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Strategies Evolve to Gain Control of Complicated Gram-Positive Infections

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 - 23rd European Congress on Clinical Microbiology and Infectious Diseases

Berlin, Germany / April 27-30, 2013

Berlin - Due to evolving patterns of susceptibility, empiric and first-line therapies for challenging gram-positive infections must be adjusted, according to a series of reports at ECCMID. Alternatives to vancomycin, which is identified as first-line in many such infections, should be considered when minimum inhibitory concentrations exceed 1 μg/mL, when prosthetic devices are involved or when infections are otherwise complicated with a diminished likelihood of clearing with a single agent. Due to evolving patterns in susceptibility to antibiotics, expert consensus on published guidelines, that are often based on experimental models, suggest they may no longer capture best practice in many of the most serious and complicated gram-positive infections. Due the potential for synergies, combination therapies were emphasized in many of the most challenging diseases.

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

Early initiation of an appropriate empiric therapy for Staphylococcus aureus bacteremia is associated with a mortality benefit, but the definition of an appropriate agent is evolving. Vancomycin continues to be widely considered the best option for methicillin-resistant S. aureus (MRSA), but the susceptibility of the strain is increasingly important, and vancomycin has been found inferior to alternatives for infections caused by methicillin-susceptible S. aureus (MSSA). Higher doses of vancomycin improve activity but increase toxicity.

“In the literature, high vancomycin minimum inhibitory concentrations [MICs] even though they are within the susceptible range are now being linked with increased mortality and treatment failure in MSSA and MRSA infections,” cautioned Dr. Alex Soriano, Hospital Clinic, Barcelona, Spain. Citing several studies, including a meta-analysis showing significantly poorer outcomes for vancomycin treatment of infections with high (≥1 μg/mL) relative to low MICs (Int J Antimicrob Agents 2012;40:496-509), Dr. Soriano said that alternatives are no longer for special situations and “something that we need to consider routinely.”

MRSA Bacteremia: Support for Alternatives

There is clinical evidence to support alternatives for MRSA bacteremia (MRSAB). Dr. Soriano cited a recently published retrospective cohort study in which a switch study was evaluated in MRSAB when MICs of vancomycin were found to be >1 μg/mL (Clin Infect Dis 2013;56(11):1562-9). In this study, patients either remained on vancomycin or were switched to daptomycin within 72 hours of starting vancomycin. The matching was performed in a 1:1 ratio. At 30 days, clinical failure and mortality rates were (20.0% vs. 48.2%; P<0.001 and 3.5% vs. 12.9%; P=0.047) for daptomycin and vancomycin, respectively.

The growing limitations of vancomycin for MRSAB was also derived from some recently published Canadian data in which survival in MRSA patients with septic shock was predicted by being younger and with better renal function prior to infection but also by achieving higher serum trough levels (Int J Antimicrob Agents 2013;41:255-60). According to the data, the survival rate was 2.5-fold greater in patients who reached vancomycin troughs ≥15 mg/L (P=0.001), but Dr. Soriano cautioned that raising vancomycin doses to achieve these levels invites higher levels of toxicity, particularly in immunocompromised patients with multiple concomitant disorders.

Combination Regimens: Exploring Synergy

Similar concern about the correspondence between rising rates of vancomycin treatment failure and rising MICs was expressed by Dr. Peter M. Hawkey, Institute of Microbiology and Infection, University of Birmingham, UK. Of therapeutic alternatives, he also listed daptomycin as a viable choice, noting safety advantages for this agent in a head-to-head comparison with vancomycin for S. aureus bacteremia and endocarditis (N Engl J Med 2006;355:653-65). However, he placed particular emphasis on using this agent or other vancomycin alternatives in combination regimens because of synergies useful in complicated and resistant infections.

“Combinations raise the bar for selection of resistant mutants, but in some cases the mechanisms of two agents can prove synergistic,” Dr. Hawkey noted. He cited several examples, such as the ability of beta lactams to increase uptake of aminoglycosides, but in a further exploration of the role of daptomycin as a substitute for vancomycin, he noted that this agent is particularly well suited to combination therapy in biofilm-associated or deep-seated infections. According to Dr. Hawkey, mutations that result in a change in the surface charge of the bacterial cell membrane could lead to daptomycin non-susceptibility, but a number of agents, including nafcillin, oxacillin, rifampin and fosfomycin, revert the surface charge to restore the activity of daptomycin while contributing their own bactericidal effect.

