in jaundiced neonates because the potential competitivedisplacement of bilirubin from albumin facilitates the diffusion of bilirubin into the brain.

Multiple factors at the site of infection can also alter antimicrobial activity. Examples include the presence of

purulent material, which can bind and inactivate aminoglycosides; copathogens such as Bacteroides and

Prevotella, which produce -lactamase and can hydrolyze -lactam agents [23] ; hematoma, which lowers

the SAV/V and contains hemoglobin that binds penicillins and tetracyclines [24] ; low oxygen tension in

abscesses or ischemic tissue, which impairs active transport of aminoglycosides into bacterial cells; acid pH

in tissue or urine, which impairs the activity of aminoglycosides, nitrofurantoin, and methenamine; alkaline

pH, which enhances the activity of aminoglycosides and clindamycin; high-density infection such as

streptococcal necrotizing fasciitis, which slows the bacterial growth rate, thereby downregulating target

transpeptidases for -lactam agents [25] ; and the presence of a foreign body, which protects the organism

from host bactericidal mechanisms.

Intracellular Infections

The unique properties of antimicrobial agents must be considered when the site of infection is intracellular

because many antibiotics do not penetrate eukaryotic cells (see Table 289-1 ). -Lactam antibiotics, for

example, are almost exclusively confined to plasma water and the interstitial fluid space. Such localization

explains some discrepancies between apparent in vitro activity and therapeutic ineffectiveness; the

performance of susceptibility tests in cocultivation with phagocytic cells may be more predictive. Intracellular

pathogens include Listeria monocytogenes, Salmonella, Brucella, Legionella, Mycobacterium, Rickettsia,

and Toxoplasma, as well as persisting infections with Staphylococcus aureus and E. coli. Antibiotics that

enter cells do so by a variety of mechanisms, such as diffusion of relatively small lipid-soluble agents across

a concentration gradient, pinocytosis of water-soluble agents, and carrier-mediated transport. [26] Cellular

accumulation of drug does not necessarily translate into efficacy against intracellular organisms; efficacy

depends on whether the microbe and the drug are at the same intracellular site, how avidly the d rug isbound, and the molecular charge of the intracellular antibiotic.

Aminoglycosides accumulate slowly in intracellular lysosomes and mitochondrial organelles, where they

bind irreversibly and thus have no antibacterial effect. Clindamycin, macrolides, and azalides are tropic for

lysosomes, where they become protonated and concentrated. [26] This change can enhance therapeutic

efficacy, but in one study, neither agent was active against susceptible strains ofS. aureus within

neutrophils. [27] Quinolones have a large volume of distribution and a h igh tissue-to-serum ratio, and

low-affinity intracellular binding; much of the quinolone body load is thus present intracellularly. For


0 de 25 05-04-2010 2


11/25

azithromycin, an even more dramatic intracellular location of antibiotic has been documented, particularly

within phagocytic cells. The pharmacokinetic properties and intracellular accrual of azithromycin are

responsible for unique applications and shortened courses of therapy [28] [29] ; at the same time, it is

noteworthy that drug concentrations in serum, CSF, and the aqueous humor of the eye a re almost

negligible. [30]

DOSING, ROUTE, AND DURATION OF THERAPY

Optimal dosing of an antimicrobial agent depends on relationships between the concentration at the site ofinfection, the characteristics of antimicrobial activity, and the particulars of its elimination and adverse

effects (see Chapter 291 , PharmacokineticPharmacodynamic Basis of Optimal Antibiotic Dosing).

Unfortunately, the optimal route of administration of antibiotics is often exchanged for the optimal setting of

administration. Parenteral administration is required if an agent is poorly absorbed from the gastrointestinal

tract, if a condition precludes administration or absorption of a usually absorbed drug, if an unusually high

tissue concentration of drug is required, or if adherence to an oral regimen for treatment of a significant

disease cannot be ensured. Otherwise, substitution o f oral for parental agents is frequently possible, even

for serious diseases (e.g., pneumonia, osteomyelitis, pyogenic arthritis, orbital cellulitis) during convalescent

therapy.

Oral therapy can replace parenteral therapy when highly absorbed agents are used to treat h ighly

susceptible pathogens (e.g., trimethoprim-sulfamethoxazole forPneumocystis carinii), when the tissue

concentrations of drugs at relevant sites are uniquely favorable (e.g., clindamycin or fluoroquinolone in

bone), and when the pa tient adheres to the p lan for use of oral agents (at home or in the hospital). With a

less favorable profile, parenteral therapy is given for the entire duration of therapy (at home or in the

hospital). Abundant evidence for the effectiveness of many approaches is available when patient

screening, selection of medical conditions, and follow-up are performed diligently. [13] [31] [32] Advocacy for

the best treatment of a child's infection, with the risk of failure of therapy and the impact of the outcome

taken into account, is the paramount consideration.

The duration of antibiotic therapy is determined more by experience than by experiment for most infections.

