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PRIORITY PRESS - 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Barcelona, Spain / May 10-13, 2014

Barcelona - Gram-positive organisms, especially Staphylococcus aureus, are responsible for a large proportion of infections in North American today. Some are mild, others such as bacteremia and infective endocarditis, are life-threatening. Antibiotic pressure over time has led to increasing numbers of S. aureus isolates becoming resistant to not only methacillin but more recently the glycopeptides. There are now a number of alternatives to glycopeptide therapy that do help expand therapeutic options where needed. Some of these alternatives are proving to be even more active when given in high doses or in specific combinations with other antibiotics. Taken together, new approaches should be able to bring even life-threatening infections under control and optimize patient outcomes.  

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

Gram-positive organisms contribute to a significant proportion of healthcare and community-acquired infections. In the United States, Staphylococcus aureus alone causes roughly half of these infections, the severity of which can range from relatively mild skin and soft tissue infections (SSTIs) to life-threatening bacteremia and endocarditis. With antibiotic pressure over time, an increasing number of S. aureus isolates have developed resistance to methicillin; these have commonly been treated with vancomycin to eradicate difficult-to-treat MRSA infections.  

Increasing Resistance

More recently, many institutions are reporting at least a trend towards increasing resistance to vancomycin, resulting in the greater risk of treatment failure, relapse and even mortality. Wild-type or non-mutated strains of S. aureus have a vancomycin MIC of around 0.5 mg/L, (or µg/mL) as noted Dr. Ian Gould, Director of Medical Microbiology, Aberdeen Royal Infirmary, Aberdeen, Scotland. With increasing resistance, “you see mutations and the more mutations there are, the higher the MIC,” he added.

By the time isolates have a MIC of 2 mg/L, “about 50% of your strains have evolved into heteroresistant VISA (vancomycin-intermediate S. aureus) strains,” Dr. Gould said. With other classes of antibiotics, simply increasing the dose can often overcome antimicrobial resistance. This is not possible with vancomycin, speakers here agreed, because of the risk of toxicity, especially nephrotoxicity. Citing the need to achieve an AUC/MIC ratio of at least 400 to reach a maximum bactericidal effect from vancomycin, Patel et al. (Clin Infect Dis 2011;52:969) showed that even using the most aggressive dosing regimen (2 g every 12 hours), there was less than a 60% probability of reaching that maximum bactericidal effect when vancomycin MICs reached 2 mg/L. While at the same time, the probability of inducing nephrotoxicity, at least in ICU patients, was upward of 35%—an unacceptably high risk as the authors concluded. “If you push the dose and the trough levels of vancomycin too high, you run into toxicity,” confirmed Dr. Joseph Blondeau, Head, Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon. “So there is a therapeutic limitation as to how much of the drug you can use and if these MIC creeps get higher, there will be more people who will likely fail therapy.”

New Anti-MRSA Antibiotics

Five different antibiotics have now been approved for the treatment of MRSA infections. As observed by Dr. Eric Senneville, Department Head, Hospital of Tourcoing, France, all 5 agents are effective against difficult MRSA infections but each has a distinct safety profile that needs to be taken into consideration when selecting the right agent for individual patients. For example, linezolid has no bactericidal or biofilm activity but it can be given orally, whereas the other 4 anti-MRSA agents must be given intravenously (IV). The main toxicities with linezolid are both hematologic and neurotoxic, as Dr. Senneville observed.

Tigecycline in turn is similar in its activity to linezolid and is used when warranted, but because of excess mortality in certain serious infections observed in recent reviews, the FDA has issued a black box warning that accompanies tigecycline use (Expert Rev Anti Infect Ther 2014;12(4):397-400). Daptomycin does have bactericidal activity, as do both ceftaroline and telavancin. Again, toxicities vary between these 3 anti-MRSA agents, with elevations (though rare) in creatine phosphokinase for daptomycin; allergy for ceftaroline, and renal toxicity for telavancin. Due to its bactericidal action, an agent such as daptomycin is a good candidate for the treatment of MRSA bacteremia, especially when vancomycin MICs are high.

In one such study (Clin Infect Dis 2013;56:1592), Murray et al. reported mortality and persistent bacteremia rates were significantly lower at 30 days in the group switched to the alternative anti-MRSA agent compared to those who remained on vancomycin. In another, Moore et al. (Clin Infect Dis 2012:54:51-8) reported that patients with MRSA bloodstream infections (BSI) due to isolates with higher vancomycin MICs had a higher probability of survival at 60 days when again switched to the same anti-MRSA antibiotic.

