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Daptomycin in Combination With Other Antibiotics for the Treatment of Complicated Methicillin-Resistant Staphylococcus aureus Bacteremia

      Abstract

      Purpose

      Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important nosocomial pathogens. Resistance to antibiotic therapy has been known to emerge especially in clinically complex scenarios, resulting in challenges in determining optimal treatment of serious MRSA. Daptomycin, in combination with other antibiotics, has been successfully used in the treatment of these infections, with the aims of resulting in reducing the prevention of antimicrobial resistance and increased killing compared with daptomycin monotherapy.

      Methods

      This article reviews all the published studies that used daptomycin combination therapy for the treatment of bacteremia and associated complicated infections caused by gram-positive organisms, including MRSA. We discuss the rationale of combination antibiotics and the mechanisms that enhance the activity of daptomycin, with special focus on the role of β-lactam antibiotics.

      Findings

      There are limited clinical data on the use of daptomycin in combination with other antibiotics. Most of this use was as successful salvage therapy in the setting of failing primary, secondary, or tertiary therapy and/or relapsing infection. Synergy between β-lactams and daptomycin is associated with several characteristics, including increased daptomycin binding and β-lactam–mediated potentiation of innate immunity, but the precise molecular mechanism is unknown.

      Implications

      Use of daptomycin in combination with other antibiotics, especially β-lactams, offers a promising treatment option for complicated MRSA bacteremia in which emergence of resistance during treatment may be anticipated. Because it is currently not possible to differentiate complicated from uncomplicated bacteremia at the time of presentation, combination therapy may be considered as first-line therapy, with de-escalation to monotherapy in uncomplicated cases and cases with stable pharmacologic and surgical source control.

      Key words

      Introduction

      This article reviews all the published studies that used daptomycin combination therapy for the treatment of bacteremia and associated complicated infections caused by gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). We discuss the rationale of combination antibiotics and the mechanisms that enhance the activity of daptomycin, with special focus on the role of β-lactam antibiotics.

