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Resistant Gram-Positive Infections: Where Have We Been, Where Are We Now, and Where Are We Going?

      As I gather my thoughts about this Drugs and Biologics Update, I am mindful of the debt I owe to my mentor, Bob Moellering, whose untimely death at the age of 77 earlier this year leaves a tremendous void in the infectious diseases community. I had the privilege of serving as Bob’s Chief Resident, Infectious Disease Fellow, and infectious diseases faculty member at New England Deaconess Hospital, Boston, MA, where Bob was Chief of Medicine. For those of us who were fortunate to work with him, it was impossible not to appreciate—indeed, be awed by—the depth of the knowledge he shared with such humility and his patience, kindness, guidance . . . and love of a good time. Bob’s journey in infectious diseases began with isolating enterococci in the Solomon Islands; his work defining the molecular mechanisms of resistance in enterococci and methicillin-resistant Staphylococcus aureus (MRSA) spanned nearly a half-century. His contributions to our knowledge mark his legacy as a supreme scientist and thought leader. The articles in this issue are a testament to Bob’s heritage, as he continued to collaborate worldwide to meet the challenge of growing gram-positive resistance. George Sakoulas trained in Bob’s lab; Abhay Dhand trained here at Tufts with those of us who also trained under Bob—Bob’s tendrils are everywhere.
      The problem of resistant gram-positive infections is well described. Our patients and their families fear the term MRSA, infection-control practitioners combat the spread of resistant gram-positive organisms on a daily basis, and our intensive care units are filled with patients requiring isolation and toxic or expensive antibiotics to control infections, with varying outcomes. Where we have been covers a billion years, with evidence of staphylococci in fossils and coevolution of antibiotics, bacteria, and resistance.
      • Baltz R.H.
      Genomics and the ancient origins of the daptomycin biosynthetic gene cluster.
      Where we are now challenges us to devise “concoctions” to save patients from overwhelming gram-positive infections, some of which you will read about in this issue of Clinical Therapeutics. Where we are headed encompasses applying our ability to isolate resistance mechanisms in concert with rapid molecular diagnostics, the development and approval of new drugs, and harnessing innate host immune responses—a challenge for young researchers of infectious diseases, microbiology, pharmacology, immunology, and animal husbandry everywhere.
      MRSA is the most prevalent resistant gram-positive organism causing infections today. Soon after the introduction of penicillin, the organism developed resistance by producing penicillinase, a β-lactamase that disrupts the β-lactam ring, rendering the drug ineffective. Noble and Naidoo
      • Noble W.C.
      • Naidoo J.
      Evolution of antibiotic resistance in Staphylococcus aureus: the role of the skin.
      argued that dermatophytes producing penicillin facilitate the development of resistance in S aureus in vitro and in vivo, such that one does not need to look beyond the skin for the evolution of penicillin-resistant S aureus. The effectiveness of semisynthetic penicillins such as methicillin, oxacillin, and nafcillin was short-lived due to the acquisition of the mecA gene carried on the staphylococcal chromosome cassette (SCC) mec, which encodes penicillin-binding protein 2a (PBP2a), an alternative transpeptidase with a low affinity for β-lactams, therefore allowing the continuation of cell wall cross-linking even in the presence of these drugs. MRSA clones were generally limited to hospital/health care settings
      • Bradley J.S.
      Which antibiotic for resistant Gram-positives, and why?.
      until the 1990s, when non–health care associated infections—so-called “community-associated (CA)-MRSA infections”—began appearing. These organisms, now harboring different SCCmec elements, imposed on a genetic background containing a broader repertoire of virulence factors, took the combination of “fitness” and antimicrobial resistance to a new level. The predominant clone is USA300 and contains genes that produce Panton-Valentine leukocidin, a pore-forming protein that is epidemiologically linked to serious CA-MRSA infections.
      • David M.Z.
      • Daum R.S.
      Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic.
      What infectious disease practitioner or pharmacist today has not encountered a patient with a life-threatening CA-MRSA infection? Although hospital-associated (HA)-MRSA strains prevailed as a cause of infection in the hospital setting until a decade ago, rapid expansion of the USA300 clone worldwide has been well documented.
      • David M.Z.
      • Daum R.S.
      Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic.
      Indeed, a recent study documented that the CA-MRSA USA300 clone accounted for nearly as many inpatient isolates as HA-MRSA clones between 2004 and 2008, increasing from 12% of all isolates in 2004 to 38% in 2006.
