Session on Pneumonia Management

Strategies: Hype or Real?

Topic: New Drugs for Old Bugs?

Through a CME Grant sponsored by

JAIME C. MONTOYA, MD, MSc

Professor V, Department of Medicine

University of the Philippines College of Medicine

Executive Director

Philippine Council for Health Research and Development

Department of Science and Technology

Consultant, Clinical Department

Research Institute for Tropical Medicine

Department of Health

RONPAKU Fellow for PhD, Juntendo University College of Medicine

Tokyo, Japan

Master of Science, Clinical Tropical Medicine, London School of Hygiene and

Tropical Medicine, University of London

Fellowship in Infectious Diseases, UP-PGH Medical Center

Doctor in Medicine, UP College of Medicine

New Drugs for Old Bugs

Jaime C. Montoya, MD, MSc, PhD

Professor V, UP College of Medicine

Outline of Talk

• Background on Antibiotics

• Problem of Antimicrobial Resistance

• Core Strategies in Prevention of Antimicrobial Resistance

• Issues in Drug Development

• New Antibiotics in the Pipeline

• New Trends in Management of Infections

Antibiotics

• Represent a special class of therapeutic agents whose misuse affects not just the individual patient but the broader community.

• This is due to the almost inevitable selection for antibiotic-resistant bacteria that arise in clinically significant waves at some point after widespread introduction and use of a new antibiotic (both in veterinary and human populations).

Antimicrobial Resistance

• Extensive use, misuse and overuse in both animal and human health have raised levels of antimicrobial resistance in a wide range of pathogens (bacteria, viruses, fungi and parasites).

• Increasing travel and trade in food have facilitated the spread of antimicrobial resistance

Antimicrobial Resistance

• NDM-1, a metallo-beta-lactamase which confers resistance to carbapenems was first detected in India in 2008 but has now been found in all continents

• New resistance mechanisms are emerging

• Development of new antibiotics and interventions not keeping pace

Antimicrobial Resistance

• Infections caused by drug-resistant pathogens increase mortality across all settings leading to prolonged stay in hospitals and ICUs

• Beyond the immediate public health impact, antibiotic resistance incurs substantial health economic costs

• Losses of GDP from antimicrobial resistance range from 0.4% to 1.6%

Philippine Resistance Data 2012

• E. coli resistant to 3rd Gen Ceph 26.7%

• E. coli resistant to Fluoroquinolones 40.9%

• Kleb pneumoniae R to 3rd Gen Ceph 30%

• Kleb pneumoniae R to carbapenems 3.8%

• Methicillin Resistant Staph aureus 54.9%

• Penicillin Resistant Strep pneumo 0

Core Actions on the Prevention of Drug Resistance• Prevent Infections

• Track Resistance Patterns

• Improve the Use of Antibiotics

• Develop New Antibiotics and Diagnostic Tests

Antimicrobial Stewardship

Involves selecting an appropriate drug andoptimizing its dose and duration to cure aninfection while minimizing toxicity andconditions for selection of resistant bacterialstrains

Fishman. Am J Med 2006;119(6A):S53-S61

Antimicrobial Stewardship

1) Educational programs2) Restricted antimicrobial formularies3) Prior approval programs4) Streamlining programs5) Antibiotic cycling/mixing6) Differentiation of infection,

contamination and colonization7) Discontinuation of antibiotic therapy8) Infection Control

Use Local Data

Fact: The prevalence of resistance can vary by locale, patient population, hospital unit, and length of stay.