      Results

      Daptomycin

      Daptomycin, a fermentation product of Streptomyces roseosporus, is a cyclic lipopeptide antibiotic with potent bactericidal activity against most gram-positive organisms. It is approved for the treatment of complicated skin and skin structure infections and S aureus bacteremia, including those with right-sided infective endocarditis, caused by methicillin-susceptible S aureus and MRSA.
      • Steenbergen J.N.
      • Alder J.
      • Thorne G.M.
      • Tally F.P.
      Daptomycin: A lipopeptide antibiotic for the treatment of serious Gram-positive infections.
      It has a unique structure among currently available antibiotics and a novel mechanism of action involving insertion of the lipophilic daptomycin tail into the bacterial cell membrane in a calcium-dependent manner, causing a potassium ion efflux and rapid membrane depolarization. This action is followed by arrest of DNA, RNA, and protein synthesis, resulting in bacterial cell death.
      • Silverman J.A.
      • Perlmutter N.G.
      • Shapiro H.M.
      Correlation of daptomycin bactericidal activity and membrane depolarization in staphylococcus aureus.
      In a simulated endocardial vegetation model, daptomycin remained bactericidal (99.9% kill within 24 hours) against stationary phase cultures of both methicillin-susceptible S aureus and MRSA present at high density (109 CFU).
      • Tedesco K.L.
      • Rybak M.J.
      Daptomycin.
      Daptomycin demonstrates concentration-dependent activity, a half-life of 8 hours, a prolonged postantibiotic effect (PAE) up to 6.8 hours, and linear pharmacokinetics with minimal drug accumulation.
      • Dvorchik B.H.
      • Brazier D.
      • DeBruin M.F.
      • Arbeit R.D.
      Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects.
      Daptomycin is primarily renally excreted, with the majority of the drug remaining intact in the urine. Because of daptomycin׳s unique mechanism of action and because it is not metabolized by cytochrome P-450 or other hepatic enzymes, it has minimal drug interactions.
      • Safdar N.
      • Andes D.
      • Craig W.A.
      In vivo pharmacodynamic activity of daptomycin.
      • Oleson F.B.
      • Berman C.L.
      • Li A.P.
      An evaluation of the P450 inhibition and induction potential of daptomycin in primary human hepatocytes.
      Based on its concentration-dependent activity, linear pharmacokinetics, and favorable safety profile, daptomycin has been used and studied at higher-than-indicated doses. Infectious Diseases Society of America guidelines from 2011 suggest using high-dose daptomycin (10 mg/kg/d), if the isolate is susceptible, in combination with another agent (eg, gentamicin 1 mg/kg IV every 8 hours, rifampin 600 mg PO/IV daily, or 300–450 mg PO/IV BID, linezolid 600 mg PO/IV BID, trimethoprim/sulfamethoxazole 5 mg/kg IV BID, or a β-lactam antibiotic) in the management of persistent MRSA bacteremia and vancomycin treatment failures in adult patients (B-III indication).
      • 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.
      Overall rates of resistance of daptomycin in staphylococci and enterococci remain rare. However, there are numerous reports of emergence of resistance during treatment with daptomycin in settings of at least one of the following factors: (1) high inoculum infections; (2) endovascular infections; (3) infections of biomedical devices with prolonged retention; (4) bone and joint infections; (5) hemodialysis patients; and (6) lower than recommended doses of daptomycin monotherapy.
      • Moise P.A.
      • North D.
      • Steenbergen J.N.
      • Sakoulas G.
      Susceptibility relationship between vancomycin and daptomycin in staphylococcus aureus: Facts and assumptions.
      Mechanisms of daptomycin resistance are still being elucidated and remain diverse. Daptomycin-resistant S aureus is usually caused by modification of the cell membrane. Resistant isolates often exhibit progressive accumulation of single nucleotide polymorphisms in the multipeptide resistance factor gene (mprF) and the yycFG components of the yycFGHI operon. Both of these loci are involved in key cell membrane events. mprF is responsible for the synthesis and outer cell membrane translocation of positively charged lysyl-phosphatidylglycerol. The resultant phenotype readout is increased in the relative positive surface charge and is associated with decreased daptomycin binding. It has also been demonstrated that the VraSR 2-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin.
      • Mehta S.
      • Cuirolo A.X.
      • Plata K.B.
      • et al.
      VraSR two-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin in in vivo-selected clinical strains of methicillin-resistant staphylococcus aureus.
      Other cell membrane mechanisms associated with daptomycin resistance in S aureus isolates are altered cell membrane order, increased cell membrane pigment production, resistance to depolarization and/or permeabilization, and reduced cell membrane peptidoglycan content. Modifications of the cell wall (including enhanced expression of dlt operon and progressive cell wall thickening) also contribute to daptomycin resistance.
      • Bayer A.S.
      • Schneider T.
      • Sahl H.G.
      Mechanisms of daptomycin resistance in staphylococcus aureus: Role of the cell membrane and cell wall.
      The mechanism of daptomycin resistance in enterococci may be associated with various gene mutations, increased septum formation, and alterations in membrane charge and phospholipid content. Whole-genome analysis suggests that mutations in several genes may play a role in the development of daptomycin resistance in enterococci. These include: (1) a 3-component regulatory system (designated liaFSR) that orchestrates the cell envelope response to antibiotics; (2) genes encoding proteins involved in phospholipid metabolism, including glycerophosphoryl diester phosphodiesterase (gdpD) and cardiolipin synthase (cls); and (3) a putative histidine kinase gene yycG, a member of the YycFG system that is involved in cell envelope homeostasis and daptomycin resistance in other gram-positive cocci. Nevertheless, none of the aforementioned gene mutations alone is sufficient to confer clinical levels of daptomycin resistance.
      • Arias C.A.
      • Panesso D.
      • McGrath D.M.
      • et al.
      Genetic basis for in vivo daptomycin resistance in enterococci.
      Furthermore, analysis of an isolated cave microbiome, in low G+C gram-positive bacteria, revealed a novel mechanism of daptomycin resistance that involved inactivation by hydrolytic cleavage of the ester bond between the threonine and kynurenine residues, resulting in ring-opening inactivation.
      • Bhullar K.
      • Waglechner N.
      • Pawlowski A.
      • et al.
      Antibiotic resistance is prevalent in an isolated cave microbiome.