Endocarditis is a possible exception. [33] Many factors are considered in the decision regarding the

duration of therapy, including the intrinsic pathogenicity of the microbe, susceptibility to the agent used,

the site of infection and penetration of the antibiotic, the use of synergistic combination therapy, the

replication rate of the pathogen, the presence of a foreign body, and host factors that impair bactericidal

capacity. In many situations, the severity of infection in all children is not uniform (e.g., pyelonephritis,

soft-tissue abscess), leading to differences in the timecourse of the child's response to antibiotic therapy.

In children with pneumonia, treatment may be given parenterally until a clinical (and presumed

microbiologic) response has occurred, then oral convalescent therapy can be provided for a defined time to

achieve the desired to tal duration of therapy. With all infections, a recommendation for duration of therapy

is based on the best available information for that child's infection. Longer treatment courses may be more

appropriate for more resistant organisms, or for immune-compromised hosts, as delayed eradication of

pathogens from the site of infection can occur in both of these situations. The family should always be

cautioned at the end of the treatment course to be alert for the signs and symptoms of relapse. Table

289-2 presents examples of the duration of treatment based on scientific information (when available),

consensus, or experience.

TABLE 289-2 -- Duration of Systemic Antibiotic Therapy for Certain Bacterial Infections

Infection

Duration of

Therapy Comments/Duration within Range

Cellulitis/impetigo 10 days Few data

Orbital cellulits 10 days or

longer

Depending on the pathogen (Haemophilus influenzae,

Streptococcus pneumoniae shorter) and predisposition


1 de 25 05-04-2010 2


12/25

Infection

Duration of


(chronic sinusitis in adolescent longer)

Pharyngitis

(streptococcal) [72]10 days

Acute otitis media [28] [73] 10 days 1-, 3-, and 5-day courses may be adequate in certa in cases

(older age, rapid response, otoscopic improvement) with certain

antibiotics (azithromycin, and certain oral beta-lactams agents)

Acute sinusitis [74] 1421 days At least 1 week after resolution of symptoms

Acute mastoiditis 14 days or

longer

Generally at least 1 week afebrile

Uncomplicated pneumonia 10 days Few data; genera lly at least 5 days afebrile

Complicated pneumonia

(necrotizing or with lung

abscess, empyema)

1421 days or

longer

Depending on the clinical response, drainage, pathogen

(Staphylococcus aureus, Streptococcus pyogenes longer;

Haemophilus influenzae, anaerobes shorter); generally at

least 1 week afebrile after drainage ceases)

Purulent pericarditis 1014 days or

longer

Depending on the pathogen (Staphylococcus aureus, enteric

bacilli longer; Neisseria meningitidis shorter); generally at

least 710 days afebrile

Endocarditis (native

valve) [46]

Penicillin-susceptible

viridans streptococcus or

Streptococcus bovis

Penicillin, 28

days;

or

Penicillin, 14

days

plusGentamicin, 14

days; [a]

or

Vancomycin, 28

days

Penicillin-nonsusceptible

viridans

Pencillin, 28

days

Penicillin streptococcus or

Streptococcus bovis

plus

Gentamicin, 14

days [a]

or

Vancomycin, 28

days

Enterococcus species

(moderately susceptible to

ampicillin) [b]

Penicillin,

or

ampicillin, 46

weeks

Vancomycin,

Depending on the duration of symptoms (< 3 months shorter;

> 3 months longer)


2 de 25 05-04-2010 2


13/25

Infection

Duration of


plus

Gentamicin, 46

weeks [a]

Methicillin-susceptible

Staphylococcus aureus [c]

Nafcillin or

vancomycin, 46weeks

plus

Optional

gentamicin, 35

days [a]

Methicillin-resistant Vancomycin,

46 weeks

Additional therapy with aminoglycoside or rifampin also is given

frequently

Staphylococcus aureus [c]

HACEK microorganisms Ceftriaxone, 28

days

or

Ampicillin plus

gentamicin, 28

days [a]

Meningitis [75]

Group B streptococcus 14 days or

longer

Gentamicin is also given frequently for 72 hours and until CSF

is proved sterile; if isolate is penicillin-tolerant, gentamicin is

continued

Listeria monocytogenes 14 days or

longer

Gentamicin is also given usually for 72 hours and until CSF is

proved sterile

Enteric gram-negativebacilli

21 days orlonger

At least 21 days and 14 days after CSF is proved sterile,whichever is longer; longer depending on the presence of

infarction, abscess

Streptococcus

pneumoniae

1014 days A least 710 days after CSF is proved sterile; the duration of

therapy for pneumococci that are penicillin-nonsusceptible is

not known

Haemophilus influenzae 10 days

Neisseria meningitidis 57 days

Brain abscess 2128 days or

longer

Depending on the pathogen (gram-negative bacilli longer),

drainage (at least 1014 days after drainage), and diminution

on imaging study

Pyelonephritis 1014 days

Cystitis 710 days

Acute pyogenic arthritis 1421 days o r

longer

Depending on the course, prompt and adequate drainage,

pathogen (Staphylococcus aureus longer), and site (hip or

shoulder longer); generally at least 710 days afebrile and


3 de 25 05-04-2010 2


14/25

Infection

Duration of


after last drainage; therapy for 35 days has been adequate

for gonococcal arthritis in adults

Acute osteomyelitis 2142 days o r

longer

Depending on the course, drainage, and pathogen

(Staphylococcus aureus, enteric bacilli longer); generally at

least 1014 days afebrile and until the sedimentation rate isalmost normal

Bacteremia without tissue

focus

5-7 days or

longer

Depending on the underlying condition, persistence of positive

blood culture, and pathogen (Staphylococcus aureus, enteric

bacilli longer); at least 35 days afebrile

Data forTable 289-2from references 3739.