      • O’Hara F.P.
      • Amrine-Madsen H.
      • Mera R.M.
      • et al.
      Molecular characterization of Staphylococcus aureus in the United States 2004-2008 reveals the rapid expansion of USA300 among inpatients and outpatients.
      Polyclonal methicillin-susceptible S aureus isolates decreased in frequency as they were replaced by the USA300 MRSA clone.
      • O’Hara F.P.
      • Amrine-Madsen H.
      • Mera R.M.
      • et al.
      Molecular characterization of Staphylococcus aureus in the United States 2004-2008 reveals the rapid expansion of USA300 among inpatients and outpatients.
      The same group, utilizing isolates and data from the surveillance network (Eurofins Medinet) and the National Hospitalization Discharge Survey, reported that over the 10-year period from 1998 to 2007, CA-MRSA USA300 accounted for 66% of all MRSA strains and an 8-fold increase in MRSA per 1000 hospital discharges by 2007.
      • Mera R.M.
      • Suaya J.A.
      • Amrine-Madsen H.
      • et al.
      Increasing role of Staphylococcus aureus and community-acquired methicillin-resistant Staphylococcus aureus infections in the United States: a 10-year trend of replacement and expansion.
      The fact that CA-MRSA, a more virulent organism, is here to stay is undisputed.
      The glycopeptide vancomycin remains the first-line treatment option for MRSA infections.
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary.
      Its used has skyrocketed in the past decade due to the increased need for empiric and directed therapy against suspected or documented MRSA infections driven by the USA300 epidemic. However, evidence that it may not be the best option for serious, life-threatening infections is mounting. A number of agents approved in the past decade, including some in just the past 6 months, have expanded the treatment options: daptomycin for MRSA bacteremia and right-sided endocarditis
      • Fowler Jr, V.G.
      • Boucher H.W.
      • Corey G.R.
      • et al.
      Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.
      ; linezolid for MRSA pneumonia
      • Wunderink R.G.
      • Niederman M.S.
      • Kollef M.H.
      • et al.
      Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study.
      ; and daptomycin, linezolid, ceftaroline, dalbavancin, telavancin, and tedizolid for acute bacterial skin and skin structure infections.
      • Chang M.H.
      • Kish T.D.
      • Fung H.B.
      Telavancin: a lipoglycopeptide antimicrobial for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria in adults.
      • Corey G.R.
      • Wilcox M.
      • Talbot G.H.
      • et al.
      Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.
      • Jauregui L.E.
      • Babazadeh S.
      • Seltzer E.
      • et al.
      Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections.
      • O’Riordan W.
      • Green S.
      • Mehra P.
      • et al.
      Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary.
      • Yogev R.
      • Patterson L.E.
      • Kaplan S.L.
      • et al.
      Linezolid for the treatment of complicated skin and skin structure infections in children.
      Despite these additions to the arsenal, the morbidity and mortality associated with serious MRSA infections remain high. Infections characterized by prolonged bacteremia not cleared with first-, second-, or even third-line agents remain a particular challenge.
      As antibiotic use marches along, so, too, does antibiotic resistance, and glycopeptides and lipopeptides are no exception. In the late 1990s, staphylococci with higher vancomycin minimum inhibitory concentrations (MICs) were seen with increasing frequency, with worse outcomes in those with MICs ≥2 µg/mL.
      • Gilbert M.
      • MacDonald J.
      • Gregson D.
      • et al.
      Outbreak in Alberta of community-acquired (USA300) methicillin-resistant Staphylococcus aureus in people with a history of drug use, homelessness or incarceration.
      • Gould I.M.
      • Bal A.M.
      New antibiotic agents in the pipeline and how they can help overcome microbial resistance.
      • Soriano A.
      • Marco F.
      • Martinez J.A.
      • et al.
      Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia.
      • Yoon Y.K.
      • Kim J.Y.
      • Park D.W.
      • et al.
      Predictors of persistent methicillin-resistant Staphylococcus aureus bacteraemia in patients treated with vancomycin.
      Although daptomycin is active against most strains of vancomycin-intermediate S aureus (VISA) and hetero-vancomycin-intermediate S aureus, cross-resistance has been reported.
      • Fowler Jr, V.G.
      • Boucher H.W.
      • Corey G.R.
      • et al.
      Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.
      • Cui L.
      • Tominaga E.
      • Neoh H.M.