      Rationale of Combination Antibiotics

      Combinations of antibiotics are used to take advantage of the agents’ different mechanisms of action and toxicity profiles. Common indications for combination antibiotic therapy is broad-spectrum empiric treatment of life-threatening infections, treatment of polymicrobial infections, minimization of drug toxicity by using relatively low doses of ≥2 drugs with additive efficacies but independent toxicities, prevention of emergence of antibiotic resistance to a single agent, and exploitation of the possibility of synergistic inhibitory or bactericidal activities. Antibiotic synergy refers to a net increased antimicrobial effect resulting from the interaction of ≥2 drugs that is greater than the sum of their independent contributions.
      • Moellering Jr, R.C.
      Rationale for use of antimicrobial combinations.
      • Eliopoulos G.M.
      Synergism and antagonism.
      Various mechanisms of this synergistic activity have been proposed. A cell wall–active agent with aminoglycoside proves synergistic activity, with increased intracellular uptake of aminoglycosides leading to enhanced killing and bactericidal activity in certain gram-positive organisms.
      • Holm S.E.
      Interaction between beta-lactam and other antibiotics.
      In addition, inactivating enzyme inhibitors (eg, a combination of a β-lactam agent plus β-lactamase inhibitors) are another possible mechanism of this synergistic activity. Other examples include combinations of drugs acting at proximate steps of a metabolic pathway (eg, trimethoprim/sulfamethoxazole rendering the combination drug bactericidal and less prone to resistance) and combinations of drugs acting at various levels of peptidoglycan synthesis (eg, β-lactams, fosfomycin, glycopeptides, and lipopeptides).
      • Rybak M.J.
      • McGrath B.J.
      Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician.
      Synergy in PAE is another possible mechanism. Synergistic PAEs have been observed classically in combinations of β-lactams with aminoglycosides and by addition of rifampin to other classes of drugs. Prolongation of PAE may provide higher protection against organism regrowth in situations when one or both antibiotics become subtherapeutic during the dosing interval.
      • Leggett J.E.
      • Ebert S.
      • Fantin B.
      • Craig W.A.
      Comparative dose-effect relations at several dosing intervals for beta-lactam, aminoglycoside and quinolone antibiotics against Gram-negative bacilli in murine thigh-infection and pneumonitis models.
      Disadvantages of combination therapy includes the possibility of antagonism, increased risk of adverse effects, risk of emergence of other resistant organisms, Clostridium difficile infection, and increased cost of therapy. Short-course, low-dose gentamicin combined with vancomycin for MRSA bacteremia and native valve endocarditis and in combination with other β-lactams may be associated with an increased risk of nephrotoxicity.
      • Cosgrove S.E.
      • Vigliani G.A.
      • Fowler Jr, V.G.
      • et al.
      Initial low-dose gentamicin for staphylococcus aureus bacteremia and endocarditis is nephrotoxic.
      • Buchholtz K.
      • Larsen C.T.
      • Hassager C.
      • Bruun N.E.
      Severity of gentamicin’s nephrotoxic effect on patients with infective endocarditis: A prospective observational cohort study of 373 patients.
      Based on the National Healthcare Safety Network data, in 2009–2010, S aureus remained the most common cause of health care–associated infection, with MRSA accounting for >50% of the clinical S aureus isolates recovered in US hospitals.
      • Sievert D.M.
      • Ricks P.
      • Edwards J.R.
      • et al.
      Antimicrobial-resistant pathogens associated with healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010.
      Infection with MRSA is associated with increased morbidity, requirement for a longer duration of antibiotic therapy, higher health care costs, prolonged hospitalization, and an increased risk of death.
      • Cosgrove S.E.
      • Sakoulas G.
      • Perencevich E.N.
      • et al.
      Comparison of mortality associated with methicillin-resistant and methicillin-susceptible staphylococcus aureus bacteremia: A meta-analysis.
      S aureus bacteremia is associated with a poor outcome and a high rate of secondary infections such as infective endocarditis, septic arthritis, and osteomyelitis.
      • Fowler Jr, V.G.
      • Olsen M.K.
      • Corey G.R.
      • et al.
      Clinical identifiers of complicated staphylococcus aureus bacteremia.
      Vancomycin has been the cornerstone of treatment of patients with serious MRSA infections for 5 decades. Consequently, vancomycin use has been increasing since the mid-1980s, resulting in the emergence of MRSA with reduced susceptibility to vancomycin. S aureus strains with reduced susceptibility can be divided into 3 categories; vancomycin-resistant strains (MIC, ≥16 μg/mL); vancomycin-intermediate strains (VISA; MIC, ≥4 μg/mL); and heterogeneous VISA, which have MIC <4 μg/mL but subpopulations that grow at higher MICs.
      Within the populations of S aureus that are considered to be susceptible, a changing pattern of vancomycin MICs has been observed in some centers, demonstrating an overall population drift in the clinical isolates of S aureus toward reduced vancomycin susceptibility. This phenomenon of “vancomycin MIC creep” varies considerably around the world and may not be uniformly applicable in all health care settings.
      • Dhand A.
      • Sakoulas G.
      Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