References forTable 289-2 : 3739, 69, 72-75.

Abbreviations: CSF, cerebrospinal fluid; HACEK, Haemophilus aphrophilus, Actinobacillus

actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae.

a The gentamicin dose is 3 mg/kg ideal body weight per day.

b Simila r therapy is given for penicillin -resistant viridans streptococcus (minimal inh ibitory concentration, > 0.5 Lig/mL), for

nutritional ly variant viridans streptococcus, and for prosthetic valve endocard itis caused by viridans streptococcus orStreptococcus

bovis.

c In the presence o f a prosthetic valve or o ther material, nafcillin or van comycin is given for 6 weeks.

ANTIMICROBIAL COMBINATIONS

Prevention of Emergence of Resistance

Antibiotics are sometimes used in combination in an attempt to create synergy, or to prevent or delay the

emergence of drug-resistant subpopulations of the pathogen. In most circumstances, data are insufficient

to prove these effects. [3] [4] Mycobacterium tuberculosis provides the best clinically documented example.

With a spontaneous mutation frequency of approximately 10 -8 , the initial use of two or more agents to

which the organism is susceptible reduces the probability that resistant organisms can emerge to a very low

level. Treatment ofPseudomonas infection with a -lactam, quinolone, or aminoglycoside antibiotic alone is

associated with the emergence of resistant strains; dual-combination therapies may reduce the incidence

of resistance to either component. [35] However, each antibiotic must provide the necessary exposure to

pathogens in the infected tissues to ensure eradication of susceptible organisms. Inadequate dosing or

poor tissue penetration of one antibiotic in a combination may lead to the selection of organisms resistant

to that agent, despite the use of dual therapy.

Rifampin is one antibiotic that is never used alone for the treatment of infection because o f the rapid

development of resistance. Combining rifampin with vancomycin for coagulase-negative staphylococcal

prosthetic valve endocarditis or ventriculoperitoneal shunt infection, or with a semisynthetic penicillin forS.

aureus infections, may reduce the emergence of resistance while taking advantage of the unique

properties of rifampin.

Alteration of Pharmacokinetics

The coadministration of a drug such as the uricosuric agent probenecid, which has no intrinsic antimicrobial

activity, can have a significant impact on efficacy by delaying the renal excretion of a penicillin, thus

increasing the time above MIC at the site of infection. Similarly, cilastatin, an inhibitor of renal


4 de 25 05-04-2010 2


15/25

dehydropeptidase, has no intrinsic antimicrobial activity but, in fixed combination with imipenem, prevents

the degradation of imipenem and increases the serum half-life.

Inhibition of -Lactamases

Sometimes the site of action of a drug is not the vital microbial target binding site but a product of the

microbe rendering resistance to antimicrobial agents. Antistaphylococcal penicillins such as methicillin and

nafcillin are degraded by staphylococcal -lactamases. -Lactamase-inhibiting agents such as clavulanic

acid, sulbactam, and tazobactam each display a specific affinity for and a degree of irreversible binding tothe various bacterial -lactamase enzymes, thereby protecting the companion -lactam antibiotic from

hydrolysis and permitting its access to the penicillin-binding proteins. [36] [37] Amoxicillin-clavulanate is

especially useful in children when the potential causative pathogens are susceptible to amoxicillin except

for the presence of -lactamases produced by the pathogen (Moraxella catarrhalis, Haemophilus

influenzae, Staphylococcus aureus, and Bacteroides fragilis). Piperacillin-tazobactam is a useful agent that

extends the spectrum of activity of piperacillin to include additional gram-negative bacilli and methicillin-

susceptible staphylococci; it does not, however, enhance the activity of piperacillin against Pseudomonas

as tazobactam does not effectively inhibit many of the beta-lactamases produced by P. aeruginosa.

