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New Antibiotics and Emerging Bacterial Resistance

Emerging Antimicrobial Resistance

Gram-positive bacteria

Staphylococcus aureus

Methicillin resistance

Wide distribution limits treatment options

Low affinity penicillin binding protein 2a mediated by meca

Fluoroquinolone resistance.

Rapid local emergence of resistance

Glycopeptide resistance

Threatens best alternative therapy to date

Vancomycin-intermediate staph

Not related to vancomycin-resistant enterococcus problem

Laboratory mutants

Low level resistance from lab

Shown in vitro, in vivo, not clinically

Coagulase-negative staphylococci

Pneumococcus as a problem pathogen

Penicillin resistance

-Due to multiple penicillin binding protein alterations

b. Cephalosporin resistance

-Similar mechanism, limits options

c. Multiple drug resistance

-Alarming coincidence of resistances

d. International spread of clones

-Similar clones in Spain, US, Iceland.

4. The enterococcus

a. High-level aminoglycoside resistance

-Surprisingly rapid spread < 10 years

b. Increasing beta-lactam resistance in E. faecium

-Recent rise in levels of penicillin resistance

c. Vancomycin resistance: mechanisms

-Transposon mediating VanA-type resistance

d. VRE in the United States

-Recent numbers. Increasing in/out of ICUs

B. Gram-negative bacteria: problem pathogens

1. Intrinsic beta-lactam resistance

-Inducible beta-lactamases mediate resistance

a. Enterobacter spp.

-Clinical study of enterobacter bacteremia

b. Pseudomonas aeruginosa

-Resistance common with several agents

c. Stenotrophomonas, Burkholderia, etc.

-Primarily nosocomial multi-resistant pathogens

2. Extended-spectrum beta lactamases

a. Plasmid-mediated resistance to beta-lactams

-Resistance to 3rd generation drugs

-inhibited by beta-lactamase inhibitors

b. New enzymes: vs. cephamycins and carbapenems.

-Plasmid-mediated, like Enterobacter enzyme

-New ones confer carbapenem resistance

II. New and Novel Antimicrobials

A. Carbapenems

1. Meropenem

a. Approved agent

b. Active against gram-positive and -negative organisms

c. Possible use in meningitis

-Meningococcus, haemophilus

2. Agents with potential against methicillin-resistant staph (investigational)

-Increased affinity for PBP2a

B. Cefepime as a broad-spectrum cephalosporin

C. Novel glycopeptides as potential therapeutic agents (investigational)

-May overcome vancomycin-resistance problem

-Early in development

D. New quinolones and quinolone-like agents

1. Sparfloxacin

-Gram-positive enhanced

2. Clinafloxacin (investigational)

3. Trovafloxacin (investigational)

4. Novel pyridones (early development)

-Quinolone-like agents; no immediate candidate

E. Experimental tetracyclines: glycylcyclines

-Active against tet-resistant strains; no candidate

F. Oxazolidinones (investigational)

-Novel structure. In clinical trials. Gram-positives.

G. Macrolides and related antibiotics

1. Ketolides (investigational)

-Like erythromycin; more active v. strept., enterococci

2. Streptogramins (investigational)

a. Dalfopristin-quinupristin in vitro

-One of few agents active against VRE (faecium)

b. Clinical trials against VRE (faecium)

III. Conclusions

A. Resistance has increased significantly in both nosocomial and community isolates.

B. Multiple resistances are common. Once established, a resistant strain may persist under selective pressure from numerous antimicrobials.

C. Therefore, all antibiotics must be used prudently.

D. New antimicrobials are on the horizon, but history suggests resistance to these will emerge sooner or later.

E. There is an important role for infection control measure in health care settings.