      Infections caused by MRSA with higher vancomycin MICs are seen in patients with recent exposure to vancomycin within 1 month of the current infection, recent hospitalization, surgery within the last 6 months, and those with bloodstream infections before admission in intensive care units. In the treatment of MRSA bloodstream infections with vancomycin, higher vancomycin MIC values (≥1.5 μg/mL), regardless of MIC testing method and infection source, are predictive of treatment failure and associated with higher mortality.
      • van Hal S.J.
      • Lodise T.P.
      • Paterson D.L.
      The clinical significance of vancomycin minimum inhibitory concentration in staphylococcus aureus infections: A systematic review and meta-analysis.
      These data highlighting such poor outcomes in patients with serious MRSA infections (including bacteremia) suggest that in many of these instances, the treatment strategy of vancomycin specifically, and monotherapy in general, seems to be failing. Evidence is mounting that serious MRSA infections such as bacteremia may require combination antibiotic therapy for optimal management, improving antibiotic durability and slowing the rate of emergence of resistance.
      • Gould I.M.
      • Miro J.M.
      • Rybak M.J.
      Daptomycin: The role of high-dose and combination therapy for Gram-positive infections.
      • 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.
      • McConeghy K.W.
      • Bleasdale S.C.
      • Rodvold K.A.
      The empirical combination of vancomycin and a beta-lactam for staphylococcal bacteremia.
      • Sakoulas G.
      • Moise P.A.
      • Casapao A.M.
      • et al.
      Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.
      • Dilworth T.J.
      • Ibrahim O.
      • Hall P.
      • et al.
      Beta-lactams enhance vancomycin activity against methicillin-resistant staphylococcus aureus bacteremia compared to vancomycin alone.
      Although new antimicrobial drugs (eg, linezolid, daptomycin, tigecycline, telavancin, ceftaroline) have been developed, none has been shown to be consistently superior to vancomycin for the treatment of MRSA infections.
      • Gould I.M.
      • David M.Z.
      • Esposito S.
      • et al.
      New insights into methicillin-resistant staphylococcus aureus (MRSA) pathogenesis, treatment and resistance.
      • Culos K.A.
      • Cannon J.P.
      • Grim S.A.
      Alternative agents to vancomycin for the treatment of methicillin-resistant staphylococcus aureus infections.
      • Rodvold K.A.
      • McConeghy K.W.
      Methicillin-resistant staphylococcus aureus therapy: Past, present, and future.
      This finding is likely due to the fact that most of the randomized clinical trials comparing the newer antibiotics with vancomycin are restricted to relatively “low-risk” clinical situations because of the use stringent exclusionary criteria.
      The optimal treatment of complicated MRSA infections thus remains a challenge. Physicians and pharmacists are meeting these challenges in a variety of ways, including: (1) the adoption of rapid molecular tests to quickly differentiate MRSA from β-lactam– susceptible strains and, therefore, convert patients with the latter more rapidly to superior β-lactam therapy; (2) optimization of antibiotic doses targeting higher trough levels for vancomycin and higher daptomycin levels for breakthrough MRSA infections and serious vancomycin-resistant enterococci infections; (3) switching early-on to alternative agents for MRSA infections when vancomycin MIC is 2 mg/L; and (4) using combination antibiotic therapy.
      The combination of high-dose daptomycin with a second antibiotic has been used to treat refractory S aureus bacteremia because: (1) vancomycin first-line therapy has been shown to elicit changes that confer cross-resistance to daptomycin
      • Sakoulas G.
      • Alder J.
      • Thauvin-Eliopoulos
      • et al.
      Induction of daptomycin heterogeneous susceptibility in Staphylococcus aureus by exposure to vancomycin.
      ; (2) in vivo persistence under selection pressure from innate cationic host defense peptides also independently select for reduced susceptibility 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.
      ; and (3) organisms that establish endovascular infections such as endocarditis that frequently are the cause of persistent bacteremia demonstrate a fitness advantage of intrinsic resistance to cationic host defense peptides, with resulting increased heteroresistance to daptomycin.
      • Gould I.M.
      • Miro J.M.
      • Rybak M.J.
      Daptomycin: The role of high-dose and combination therapy for Gram-positive infections.
      • Mishra N.N.
      • Yang S.J.
      • Chen L.
      • et al.
      Emergence of daptomycin resistance in daptomycin-naive rabbits with methicillin-resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms.
      • Moise P.A.
      • Forrest A.
      • Bayer A.S.
      • et al.
      Factors influencing time to vancomycin-induced clearance of nonendocarditis methicillin-resistant Staphylococcus aureus bacteremia: role of platelet microbicidal protein killing and agr genotypes.
      • Bayer A.S.
      • Cheng D.
      • Yeaman M.R.
      • et al.
      In vitro resistance to thrombin-induced platelet microbicidal protein among clinical bacteremic isolates of Staphylococcus aureus correlates with an endovascular infectious source.
      • Sakoulas G.
      • Eliopoulos G.M.
      • Fowler Jr, V.G.
      • et al.
      Reduced susceptibility of Staphylococcus aureus to vancomycin and platelet microbicidal protein correlates with defective autolysis and loss of accessory gene regulator (agr) function.