Endocarditis, especially left-sided endocarditis, is among the most difficult-to-treat infections as it often involves both native and prosthetic valves. Left-sided endocarditis is also associated with a high mortality rate. According to Dr. Jose Miro, Associate Professor of Medicine, University of Barcelona, Spain, staphylococci are the leading cause of endocarditis worldwide. In his review of alternative strategies to treat infective endocarditis, Dr. Miro suggested that higher doses of some of the anti-MRSA agents may represent a viable treatment option to vancomycin when MICs are >1 mg/L.

“We know, for example, that in doses of up to 10 or 12 mg/kg, daptomycin is safe for patients,” Dr. Miro said. In a retrospective analysis of the European Cubicin Outcomes Registry Experience of infective endocarditis, Dohmen et al. (J Antimicrob Chemother 2013;68:936) reported an overall clinical success rate of 80% and no new safety signals in 224  difficult-to-treat patients who were failing therapy when given standard doses of this particular agent (6 mg/kg). As expected, success rates were higher for right-sided infective endocarditis than for left-sided endocarditis but success rates were similar in infections caused by MSSA and MRSA. Seventy-two patients in the same analysis received a higher dose of the same drug (≥8 mg/kg) and in these high-dose patients, there was a 90% clinical success rate overall, and virtually identical success rates in both right and left-sided infective endocarditis.

In another key study cited by Dr. Miro, (Kuller et al. Pharmacotherapy 2011;31:527-36), physicians treated 250 patients with MRSA as well as vancomycin-resistant Enterococci (VRE) infections with high doses of daptomycin (median dose of 10 mg/kg for MRSA infections and 13 mg/kg for VRE infections). “Despite these high doses, between 5 to 10% of patients had clinical and microbiological failure and these were the patients with complicated bacteremia and native and prosthetic endocarditis,” Dr. Miro observed. “So for patients with endocarditis, it is not enough to increase the dose of this agent, we need to use combination therapy.”

Combination Therapy

As noted by researchers from Wayne State University, Detroit, Michigan (eP177), MRSA organisms which have intermediate resistance to glycopeptides often have increased susceptibility to beta-lactams, a phenomenon known as the “seesaw effect.”

In vitro data have shown that daptomycin plus the combination of beta-lactams have synergy against multiple MRSA isolates, as well as against Entercoccus faecalis and Enterococcus faecium. As investigators reported, susceptibility test results showed that all beta-lactam antibiotics including ceftaroline, cefepime, ceftriaxone, cefotaxime, cefoxitin, cefazolin and ampicillin demonstrated synergy against all 4 MRSA strains tested when combined with this particular anti-MRSA agent.

The one exception was the combination of daptomycin and aztreonam where no synergy was seen. Miro and colleagues have also demonstrated that the combination of the same anti-MRSA agent plus intravenous (IV) fosfomycin has “synergistic, potent and rapid bactericidal activity” against MRSA in both a rabbit model of endocarditis as well as in a handful of patients.

Encouraged by these findings, Spanish investigators have launched a multicentre, randomized trial in which they will evaluate the efficacy and safety of high-dose daptomycin plus or minus IV fosfomycin for the treatment of MRSA BSIs in a target group of 240 patients.

“Daptomycin at a dose of 10 mg/kg or more combined with cloxacillin or [IV] fosfomycin is the best empiric antibiotic for S. aureus endocarditis,” Dr. Miro concluded. He cautioned, however, that the anti-MRSA agent must be given in doses of at least 10 mg/kg and combined with either a beta-lactam or IV fosfomycin in the setting of MRSA infective endocarditis.  In contrast, beta-lactam antibiotics remain the standard of care for MSSA infective endocarditis.

Summary

Increasing the dose of antibiotics can often increase bactericidal activity and lead to more rapid resolution of the infection but increased toxicity may limit the ability to dose-escalate as is the case with vancomycin. Vancomycin may remain the preferred antibiotic in the setting of non-life threatening sepsis, but high vancomycin MICs, slow treatment response to the glycopeptides or complicated bacteremia should prompt consideration of an alternative anti-MRSA antibiotic either given alone in high doses or in combination with a synergistic agent.