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Staying Ahead of the Resistance Curve: Current and Future Strategies for More Effective Infection Control

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Denver, Colorado / September 10-13, 2013

Denver - Staying ahead of the resistance curve has never been more challenging in the management of acute and chronic infections. In the past few decades, there has been a remarkable increase in resistance to current antibiotics. As new antibiotics become available, organisms often develop ways to escape their bactericidal effects, sometimes rendering entire antibiotic drug classes useless in the treatment of a growing number of multi-drug resistant organisms. Innovative strategies directed towards preservation of current and future antimicrobials may include the maintenance and restoration of healthy intestinal microbiota that are profoundly disturbed by antibiotic therapy. Intelligent combinations of antibiotics that have synergistic effects against otherwise resistant organisms is another such strategy. More sensitive susceptibility testing may also help identify agents which could be ineffective against drug-resistant organisms in the context of a high bacterial burden. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

As speakers here concurred, innovative strategies must be directed towards the preservation of current and future antimicrobials if infection control is to be sustainable. The most radical of these strategies will likely be directed towards “tending” the microbiome. “Every time someone takes an antibiotic, profound perturbations occur in the microbiota in the large intestine,” Dr. Cliff McDonald, Chief, Prevention and Response Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, told delegates here. For too long, the medical community has focused on how antibiotic pressure selects for resistance within individual microbial species, he added.

Now, with a deeper understanding of how organisms—especially multi-drug resistant organisms such as C. difficile—colonize, expand and eventually dominate the human microbiome, attention must shift away from the “scorched microbial earth” strategy being practised in medicine today to one where the microbiome is restored to its healthy unperturbed state. It is thought that by doing this, antibiotic pressure on the microbiome—perhaps the most important perpetrator of antibiotic resistance today—will be interrupted, as Dr. McDonald suggested. In one of the first therapeutic attempts to restore the microbiome, Alan Walker, Staff Scientist, Wellcome Trust Sanger Institute, Cambridge UK, and colleagues first cultured numerous isolates from donor mice feces from which they identified 6 different strains. When the “magic elixir” was administered to a mouse model of C. difficile, they found it completely cured the infection and stopped its spread.

“What we think these 6 strains are doing is essentially tipping the balance against C. difficile,” Dr. Walker explained. “So by using only a small number of cultured anerobes, you can capture the same effect as you get by using a whole fecal transplant and it allows the suppressed microbiome to come back and re-establish itself. It’s very exciting and opens up a large number of possibilities.”

Multi-drug Resistance

Another strategy that may help overcome multi-drug resistance is to use combinations of antibiotics which act synergistically to improve bactericidal kill. In what was a high-inoculum study, Catherine Bulik, PharmD, Institute for Clinical Pharmacodynamics, Latham, New York, and colleagues assessed the potentially synergistic effect of daptomycin, the first lipopeptide to be approved for the treatment of gram-positive organisms including highly resistant species such as methicillin-resistant S. aureus (MRSA), given together with nafcillin, an antistaphylocccal beta-lactam. As she reported, monotherapy with either agent did not demonstrate efficacy against any of the daptomycin susceptible S. aureus (DSSA) or against daptomycin non-susceptible (DNSA) isolates in a high-inoculum, 48-hour time kill assay.

“This is not to say that daptomycin does not kill DSSA isolates,” principal investigator Anthony Nicasio, PharmD, Assistant Professor of Infectious Disease, Albany College of Pharmacy and Health Sciences, Albany New York, said in an interview. “It’s just that you need essentially somewhere between 4 and 6 times the MIC of the isolate to achieve kill with daptomycin monotherapy [in a high-inoculum assay].” In a low-inoculum assay, the agent has bactericidal activity at around 2 times the MIC of the isolate, he added.

This appears to hold true for high-inoculum assays as well provided a beta-lactam is added to the lipopeptide. As investigators noted, very low concentrations of nafcillin—0.25 to 0.5 times the isolates’ MIC—plus the lipopeptide at 2 times the MIC were shown to be synergistic against DSSA isolates. Against DNSA isolates, nafcillin plus the lipopeptide produced synergistic decreases in bacterial burden provided daptomycin was given in a concentration of 2 times the MIC value of the DNSA isolates.

“The combination works better against DNSA strains than DSSA strains, so nafcillin is helping daptomycin activity out when faced against DNSA strains,” Dr. Nicasio emphasized. Further evidence that a beta-lactam plus the lipopeptide is a potentially potent combination against DNSA infections was provided by the same team of investigators. Using a 24 hour time-kill assay again with a high starting inoculum, investigators found that the lipopeptide plus ceftriaxone were synergistic in 6 DNSA and 2 DSSA isolates when ceftriaxone was given at 1 or 4 times the MIC and daptomycin at 4 times the MIC of the isolates.

“We need to do more testing,” Dr. Nicasio observed. “But if other models show what we’ve shown here, it’s possible these combinations would work in high-inoculum infections such as infective endocarditis.” In a separate study by Betts et al, UK investigators assessed the activity of tigecycline, a relatively new antibiotic, in combination with colistin, an old one, against a range of carbapenemase-producing Enterobacteriaceae. Using standard laboratory protocols, analyses showed that the combination approach was at least equal to or had greater bactericidal activity than either drug alone in over 80% of the bacterial strains tested.

As researchers point out, synergistic combinations of two antibiotics could increase the lifespan of each drug and enable lower doses to be used, reducing potential drug-related toxicities.

High Bacterial Burden

Vancomycin is still the principal agent used to treat serious infections including those caused by MRSA. However, in an exploration of how effective vancomycin might be at blocking growth of the least susceptible cell presenting in a high density (≥109CFU) bacterial population, Dr. Joseph Blondeau, Interim Head of Pathology and Laboratory Medicine, and Head, Clinical Microbiology, University of Saskatchewan, Saskatoon and colleagues, found some “concerning” evidence that even very high vancomycin drug concentrations may not be effective under these circumstances. For the study, 25 contemporary MRSA blood isolates were tested. As investigators point out, MICs do not detect resistant populations that may arise in higher organism densities.

They thus added mutant prevention concentrations (MPC) testing to capture the presence of resistant subpopulations with reduced vancomycin susceptibility in high bacteria inoculums. Results showed that all 25 MRSA strains tested had MIC values to vancomycin of 0.5 μg/mL and these values were consistent on repeat testing. By MPC testing, all 25 strains had vancomycin MPC values ≥16 μg/mL, suggesting that in the presence of high density MRSA infections, organisms are likely to persist despite high vancomycin concentrations.

“We know that once you cross over to say, 107 bacterial cells, there is an increased probability that there will be spontaneously resistant cells in that population, so in patients with pneumonia, for example, it’s likely that there will be some resistance,” Dr. Blondeau explained. “And we think that what we’ve shown could have a significant clinical impact because if patients are being treated with vancomycin and they have a high bacterial burden, the drug does not appear to be effective at eliminating all the organisms.”

Summary

Antibiotics are a precious resource, having saved countless lives since their introduction many decades ago.  Antimicrobial stewardship has focused too long on the containment of resistant organisms but once resistant organisms have developed, preventing their transmission is extremely difficult. New strategies, including the maintenance of a healthy human microbiome, combination therapy and susceptibility testing offer real opportunities to improve infection control and efforts to make it happen are worthy of national and international attention.  

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