      Combination of Antibiotics With Daptomycin: Clinical Data

      In vitro data of interactions between daptomycin and other antibiotics have been reviewed extensively in other publications.
      • Gould I.M.
      • Miro J.M.
      • Rybak M.J.
      Daptomycin: The role of high-dose and combination therapy for Gram-positive infections.
      • Steenbergen J.N.
      • Mohr J.F.
      • Thorne G.M.
      Effects of daptomycin in combination with other antimicrobial agents: A review of in vitro and animal model studies.
      • Nadrah K.
      • Strle F.
      Antibiotic combinations with daptomycin for treatment of staphylococcus aureus infections.
      There are limited clinical data on the use of daptomycin in combination with other antibiotics. Most of this use has occurred in the setting of failing therapy and/or relapsing infection and “difficult to treat” infections. Characteristics of the antibiotics that were used in these studies, their mechanism of action, mechanism of resistance, and possible mechanisms of interactions with daptomycin are summarized in Table I.
      • Chambers H.F.
      Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.
      • Sakoulas G.
      • Okumura C.Y.
      • Thienphrapa W.
      • et al.
      Nafcillin enhances innate immune-mediated killing of methicillin-resistant staphylococcus aureus.
      • Kuroda H.
      • Kuroda M.
      • Cui L.
      • Hiramatsu K.
      Subinhibitory concentrations of beta-lactam induce haemolytic activity in staphylococcus aureus through the SaeRS two-component system.
      • Kirby W.M.
      Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci.
      • Arias C.A.
      • Murray B.E.
      The rise of the enterococcus: Beyond vancomycin resistance.
      • 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”).
      • Moreira B.
      • Boyle-Vavra S.
      • deJonge B.L.
      • Daum R.S.
      Increased production of penicillin-binding protein 2, increased detection of other penicillin-binding proteins, and decreased coagulase activity associated with glycopeptide resistance in staphylococcus aureus.
      • Entenza J.M.
      • Giddey M.
      • Vouillamoz J.
      • Moreillon P.
      In vitro prevention of the emergence of daptomycin resistance in staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin.
      • Mehta S.
      • Singh C.
      • Plata K.B.
      • et al.
      Beta-lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives.
      • Campbell E.A.
      • Korzheva N.
      • Mustaev A.
      • et al.
      Structural mechanism for rifampicin inhibition of bacterial RNA polymerase.
      • Wichelhaus T.A.
      • Schafer V.
      • Brade V.
      • Boddinghaus B.
      Molecular characterization of rpoB mutations conferring cross-resistance to rifamycins on methicillin-resistant staphylococcus aureus.
      • Rand K.H.
      • Houck H.
      Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci.
      • Hitchings G.H.
      Mechanism of action of trimethoprim-sulfamethoxazole.
      • Proctor R.A.
      Role of folate antagonists in the treatment of methicillin-resistant staphylococcus aureus infection.
      • Raz R.
      Fosfomycin: An old--new antibiotic.
      • Falagas M.E.
      • Roussos N.
      • Gkegkes I.D.
      • et al.
      Fosfomycin for the treatment of infections caused by Gram-positive cocci with advanced antimicrobial drug resistance: A review of microbiological, animal and clinical studies.
      Table ICharacteristics of antibiotics used as combination therapy with daptomycin (DAP).
      DrugMechanism of ActionMechanism of ResistanceInteraction With DAP
      β-lactams
      • β-lactams act as substrate analogs for the PBPs.
      • They bind irreversibly to the PBPs’ active site, leading to termination of peptidoglycan cross-linking causing disruption of cell wall leading to cell lysis and death
        • Chambers H.F.
        Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.
      • Antistaphylococal β-lactams also sensitize MRSA for augmented clearance by innate immune effectors as phagocytes and cationic host defense peptides from keratinocytes, neutrophils, and platelets
        • Dhand A.
        • Sakoulas G.
        Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
        • Sakoulas G.
        • Okumura C.Y.
        • Thienphrapa W.
        • et al.
        Nafcillin enhances innate immune-mediated killing of methicillin-resistant staphylococcus aureus.
      • β-lactams may inhibit surface expression of fibronectin binding protein gene, thereby diminishing endovascular and osteoarticular virulence
        • Kuroda H.
        • Kuroda M.
        • Cui L.
        • Hiramatsu K.
        Subinhibitory concentrations of beta-lactam induce haemolytic activity in staphylococcus aureus through the SaeRS two-component system.
      • Staphylococci:
      • Mutations in PBPs: PBP2a, PBP2׳, resulting in decreased affinity to all β-lactams
        • Chambers H.F.
        Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.
      • Expression of blaZ gene: degradation of penicillins
        • Kirby W.M.
        Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci.
      • Enterococci:
      • High levels of resistance involves expression of PBP5-R, alterations in the PBP5 protein around the active site, increased expression of PBP5, and utilization of a β-lactam–insensitive transpeptidase for cell wall synthesis
        • Arias C.A.
        • Murray B.E.
        The rise of the enterococcus: Beyond vancomycin resistance.
      • See-saw effect:
      • Increased susceptibility of antistaphylococcal β-lactam antibiotics with reduced susceptibility to glycopeptides and lipopeptides
        • 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”).
        .
      • This is possibly mediated by reduction of PBP4 and PBP2a with a relative increase in PBP2
        • Moreira B.
        • Boyle-Vavra S.
        • deJonge B.L.
        • Daum R.S.
        Increased production of penicillin-binding protein 2, increased detection of other penicillin-binding proteins, and decreased coagulase activity associated with glycopeptide resistance in staphylococcus aureus.
      • Synergy:
      • β-lactam exposure increases the net surface negative charge on the bacterial cell wall leading to increased binding of the positively charged DAP Ca2+ complex, which results in synergy and enhanced killing.
      • β-lactam exposure leads to host defense peptide–mediated innate immune response against MRSA, resulting in additional synergy between them and DAP or vancomycin
        • Dhand A.
        • Sakoulas G.
        Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
        • Sakoulas G.
        • Okumura C.Y.
        • Thienphrapa W.
        • et al.
        Nafcillin enhances innate immune-mediated killing of methicillin-resistant staphylococcus aureus.
      • Combination of DAP and a β-lactam delays or prevents the selection of DAP-resistant variants in vitro
        • Entenza J.M.
        • Giddey M.
        • Vouillamoz J.
        • Moreillon P.
        In vitro prevention of the emergence of daptomycin resistance in staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin.
        • Mehta S.
        • Singh C.
        • Plata K.B.
        • et al.
        Beta-lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives.
      RifampinRifampin acts by interacting specifically with bacterial RNA polymerase encoded by the gene rpoB
      • Campbell E.A.
      • Korzheva N.
      • Mustaev A.
      • et al.
      Structural mechanism for rifampicin inhibition of bacterial RNA polymerase.
      • Mutations in rpoB, the gene that encodes the β subunit of RNA polymerase, are responsible for rifampin resistance.
        • Wichelhaus T.A.
        • Schafer V.
        • Brade V.
        • Boddinghaus B.
        Molecular characterization of rpoB mutations conferring cross-resistance to rifamycins on methicillin-resistant staphylococcus aureus.
      • Because of the rapid development of resistance, it should not be used as monotherapy but may be used in combination with another active antibiotic in selected scenarios
      • In vitro synergy has been show with various antibiotics, including DAP.
      • In the presence of DAP, a striking reduction in the rifampicin MIC was seen in 11 of 15 (73.3%) VRE that were resistant to rifampicin
        • Rand K.H.
        • Houck H.
        Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci.
      TMP/SMTThe 2 components, TMP and SMT, work sequentially to inhibit enzyme systems involved in the bacterial synthesis of tetrahydrofolic acid. Reduced availability of tetrahydrofolic acid inhibits thymidine synthesis and, subsequently, DNA synthesis. The combination (TMP/SMT) has a broader spectrum of antimicrobial activity, is more rapidly bactericidal, and is less susceptible to the development of resistance than either of the component drugs
      • Hitchings G.H.
      Mechanism of action of trimethoprim-sulfamethoxazole.
      • Overproduction of para-aminobenzoic acid causes resistance to sulfonamides.
      • Amino acid substitutions in both enzymes (dihydropteroate synthase and tetrahydrofolate reductase).
      • Exogenous thymidine as produced by some staphylococci also renders TMP/SMT inactive because it bypasses the double biosynthetic blockade
        • Proctor R.A.
        Role of folate antagonists in the treatment of methicillin-resistant staphylococcus aureus infection.
      In vitro synergy has been show with various antibiotics, including DAP
      FosfomycinTargets the bacterial mucopeptide synthesis by inhibiting phosphoenolpyruvate transferase, which is involved in peptidoglycan synthesis. This results in a broad-spectrum bactericidal effect
      • Raz R.
      Fosfomycin: An old--new antibiotic.
      In gram-positive organisms, resistance may be mediated by fosfomycin resistance proteins (FosA, FosB, or FoX) that chemically modify and inactivate the drug
      • Raz R.
      Fosfomycin: An old--new antibiotic.
      • In vitro synergy has been show with various antibiotics, including DAP.
        • Falagas M.E.
        • Roussos N.
        • Gkegkes I.D.
        • et al.
        Fosfomycin for the treatment of infections caused by Gram-positive cocci with advanced antimicrobial drug resistance: A review of microbiological, animal and clinical studies.
      • Similar to other cell wall active agents such as β-lactams, fosfomycin may also lead to increased DAP binding by altering the charge of the outer membrane.