      • Hiramatsu K.
      Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus.
      • Patel J.B.
      • Jevitt L.A.
      • Hageman J.
      • et al.
      An association between reduced susceptibility to daptomycin and reduced susceptibility to vancomycin in Staphylococcus aureus.
      • Sakoulas G.
      • Alder J.
      • Thauvin-Eliopoulos C.
      • et al.
      Induction of daptomycin heterogeneous susceptibility in Staphylococcus aureus by exposure to vancomycin.
      The observations that a laboratory mutant vancomycin-resistant S aureus isolate demonstrated a substantially reduced methicillin MIC and that clinical VISA strains showed increased susceptibility to methicillin led to the concept of the “seesaw effect”: the more resistant the MRSA strain was to vancomycin, the more susceptible it was to β-lactams.
      • Sieradzki K.
      • Roberts R.B.
      • Haber S.W.
      • Tomasz A.
      The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection.
      Soon thereafter, increased β-lactam susceptibility in increasingly vancomycin-resistant isolates was reported in vivo.
      • Sieradzki K.
      • Roberts R.B.
      • Haber S.W.
      • Tomasz A.
      The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection.
      • Adhikari R.P.
      • Scales G.C.
      • Kobayashi K.
      • et al.
      Vancomycin-induced deletion of the methicillin resistance gene mecA in Staphylococcus aureus.
      • Sendi P.
      • Graber P.
      • Zimmerli W.
      Loss of mecA gene in Staphylococcus epidermidis after prolonged therapy with vancomycin.
      • Sieradzki K.
      • Leski T.
      • Dick J.
      • et al.
      Evolution of a vancomycin-intermediate Staphylococcus aureus strain in vivo: multiple changes in the antibiotic resistance phenotypes of a single lineage of methicillin-resistant S. aureus under the impact of antibiotics administered for chemotherapy.
      Interestingly, the seesaw effect between daptomycin and β-lactams has been documented as well.
      • Barber K.E.
      • Werth B.J.
      • Ireland C.E.
      • et al.
      Potent synergy of ceftobiprole plus daptomycin against multiple strains of Staphylococcus aureus with various resistance phenotypes.
      • Lee C.H.
      • Wang M.C.
      • Huang I.W.
      • et al.
      Development of daptomycin nonsusceptibility with heterogeneous vancomycin-intermediate resistance and oxacillin susceptibility in methicillin-resistant Staphylococcus aureus during high-dose daptomycin treatment.
      • Yang S.J.
      • Xiong Y.Q.
      • Boyle-Vavra S.
      • et al.
      Daptomycin-oxacillin combinations in treatment of experimental endocarditis caused by daptomycin-nonsusceptible strains of methicillin-resistant Staphylococcus aureus with evolving oxacillin susceptibility (the “seesaw effect”).
      Antimicrobial resistance in MRSA has also been studied with regard to its effect on of the innate immune system, in particular the cationic antimicrobial peptides, also known as host defense peptides (HDPs). One mechanism behind the antimicrobial activity of these peptides is an electrostatic attraction to the anionic heads of bacterial membrane phospholipids, leading to membrane depolarization.
      • Kelley W.L.
      • Lew D.P.
      • Renzoni A.
      Antimicrobial peptide exposure and reduced susceptibility to daptomycin: insights into a complex genetic puzzle.
      The lipopeptide daptomycin, when complexed with calcium, is similar to HDPs by virtue of its peptide content, positive charge, and mechanism of action targeting cellular membrane depolarization.
      • Kelley W.L.
      • Lew D.P.
      • Renzoni A.
      Antimicrobial peptide exposure and reduced susceptibility to daptomycin: insights into a complex genetic puzzle.
      Cross-resistance between daptomycin, and specific endovascular HDPs has been demonstrated in S aureus, suggesting that exposure to daptomycin induces resistance to HDPs.
      • Mishra N.N.
      • McKinnell J.
      • Yeaman M.R.
      • et al.
      In vitro cross-resistance to daptomycin and host defense cationic antimicrobial peptides in clinical methicillin-resistant Staphylococcus aureus isolates.
      To determine whether exposure to HDPs contributes to resistance to daptomycin even before exposure to the drug, the same authors studied the “priming effects” of HDPs in the evolution of daptomycin resistance in isolates of S aureus from bacteremic patients without endocarditis.
      • Mishra N.N.
      • Bayer A.S.
      • Moise P.A.