Synergy

Target Site Synergy

Combinations of an timicrobial agents can have a variety of effects on the target sites of a g iven organism

in vitro. The combination can be: (1) synergistic, when the combined effect of the drugs is significantly

greater than the independent effects when the drugs are tested separately; (2) antagonistic, when the

combined effect is significantly less than the drugs' independent effects when tested separately; (3)

additive, when the combined effect is the sum of the separate effects of the drugs tested; or (4) indifferent,

when the combined effect is simply the effect of the more active drug alone. The first two definitions are

dependent on the last two definitions, which are controversial and in turn depend on the intrinsic activities

of each antibiotic on an organism, the test system used, and whether the b inding site is similar or

dissimilar. [38] [39] [40] Despite the paucity of clinically validated in vitro results, [41] there is good reason to

believe that synergy has clinical relevance. [42] The notion remains appealing because the outcomes of

certain severe clinical infections that are dependent on rapid bacterial killing may be better compared with

monotherapies, and enhanced eradication of pathogens may allow for a possible shortened course of

therapy. Although it is not practical to perform studies in most clinical settings, concepts regarding classes

of drugs and microbes have evolved to guide therapeutic choices.

An exposition of the laboratory methods used to detect the effects of combinations of antibiotics is

available elsewhere [39] ; summary points about commonly used tests are made here. The broth or agar

dilution checkerboard technique evaluates the inhibitory effect at a single point in time after 18 to 24 hours

of incubation. Synergy is present when a t least a fourfold reduction in the MIC of each antibiotic occurs

when the agents a re combined as compared with the MIC of each antibiotic tested separately, whereas

antagonism results in corresponding increases in the MICs when antibiotics are combined ( Figure 289-1 ).

The time-kill curve methodmeasures the bactericidal effect at predetermined intervals (4, 8, or 24 hours)

during incubation and compares the rate of killing by combinations of drug and d rugs tested separately (

Figure 289-2 ). These methods are time-consuming and lack the ability to detect an additive response or

synergy if both drugs have potent activity; furthermore, drug concentrations are constant over the timed

experiment, and there is not agreement whether relevant concentrations of agents should be above or

below the MIC. An E-testsynergy method is also available. [43]


5 de 25 05-04-2010 2


16/25

Figure 289-1 The results of three theore tical checkerboard microd ilution tests showing additive (A), synerg istic (B), and

antagonistic (C) effects of drugs A and B. Visible turbid ity exists in each darkened well due to bacterial g rowth. The min imum

inhibitory concentration (MIC) of each an tibiotic tested alone aga inst this organism is 2.0 g/mL. Doubling antibio tic

concentrations for drug A are present on the abscissa and for drug B on the ordinate.


6 de 25 05-04-2010 2


17/25

Figure 289-2 Quantitative bacterial killing curves illustrating the (A) indifferent, (B) synergistic, and (C) antagonistic effects of

two theo retical antibiotics (A and B) at specific concentrations aga inst a single o rgan ism.

The basic checkerboard antibiotic interaction method is standardized by the CLSI, and reproducible in

assessing inhibition of growth. However, drug interactions providing bactericidal activity or antagonism are

less well standardized, [44] and have not been well correlated with clinical outcomes. An example is testing

of the combination of a -lactam agent plus an aminoglycoside against resistant strains ofP. aeruginosa;checkerboard tests can show indifference while killing curves show synergy. [38] Another example is the

combination of ampicillin or vancomycin with an aminoglycoside against enterococci, which shows

synergistic killing without enhancement of inhibition.

Inhibition of Multiple Interrelated Targets

A classic example of synergy of targeted activity at consecutive metabolic steps is represented by the

combination of a sulfonamide with a dihydrofolate reductase inhibitor such as trimethoprim. The resulting


7 de 25 05-04-2010 2


18/25

inhibition of consecutive steps in the folic acid pathway results in a significantly reduced MIC and can also

enhance the drug's bactericidal capacity. Streptogramin antibiotics (quinupristin-dalfopristin) include two

biochemically distinct bacteriostatic compounds produced by Streptomyces that produce bactericidal

activity when used in combination. The binding of the type A streptogramin at the acyl-amino tRNA

acceptor site on the ribosome both prevents the b inding of tRNA and also causes a conformational

change in the ribosome, which enhances the binding of the type B streptogramin, which then causes steric

hindrance to the extrusion of newly formed polypeptide chains from within the ribosome.

Combination of Cell Wall-Active Agents with Ribosomal-Active Agents

Some instances of antibiotic resistance (e.g., to aminoglycosides) can be due to a permeability barrier that

precludes the d rug reaching the intracellular target site. Agents that act on the cell wall (e.g., -lactam

agents, vancomycin) could enhance the entry of an aminoglycoside; unless the drug is rendered

ineffective by aminoglycoside-modifying enzymes or resistance occurs at the ribosomal level, a combination

would be expected to be synergistic. Such bactericidal synergy is demonstrable for viridans streptococci,

group B streptococci, enterococci, staphylococci, Listeria and Corynebacterium species, P. aeruginosa,

and Enterobacteriaceae. For gram-negative bacilli, exposure to aminoglycosides can enhance the

permeability of the outer cell envelope to -lactam antibiotics due to aminoglycoside-mediated production

of a ltered, nonfunctional proteins that are incorporated into the cell wall. Generally forEnterococcus,

streptomycin, gentamicin, and tobramycin are predictably synergistic with cell wall-active agents if the

enterococcal strain is susceptible to aminoglycosides at 2000 g/mL; laboratories provide standardized

testing at this single-drug concentration.