      PBP = penicillin-binding proteins; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant enterococci; TMP/SMT = trimethoprim/sulfamethoxazole.
      Table II
      • Dhand A.
      • Sakoulas G.
      Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
      • Arias C.A.
      • Torres H.A.
      • Singh K.V.
      • et al.
      Failure of daptomycin monotherapy for endocarditis caused by an enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster.
      • Sakoulas G.
      • Bayer A.S.
      • Pogliano J.
      • et al.
      Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant enterococcus faecium.
      • Rose W.E.
      • Schulz L.T.
      • Andes D.
      • et al.
      Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible staphylococcus aureus during therapy improves antibacterial activity.
      • Sierra-Hoffman M.
      • Iznaola O.
      • Goodwin M.
      • Mohr J.
      Combination therapy with ampicillin and daptomycin for treatment of enterococcus faecalis endocarditis.
      • Moise P.A.
      • Amodio-Groton M.
      • Rashid M.
      • et al.
      Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant beta-lactams in patients with staphylococcus aureus bacteremia and mild to moderate renal impairment.
      • Sakoulas G.
      • Nonejuie P.
      • Nizet V.
      • et al.
      Treatment of high-level gentamicin-resistant enterococcus faecalis endocarditis with daptomycin plus ceftaroline.
      • Stevens M.P.
      • Edmond M.B.
      Endocarditis due to vancomycin-resistant enterococci: Case report and review of the literature.
      • Ahmad N.M.
      • Rojtman A.D.
      Successful treatment of daptomycin-nonsusceptible methicillin-resistant staphylococcus aureus bacteremia with the addition of rifampin to daptomycin.
      • Lee D.H.
      • Palermo B.
      • Chowdhury M.
      Successful treatment of methicillin-resistant staphylococcus aureus meningitis with daptomycin.
      • Jugun K.
      • Vaudaux P.
      • Garbino J.
      • et al.
      The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections.
      • Rose W.E.
      • Berti A.D.
      • Hatch J.B.
      • Maki D.G.
      Relationship of in vitro synergy and treatment outcome with daptomycin plus rifampin in patients with invasive methicillin-resistant staphylococcus aureus infections.
      • Avery L.M.
      • Steed M.E.
      • Woodruff A.E.
      • et al.
      Daptomycin-nonsusceptible vancomycin-intermediate staphylococcus aureus vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole.
      • Di Carlo P.
      • D’Alessandro N.
      • Guadagnino G.
      • et al.
      High dose of trimethoprim-sulfamethoxazole and daptomycin as a therapeutic option for MRSA endocarditis with large vegetation complicated by embolic stroke: A case report and literature review.
      • Miro J.M.
      • Entenza J.M.
      • Del Rio A.
      • et al.
      High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant staphylococcus aureus endocarditis.
      • Chen L.Y.
      • Huang C.H.
      • Kuo S.C.
      • et al.
      High-dose daptomycin and fosfomycin treatment of a patient with endocarditis caused by daptomycin-nonsusceptible staphylococcus aureus: Case report.
      • Teng S.
      • Lee W.
      • Ou T.
      Combination therapy of daptomycin and fosfomycin for vancomycin tolerant methicillin-resistant staphylococcus aureus endocarditis complicating metastatic osteomyelitis.
      • Jenkins I.
      Linezolid- and vancomycin-resistant enterococcus faecium endocarditis: Successful treatment with tigecycline and daptomycin.
      • Schutt A.C.
      • Bohm N.M.
      Multidrug-resistant enterococcus faecium endocarditis treated with combination tigecycline and high-dose daptomycin.
      • Kelesidis T.
      • Humphries R.
      • Ward K.
      • et al.
      Combination therapy with daptomycin, linezolid, and rifampin as treatment option for MRSA meningitis and bacteremia.
      summarizes the clinical data regarding the use of daptomycin in combination with other antibiotics for the treatment of complicated bacteremia and other associated invasive infections caused by resistant gram-positive organisms. In these studies, daptomycin was used in combination with β-lactams, rifampin, trimethoprim-sulfamethoxazole, fosfomycin, tigecycline, and linezolid. Because most of the available clinical and in vitro data are for the combination therapy of daptomycin with various β-lactam agents, further discussion will focus primarily on this combination.
      Table IISummary of clinical studies with daptomycin (DAP) combination therapy for disseminated infections.
      StudyAntibioticInfectionOutcomeComments
      Antibiotic combination of DAP + β-lactam agent
       Arias et al,
      • Arias C.A.
      • Torres H.A.
      • Singh K.V.
      • et al.
      Failure of daptomycin monotherapy for endocarditis caused by an enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster.
      2007
      DAP 8 mg/kg/dEnterococcus faecium (VRE)Cure at 6-month follow-upDAP heteroresistance noted
      Ampicillin 16 gm/dMV endocarditisDAP MIC, 2–4; ampicillin MIC, 16–34
      Gentamicin 1 mg/kg q 12 × 6 weeksRelapsing bacteremia