      • et al.
      Reduced susceptibility to host-defense cationic peptides and daptomycin coemerge in methicillin-resistant Staphylococcus aureus from daptomycin-naive bacteremic patients.
      They showed higher daptomycin MICs among daptomycin-susceptible isolates from patients who had never received daptomycin, which suggests that resistance developed with endogenous exposure to the peptide. The authors postulated that because daptomycin contains a large peptide moiety that might contain a positive charge, similar to HDPs, the mechanism of bacterial killing was similar between the two, and resistance could be promoted in the bacteria by exposure to HDPs even before exposure to daptomycin.
      • Mishra N.N.
      • Bayer A.S.
      • Moise P.A.
      • et al.
      Reduced susceptibility to host-defense cationic peptides and daptomycin coemerge in methicillin-resistant Staphylococcus aureus from daptomycin-naive bacteremic patients.
      At the same time, other investigations reported that anti-staphylococcal β-lactams appear to enhance the killing of MRSA by HDPs.
      • Dhand A.
      • Bayer A.S.
      • Pogliano J.
      • et al.
      Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding.
      These observations have led to a novel treatment option for serious MRSA infections: the combination of a glycopeptide or lipopeptide with a β-lactam. A number of recent reports support this approach, in particular with the newer cephalosporin ceftaroline, which binds PBP2a and is thus active against MRSA in its own right.
      • Barber K.E.
      • Werth B.J.
      • Ireland C.E.
      • et al.
      Potent synergy of ceftobiprole plus daptomycin against multiple strains of Staphylococcus aureus with various resistance phenotypes.
      • Dhand A.
      • Bayer A.S.
      • Pogliano J.
      • et al.
      Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding.
      • Dilworth T.J.
      • Ibrahim O.
      • Hall P.
      • et al.
      Beta-lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone.
      • Werth B.J.
      • Barber K.E.
      • Ireland C.E.
      • Rybak M.J.
      Evaluation of ceftaroline, vancomycin, daptomycin, or ceftaroline plus daptomycin against daptomycin-nonsusceptible methicillin-resistant Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations.
      • Werth B.J.
      • Steed M.E.
      • Kaatz G.W.
      • Rybak M.J.
      Evaluation of ceftaroline activity against heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate methicillin-resistant S. aureus strains in an in vitro pharmacokinetic/pharmacodynamic model: exploring the “seesaw effect”.
      In this issue, Sakoulas et al
      • Sakoulas G.
      • Moise P.A.
      • Casapao A.M.
      • et al.
      Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.
      present their findings on the use of ceftaroline plus daptomycin as salvage therapy for persistent staphylococcal (predominantly MRSA) bacteremias from 10 medical centers. They report that the median time to clearance of bacteremia was 2 days compared with that of bacteremia persistence of 10 days before combination therapy was started. They also studied the in vitro effects of this combination in studies of synergy and sensitization to HDPs. Although that study was not of a randomized, controlled design, it does represent one of the largest clinical datasets of daptomycin plus β-lactam combination therapy, and the results are promising.
      • Sakoulas G.
      • Moise P.A.
      • Casapao A.M.
      • et al.
      Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.
      Although vancomycin and piperacillin/tazobactam are frequently used in combination for the empiric treatment of health care–associated infections and sepsis, the actual effects of the combination have not been well studied. Dilworth et al
      • Dilworth T.J.
      • Leonard S.A.
      • Vilay A.M.
      • Mercier R.-C.
      Vancomycin and piperacillin-tazobactam against methicillin-resistant Staphylococcus aureus and vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.
      present their findings on the use of these agents together in an in vitro pharmacokinetics/pharmacodynamics model. Compared with vancomycin monotherapy, the combination demonstrated a remarkable enhancement of antimicrobial activity against both MRSA and VISA.
      Finally, Dhand and Sakoulas
      • Dhand A.
      • Sakoulas G.
      Daptomycin in combination with other antibiotics for treatment of complicated methicillin-resistant Staphylococcus aureus bacteremia.
      summarize the published studies on the use of daptomycin in combination with β-lactams and other antibiotics for the treatment of resistant gram-positive infections, including MRSA. The reader will find that the tables they present provide an excellent review of current strategies.
      It has been a privilege to serve as the infectious diseases topic editor for Clinical Therapeutics for the past 2 years, and now, in particular, to depart by honoring Bob Moellering’s contributions to us all with the articles presented herein.

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