The superior clinical efficacy of combination over single-drug therapy has been documented in only limited

clinical settings. For the treatment of enterococcal endocarditis, penicillin alone, which provides only

bacteriostatic activity aga inst enterococci, results in an unacceptable relapse rate. The addition of an

aminoglycoside such as streptomycin or gentamicin results in clinical cure rates comparable with the rates

attained in the treatment of endocarditis caused by penicillin-susceptible streptococci. [45] Although similar

clinical benefit is demonstrable in the animal model of endocarditis caused by penicillin-tolerant or relatively

penicillin-resistant viridans streptococci (MIC of 1 g/mL), no advantage is shown against fully susceptible

strains; nonetheless, combination therapy for 2 weeks in patients with susceptible strains results in success

rates comparable to those achieved when penicillin is administered alone for 4 weeks. [46]

The combination of nafcillin plus gentamicin is synergistic in vitro against methicillin-susceptible strains of

Staphylococcus aureus; a retrospective, large controlled clinical trial of nafcillin plus gentamicin versus

nafcillin alone in adults with endocarditis failed to show any advantage o f combination therapy. [47]

Similarly, although tolerance to the bactericidal effect of -lactam agents among streptococci and

staphylococci can be overcome in vitro by drug combinations, superior clinical efficacy in human infections

has not been proved. Combinations of ticarcillin or piperacillin with gentamicin, tobramycin, or amikacin

exhibit in vitro synergy against many strains ofP. aeruginosa. One prospective, randomized clinical trial of

bacteremic cancer patients confirmed better survival with carbenicillin plus gentamicin versus carbenicillin

alone [48] ; another prospective, but uncontrolled study of 200 patients with Pseudomonas bacteremia

documented increased survival in patients receiving combinations, regardless of whether synergy was

demonstrable in vitro. [49]

Confirmatory clinical evidence of the superiority of combination therapy for bacteremia caused by other

gram-negative bacilli has been limited to neutropenic patients; such evidence documents the critical

importance of susceptibility to the -lactam component.[48] [50] [51]

With the advent of more potent, highlybactericidal agents such as the th ird-generation cephalosporins and carbapenems. The benefit of the

addition of an aminoglycoside may be d ifficult to demonstrate except under the most challenging clinical

conditions of sequestered pathogens and an absent host response at the site of infection. Prospective,

controlled studies under these conditions are not likely to be performed.

In vitro synergy of clindamycin and gentamicin has been reported against some strains of viridans

streptococci and antagonism against others. [52] Limited studies have shown synergy of trimethoprim-

sulfamethoxazole p lus amikacin against Enterobacteriaceae (organisms that are susceptible to both


8 de 25 05-04-2010 2


19/25


20/25

reduced excess prescribing. Programs for judicious use have been studied in private practice, managed

care organizations, emergency departments, and community clinics. [64] Successful reductions in

prescribing have been documented when groups in active intervention programs that include both

physicians and patients have been compared with groups receiving no intervention other than information.

Most importantly, decreased antibiotic use has not led to increased complications. [64] [65] Nationwide

trends toward decreased prescribing for upper respiratory tract conditions in the United States [66] [67] have

been documented. More limited but convincing evidence exists that the decrease in prescribing is leading

to slowing o f the spread of resistant bacteria. [29] [68] [69]

Guidelines for Antibiotic Stewardship from the Inffectious Diseases Society of America outlines strategies

to promote appropriate antibiotic selection and duration of therapy and evaluate the potential impact on

the development of antibiotic resistance. [70] Unfortunately, there are no prospective investigations of

impact of improved practices on a decrease in documented infections caused by antibiotic resistant

pathogens in children.

References

1. Fredricks DN, Relman DA: Application of polymerase chain reaction to the diagnosis of infectious diseases.

Clin Infect Dis 1999; 29:475-486.quiz 487-478.

2. Levison ME: Pharmacodynamics of antimicrobial drugs. Infect Dis Clin North Am 2004; 18:451-465.vii

3. Bradley JS, Dudley MN, Drusano GL: Predicting efficacy of antiinfectives with pharmacodynamics and Monte

Carlo simulation. Pediatr Infect Dis J 2003; 22:982-992.

4. Kearns GL, Abdel-Rahman SM, Alander SW, et al: Developmental pharmacology - drug disposition, action,

and therapy in infants and children. N Engl J Med 2003; 349:1157-1167.

5. Bjorkman S: Prediction o f cytochrome p450-mediated hepatic drug clearance in neonates, infants and

children: how accurate are available scaling methods?. Clin Pharmacokinet 2006; 45:1-11.

6. Drlica K, Malik M: Fluoroquinolones: action and resistance. Curr Top Med Chem 2003; 3:249-282.

7. Hansen GT, Zhao X, Drlica K, et al: Mutant prevention concentration for ciprofloxacin and levofloxacin with

Pseudomonas aeruginosa. Int J Antimicrob Agents 2006; 27:120-124.