“There are now a number of published studies demonstrating the ability of a second agent to rapidly restore efficacy in daptomycin non-susceptible infections,” reported Dr. Hawkey. A study discussed here and applicable in Canada, reported seven cases where the combination of high dose daptomycin (8-10 mg/kg/day) and antistaphylococcal beta-lactams such as oxacillin (2 g IV q4h), were used to achieve rapid bactericidal activity against MRSA bacteremia that was refractory to vancomycin and daptomycin-based therapies alone (Clin Infect Dis 2011;53:158-63).

Complicated Endocarditis: Improving Treatment Success

The author of that study, Dr. Jose M. Miro, Infectious Diseases Service, Hospital Clinic, University of Barcelona, Spain, elaborated on these results in a keynote address delivered at ECCMID. In his address, he reviewed a large body of evidence that supports combination therapy for complicated endocarditis. Like Dr. Hawkey, he sees major opportunities to improve treatment success through agent synergy with combination antibiotics to increase treatment success.

“The epidemiology of endocarditis is changing. There is going to be more health care related cases, particularly those related to intracardiac devices as procedures such as TAVI [transcatheter aortic valve implantation] become more common,” Dr. Miro reported. While he expects vancomycin MICs to continue to rise in MRSA endocarditis, he also expects device-related biofilms to further compromise both host defenses and single antibiotic regimens. He believes current guidelines are of limited use because they are unable to incorporate evolving data.

In a recent editorial in Circulation (2013;127:1763-6), Dr. Miro cited evidence of synergy to move amoxicillin and ceftriaxone forward in the treatment of Enterococcus faecalis endocarditis, but he suggested that the same principles apply to other complicated forms of endocarditis. For example, while noting that daptomycin performed better than vancomycin in the head to head trial by Fowler et al., he suggested neither is probably sufficient alone in patients with evidence of diminishing susceptibility, a high bacteria inoculum, osteomyelitis or other features that predict a suboptimal response.

“There are two strategies. One is to use high doses of a monotherapy and the other one is to use a combination,” Dr. Miro reported. While there are data to conclude that one agent might be a better choice than another in monotherapy (for example, Dr. Miro said that “it now seems clear that daptomycin is the best empirical therapy against MSSA endocarditis”), one of the major take-home messages of his keynote address is that “it is probably best in complicated cases to combine agents with evidence of a synergistic effect.”

Combination Therapy: Evolving Data

In clinical practice, combination therapy already appears to be widely used, judging from post-marketing daptomycin data presented at ECCMID. In one 6-year analysis of the use of this treatment in intra-cardiac foreign body infections, 74% were on a concomitant antibiotic. Presented by Prof. Pascal M. Dohmen, Department of Cardiovascular Surgery, Charité Hospital, Berlin, Germany, the study found an overall success rate of 78% in the 166 treated patients. It is notable that only 4% were considered to have an adverse event related to daptomycin. In a second analysis from the same database but focused on patients with an intravascular foreign body, 77% of patients took a second antibiotic, and treatment success was reported in 78% (Poster 1650).

Although important, the movement toward combination therapy for complicated gram-positive infections is likely to derive more guidance from in vitro modeling and from case series than from controlled clinical studies. In a review of combination therapies in gram-positive infections during an ECCMID symposium, Dr. Thomas Lodise, Albany College of Pharmacy and Health Sciences, New York, called combination therapy “the future for complicated Staph and other gram-positive infections,” but he also acknowledged that the supportive data remain “very limited.” Still, based on the advantages, including reduced toxin production, increased intracellular penetration and lower risk of resistance, he believes the evolution is already underway.


Due to an ongoing evolution in complicated gram-positive infections, published guidelines may no longer capture the adjustments required to achieve treatment success. In particular, the rising MICs of vancomycin, even when they remain in the susceptible range, may make other options attractive due to complications when the dosage must be increased. Single agent substitutions may be possible in some instances, but expert consensus suggests an accelerating movement to combination therapy.

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