Actions:

know your local antibiogram

know your patient population

Antibiotic Cycling vs Antibiotic Mixing

•Same protocol Cycling Mixing

Cycling versus Mixing

Cycling

• Greater heterogeneity at the level of the ward

• Difficult to implement

• Controversial results

Mixing

• Greater heterogenityat the level of the patient

• Easy implementation

Treat infection, not contaminationFact: A major cause of antimicrobial overuse is

“treatment” of contaminated cultures. Clinical correlation is very important

Actions:

use proper antisepsis for blood & other cultures

culture the blood, not the skin or catheter hub

use proper methods to obtain & process all cultures

Interpreting a “Positive” Blood Culture

True Bacteremia:

Unlikely Uncertain LikelyCorynebacterium spp. Coag negative Staph Staph aureus

Non-anthracis Bacillus spp. Strep pneumoniae

Propionibacterium acn Enterobacteriaceae

Pseudo aeruginosa

Candida albicans

Treat infection, not colonizationFact: A major cause of antimicrobial overuse is

treatment of colonization. Clinical correlation is very important.

Actions:

treat pneumonia, not the tracheal aspirate

treat bacteremia, not the catheter tip or hub

treat urinary tract infection, not the indwelling catheter

Know when to say “no” to broad spectrum antibiotics

Fact: Broad spectrum antibiotics overuse promotes emergence, selection, and spread of resistant pathogens through effect on normal host flora

Actions:

Target only most probable etiologic organisms

Use narrow spectrum antibiotics whenever possible

Stop antimicrobial treatment

Fact: Failure to stop unnecessary antimicrobial treatment contributes to overuse and resistance .

Actions:

when infection is cured

when cultures are negative and infection is unlikely

when infection is not diagnosed

Isolate the pathogen

Fact: Patient-to-patient spread of pathogens can be prevented.

Actions:

use standard infection control precautions

contain infectious body fluids

(use approved airborne/droplet/contact isolation precautions)

when in doubt, consult infection control experts

Principles in Infection Control

New Antibiotics in the PipelineTedizolid (Cubist)

• Noninferior to linezolid in treating acute bacterial skin and skin structure infections (ABSSSIs) caused by several organisms, including MRSA.

• Given once daily for 6 days, compared with twice-daily linezolid for 10 days

Oritavancin (The Medicine Group)

• A randomized, phase-3 noninferiority trial showed that oritavancin, a licoglycopeptide that is given as a single dose, was noninferior to vancomycin in the treatment of ABSSSIs.

• Also effective against MRSA

Corey GR et al. N Engl J Med 2014;370:2180-90.

New Antibiotics in the Pipeline

Ceftolozane/Tazobactam (Cubist)

• Antimicrobial combination has demonstrated effectiveness against bacteria that cause urinary tract infections and intra-abdominal infections, specifically Pseudomonas aeruginosa, extended-spectrum beta-lactamase–producing Escherichia coli and Klebsiellapneumonia

Ceftobiprole (Basilea)

• Fifth-generation cephalosporin has demonstrated noninferiority to the combined therapy of ceftazidime and linezolid in the treatment of hospital-acquired pneumonia, with the exception of ventilator-associated pneumonia.

• Approved for use in Europe but has seen some regulatory hurdles in the US

New Antibiotics in the PipelineDelamanid (Otsuka)

• Anti-tuberculosis drug was recently approved for use in Europe

• Can be used as part of a treatment regimen for patients with TB who are resistant to other medications

New Ways of Treating InfectionsUse of Bacteriophages to kill bacteria• Bacteriophages or "phage" are viruses that

invade bacterial cells and, in the case of lytic phages, disrupt bacterial metabolism and cause the bacterium to lyse [destruct].

• Phage Therapy is the therapeutic use of lytic bacteriophages to treat pathogenic bacterial infections

New Ways of Treating InfectionsBacteriophage therapy is quite attractive for killing bacteria for the following reasons:• phage particles are narrow spectrum agents, which

means they posses an inherent mechanism to not only infect bacteria but specific strains

• other pathogens may be targeted through manipulation of phage DNA

• exponential growth and natural mutational ability make bacteriophages great candidates for thwarting bacterial resistance

• minimal side effects

THANK YOU VERY MUCH!!!

Session on Pneumonia Management

Strategies: Hype or Real?

Topic: New Drugs for Old Bugs?

Through a CME Grant sponsored by