8. Kollef MH: Gram-negative bacterial resistance: evolving patterns and treatment paradigms. Clin Infect

Dis 2005; 40(Suppl. 2):S85-S88.

9. Micek ST, Lloyd AE, Ritchie DJ, et al: Pseudomonas aeruginosa bloodstream infection: importance of

appropriate initial antimicrobial treatment. Ant imicrob Agents Chemother 2005; 49:1306-1311.

10. Shorr AF, Kollef MH: Ventilator-associated pneumonia: insights from recent clinical trials.

Chest 2005; 128:583S-591S.

11. Hughes WT, Armstrong D, Bodey GP, et a l: Guidelines for the use of antimicrobial agents in neutropenic

patients with cancer. Clin Infect Dis 2002; 34:730-751.

12. Nelson JD: Skeletal infections in children. Adv Pediatr Infect Dis 1991; 6:59-78.

13. Tice AD, Rehm SJ, Dalovisio JR, et al: Practice guidelines for outpatient parenteral antimicrobial therapy.

IDSA guidelines. Clin Infect Dis 2004; 38:1651-1672.

14. Jorgensen JH: Laboratory issues in the detection and reporting of antibacterial resistance. Infect Dis Clin

North Am 1997; 11:785-802.

15. Jorgensen JH, Ferraro MJ: Antimicrobial susceptibility testing: special needs for fastidious organisms and

difficult-to-detect resistance mechanisms. Clin Infect Dis 2000; 30:799-808.


20 de 25 05-04-2010 2


21/25

16. Jorgensen JH: Who defines resistance? The clinical and economic impact of antimicrobial susceptibility

testing breakpoints. Semin Pediatr Infect Dis 2004; 15:105-108.

17. Ericsson HM, Sherris JC: Antibiotic sensitivity testing. Report of an international collaborative study. Acta

Pathol Microbiol Scand [B] Microbiol Immunol 1971; 217(Suppl. 217):211.

18. Bauer AW, Kirby WM, Sherris JC, et al: Antibiotic susceptibility testing by a standardized single disk method.

Am J Clin Pathol 1966; 45:493-496.

19. Methods for Dilution Antimicrobial Susceptibility Testing for Bacteria that GrowAerobically. Approved

standard M7-A5, Wayne, PA, National Committee for Clinical Laboratory Standards, 2000.

20. Sanders C: A problem with antimicrobial tests: for the sake of clinical labs and new drug development, such

tests should emphasize antibiotic resistance. ASM News 1991; 57:187-190.

21. Craig WA: Does the dose matter?. Clin Infect Dis 2001; 33(Suppl. 3):S233-S237.

22. Drusano GL: Antimicrobial pharmacodynamics: critical interactions of bug and drug. Nat Rev

Microbiol 2004; 2:289-300.

23. Brook I: In vitro susceptibility vs. in vivo efficacy of various antimicrobial agents against the Bacteroides

fragilis group. Rev Infect Dis 1991; 13:1170-1180.

24. Craig WA, Kunin CM: Significance of serum protein and tissue binding of antimicrobial agents. Annu Rev

Med 1976; 27:287-300.

25. Eagle H: Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal

infection in mice. Am J Med 1952; 13:389-399.

26. Donowitz GR: Tissue-directed antibiotics and intracellular parasites: complex interaction of phagocytes,

pathogens, and drugs. Clin In fect Dis 1994; 19:926-930.

27. Hand WL, King-Thompson NL: Contrasts between phagocyte antibiotic uptake and subsequent intracellular

bactericidal activity. Antimicrob Agents Chemother 1986; 29:135-140.

28. Gordon EM, Blumer JL: Rationale for single and high dose treatment regimens with azithromycin. Pediatr

Infect Dis J 2004; 23:S102-S107.

29. Low DE, Pichichero ME, Schaad UB: Optimizing antibacterial therapy for community-acquired respiratory

tract infections in children in an era of bacterial resistance. Clin Pediatr (Phila) 2004; 43:135-151.

30. Jaruratanasirikul S, Hortiwakul R, Tantisarasart T, et al: Distribution of azithromycin into brain tissue,

cerebrospinal fluid, and aqueous humor of the eye. Antimicrob Agents Chemother 1996; 40:825-826.

31. Bradley JS, Ching DK, Hart CL: Invasive bacterial disease in childhood: efficacy of oral antibiotic therapy

following short course parenteral therapy in non-central nervous system infections. Pediatr Infect Dis

J 1987; 6:821-825.

32. MacGregor RR, Graziani AL: Oral administration of antibiotics: a rational alternative to the parenteral route.

Clin Infect Dis 1997; 24:457-467.

33. Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to

streptococci, enterococci, staphylococci, and HACEK microorganisms. American Heart Association.

JAMA 1995; 274:1706-1713.

34. Craig WA: Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and

men. Clin Infect Dis 1998; 26:1-10.quiz 11-12.

35. Craig WA, Salamone FR: Do antibiotic combinations prevent the emergence of resistant organisms?. Infect


21 de 25 05-04-2010 2


22/25

Control Hosp Epidemiol 1988; 9:417-419.

36. Bush K: Classification of beta-lactamases: groups 1, 2a, 2b, and 2b'. Antimicrob Agents

Chemother 1989; 33:264-270.

37. Kuck NA, Jacobus NV, Petersen PJ, et al: Comparative in vitro and in vivo activities of piperacillin combined

with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam. Ant imicrob Agents

Chemother 1989; 33:1964-1969.

38. Cappelletty DM, Rybak MJ: Comparison of methodologies for synergism testing of drug combinations

against resistant strains of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1996; 40:677-683.

39. Eliopoulos GM, Moellering Jr RC:Antimicrobial combinations. In: Lorian V, ed.Ant ibiotics in Laboratory

Medicine, Baltimore: Williams & Wilkins; 1991:432-491.

40. Orhan G, Bayram A, Zer Y, et a l: Synergy tests by E test and checkerboard methods of antimicrobial

combinations against Brucella melitensis. J Clin Microbiol 2005; 43:140-143.

41. Eliopoulos GM, Eliopoulos CT: Antibiotic combinations: should they be tested?. Clin Microbiol

Rev 1988; 1:139-156.

42. Chadwick EG, Shulman ST, Yogev R: Correlation of antibiotic synergy in vitro and in vivo: use of an animal

model of neutropenic gram-negative sepsis. J Infect Dis 1986; 154:670-675.

43. White RL, Burgess DS, Manduru M, et al: Comparison of three different in vitro methods of detecting

synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother 1996; 40:1914-1918.

44. Rand KH, Houck HJ, Brown P, et al: Reproducibility of the microdilution checkerboard method for antibiotic

synergy. Antimicrob Agents Chemother 1993; 37:613-615.

45. Mandell GL, Kaye D, Levison ME, et a l: Enterococcal endocarditis. An analysis of 38 patients observed at

the New York Hospital-Cornell Medical Center. Arch Intern Med 1970; 125:258-264.

46. Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, antimicrobial therapy, and

management of complications: a statement for healthcare professionals from the Committee on Rheumatic

Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils

on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association:endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394-e434.

47. Le T, Bayer AS: Combination antibiotic therapy for infective endocarditis. Clin Infect

Dis 2003; 36:615-621.

48. Klastersky J, Glauser MP, Schimpff SC, et al: Prospective randomized comparison of three antibiotic

regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenic patients.

Antimicrob Agents Chemother 1986; 29:263-270.

49. Hilf M, Yu VL, Sharp J, et al: Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome

correlations in a prospective study of 200 patients. Am J Med 1989; 87:540-546.

50. Klibanov OM, Raasch RH, Rublein JC: Single versus combined antibiotic therapy for gram-negativeinfections. Ann Pharmacother 2004; 38:332-337.

51. Paul M, Benuri-Silbiger I, Soares-Weiser K, et al: Beta lactam monotherapy versus beta lactam-

aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and

meta-analysis of randomised trials. Br Med J 2004; 328:668.

52. Duperval R, Bill NJ, Geraci JE, et al: Bactericidal activity of combinations of penicillin or clindamycin with

gentamicin or streptomycin against species of viridans streptococci. Antimicrob Agents

Chemother 1975; 8:673-676.


22 de 25 05-04-2010 2


23/25

53. Parsley TL, Provonchee RB, Glicksman C, et al: Synergistic activity of trimethoprim and amikacin against

gram-negative bacilli. Antimicrob Agents Chemother 1977; 12:349-352.

54. Gombert ME, Aulicino TM: Synergism of imipenem and amikacin in combination with other antibiotics

against Nocardia asteroides. Antimicrob Agents Chemother 1983; 24:810-811.

55. Giamarellou H, Petrikkos G: Ciprofloxacin interactions with imipenem and amikacin against multiresistant

Pseudomonas aeruginosa. Ant imicrob Agents Chemother 1987; 31:959-961.

56. Tuazon CU, Miller H: Comparative in vitro activities of teichomycin and vancomycin alone and in

combination with rifampin and aminoglycosides against staphylococci and enterococci. Ant imicrob Agents

Chemother 1984; 25:411-412.

57. Lowy FD, Chang DS, Lash PR: Synergy of combinations of vancomycin, gentamicin, and rifampin against

methicillin-resistant, coagulase-negative staphylococci. Antimicrob Agents Chemother 1983; 23:932-934.

58. Tuazon CU, Shamsuddin D, Miller H: Antibiotic susceptibility and synergy of clinical isolates of Listeria

monocytogenes. Antimicrob Agents Chemother 1982; 21:525-527.

59. Korvick JA, Peacock Jr JE, Muder RR, et al: Addition of rifampin to combination antibiotic therapy for

Pseudomonas aeruginosa bacteremia: prospective trial using the Zelen protocol. Antimicrob Agents

Chemother 1992; 36:620-625.

60. McCaig LF, Hughes JM: Trends in antimicrobial drug prescribing among office-based physicians in the

United States. JAMA 1995; 273:214-219.

61. Dowell SF, Schwartz B: Resistant pneumococci: protecting patients through judicious use of antibiotics. Am

Fam Phys 1997; 55:1647-1654.1657-1658

62. Brook I, Gober AE: Prophylaxis with amoxicillin or sulfisoxazole for otitis media: effect on the recovery of

penicillin-resistant bacteria from children. Clin Infect Dis 1996; 22:143-145.

63. Dowell SF, Marcy SM, Phillips WR, et al: Principles of judicious use of 1 Ch289-F06687.qxd 8/28/07 11:53

AM Page 2 Ch289-F06687.qxd 8 /28/07 11:53 AM Page 2 2 SECTION B Anti-Infective Therapy antimicrobial

agents for pediatric upper respiratory tract infections. Pediatrics 1998; 101:163-165.

64. Arnold SR, Straus SE: Interventions to improve antibiotic prescribing practices in ambulatory care.Cochrane Database Syst Rev 2005;CD003539

65. Pichichero ME, Green JL, Francis AB, et al: Outcomes after judicious antibiotic use for respiratory tract

infections seen in a private pediatric practice. Pediatrics 2000; 105:753-759.

66. Finkelstein JA, Stille C, Nordin J, et al: Reduction in antibiotic use among US children, 1996-2000.

Pediatrics 2003; 112:620-627.

67. McCaig LF, Besser RE, Hughes JM: Antimicrobial drug prescription in ambulatory care settings, United

States, 1992-2000. Emerg Infect Dis 2003; 9:432-437.

68. Lieberman JM: Appropriate antibiotic use and why it is important: the challenges of bacterial resistance.

Pediatr Infect Dis J 2003; 22:1143-1151.

69. Stephenson J: Icelandic researchers are showing the way to bring down rates of antibiotic-resistant

bacteria. JAMA 1996; 275:175.

70. Dellit TH, Owens RC, McGowan Jr JE, Infectious Disease Society of America , Society for Healthcare

Epidemiology of America , et al: Infectious Diseases Society of America and Society for Healthcare

Epidemiology of America Guidelines for developing and institution program to enhance antimicrobial

stewardship. Clin Infect Dis 2007; 44:159-177.


23 de 25 05-04-2010 2


24/25

71. Patel SJ, Larson EL, Kubin CJ, Saiman L: A Review of antimicrobial control strategies in hospitalized and

ambulatory pediatric populations. Pediatr Infect Dis J 2007; 26:517-531.

72. Peter G: Streptococcal pharyngitis: current therapy and criteria for evaluation of new agents. Clin Infect

Dis 1992; 14(Suppl. 2):S218-S223.discussion S231-S212.

73. Diagnosis and management of acute otitis media. Pediatrics 2004; 113:1451-1465.

74. Clinical practice guideline: management of sinusitis. Pediatrics 2001; 108:798-808.

75. Feigin RD, McCracken Jr GH, Klein JO: Diagnosis and management of meningitis. Pediatr Infect Dis

J 1992; 11:785-814.

76. Ayalew K, Nambiar S, Yasinskaya Y, Jantausch BA: Carbapenems in pediatrics. Ther Drug

Monit 2003; 25:593-599.

77. Andes D, Craid WA: Treatment of infections with ESBL-producing organisms: pharmacokinetic and

pharmacodynamic considerations. Clin Microbiol Infect 2005; 11(Suppl. 6):S10-S17.

78. Craig WA, Andes D: Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect

Dis J 1996; 15:944-948.

79. James JK, Palmer SM, Levine DP, Rybak MJ: Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections. Antimicrob

Agents Chemother 1996; 40:696-700.

80. Schaad UB, McCracken Jr GH, Nelson JD: Clinical pharmacology and efficacy of vancomycin in pediatric

patients. J. Pediatr 1980; 96:119-126.

81. Lwdin E, Odenho lt I, Cars O: In vitro studies of pharmacodynamic properties of vancomycin against

Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother 1998; 42:2739-2744.

82. Yancey RJ, Sanchez MS, Ford CW: Activity of antibiotics against Staphylococcus aureus within

polymorphonuclear neutrophils. Eur J Clin Microbiol In fect Dis 1991; 10:107-113.

83. Nicolau DP: Optimizing outcomes with antimicrobial therapy through pharmacodynamic profiling. J Infect

Chemother 2003; 9:292-296.

84. Bradley JS, Dudley MN, Drusano GL: Predicting efficacy of antiinfectives with pharmacodynamics and

Montre Carlo simulation. Pediatr Infect Dis J 2003; 22:982-992.

85. de Hoog M, Mouton JW, van den Anker JN: New dosing strategies for antibacterial agents in the neonate.

Semin Fetal Neonatal Med 2005; 10:185-194.

86. Bradley JS: New

Antibiotics Prescription Pediatrics

Documents

Transcript of Antibiotics Prescription Pediatrics