       Dhand and Sakoulas,
      • Dhand A.
      • Sakoulas G.
      Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
      2011
      Daptomycin (high dose) + nafcillin/oxacillinSeries of 7 patients with noncatheter-associated persistent MRSA bacteremiaRapid clearance of bacteremia after addition of β-lactamInitial cure in 7 of 7 patients, with a delayed relapse in 2 of the 7 patients. One isolate developed DAP nonsusceptibility. In vitro studies showed enhanced DAP bactericidal activity, increased membrane DAP binding, and decreases in positive surface charge induced by ASBLs against DAP nonsusceptible MRSA
       Sakoulas et al,
      • Sakoulas G.
      • Bayer A.S.
      • Pogliano J.
      • et al.
      Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant enterococcus faecium.
      2011
      • DAP 12 mg/kg/dose
      • Ampicillin 1 g q 6
      • E faecium (VRE)
      • DAP MIC 1
      • Ampicillin MIC, >128
      Rapid clearance of persistent bacteremiaAddition of ampicillin to DAP in vitro enhanced DAP activity and binding, changed the antibiotic profile from static to bactericidal, showed slow reduction in net positive surface charge, and made VRE more susceptible to killing by innate immune response mediated by cationic host defense peptides
       Rose et al,
      • Rose W.E.
      • Schulz L.T.
      • Andes D.
      • et al.
      Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible staphylococcus aureus during therapy improves antibacterial activity.
      2012
      • DAP 10 mg/kg/dose
      • Ceftaroline 200 mg q 12
      • S aureus
      • (MRSA, DNSA, VISA)
      • HD catheter–related bacteremia, right-sided endocarditis, septic arthritis
      Clearance of bacteremiaCeftaroline restored DAP sensitivity in vivo. Improved DAP susceptibility in vitro in presence of oxacillin and ceftaroline. Rapid and sustained bactericidal activity
      Combination prevented emergence of DAP resistance in vitro. In DNSA, higher dose of DAP is required to optimize cell membrane damage
       Sierra-Hoffman et al,
      • Sierra-Hoffman M.
      • Iznaola O.
      • Goodwin M.
      • Mohr J.
      Combination therapy with ampicillin and daptomycin for treatment of enterococcus faecalis endocarditis.
      2012
      • DAP 6 mg/kg q 48
      • Ampicillin 1 g q 6 × 6 weeks
      • E faecalis
      • MV endocarditis
      Cure at 12-month follow-up
      • DAP MIC, <4; ampicillin sensitive
      • Overall efficacy of DAP was slightly enhanced (not statistically significant) with the addition of β-lactams. This benefit was most pronounced in bacteremia associated with endocarditis, osteoarticular infection, and bacteremia of unknown source. Combination therapy was well tolerated.
       Moise et al,
      • Moise P.A.
      • Amodio-Groton M.
      • Rashid M.
      • et al.
      Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant beta-lactams in patients with staphylococcus aureus bacteremia and mild to moderate renal impairment.
      2013
      Daptomycin with and without β-lactam
      • CORE data 2005–2009
      • 106 patients with S aureus bacteremia
      Addition of rifampin or gentamicin or vancomycin to DAP did not result in any significant change in outcome
       Sakoulas et al,
      • Sakoulas G.
      • Nonejuie P.
      • Nizet V.
      • et al.
      Treatment of high-level gentamicin-resistant enterococcus faecalis endocarditis with daptomycin plus ceftaroline.
      2013
      • DAP 8 mg/kg/dose
      • Ceftaroline 600 mg q 8
      • E faecalis
      • Aortic valve endocarditis
      • High-level gentamicin resistance
      • Clearance of bacteremia
      • Cure after 4 week of therapy and AVR
      • In vitro: 4-fold decrease in DAP MIC with addition of ampicillin or ceftaroline and synergy between DAP and ceftaroline.
      • Enhancement of cathelicidin peptide activity and DAP binding in presence of ceftaroline
      Antibiotic combination of DAP + rifampin
       Stevens and Edmond,
      • Stevens M.P.
      • Edmond M.B.
      Endocarditis due to vancomycin-resistant enterococci: Case report and review of the literature.
      2005
      • DAP 8 mg/kg/dose
      • Rifampin 300 mg q 8 h
      • Gentamicin after HD
      • 11 weeks
      • E faecium (VRE)
      • Prosthetic MV endocarditis
      • DAP MIC, 4
      No microbiologic reoccurrence after 4 weeks of completionIn vitro synergy noted between DAP/rifampin/gentamicin
       Ahmad and Rojtman,
      • Ahmad N.M.
      • Rojtman A.D.
      Successful treatment of daptomycin-nonsusceptible methicillin-resistant staphylococcus aureus bacteremia with the addition of rifampin to daptomycin.
      2010
      • DAP 6 mg/kg/dose
      • Rifampin 300 mg q12 h
      • 6 weeks
      • Persistent MRSA bacteremia
      • DAP MIC increased to 2 while on DAP therapy
      • Rapid clearance of bacteremia after adding rifampin.
      • Cure at 4-month follow-up
      No in vitro synergy was noted
       Lee et al,
      • Lee D.H.
      • Palermo B.
      • Chowdhury M.
      Successful treatment of methicillin-resistant staphylococcus aureus meningitis with daptomycin.
      2008
      • DAP 6 mg/kg/dose
      • Rifampin 6 weeks
      MRSA Bacteremia, Likely AV graft infection, Septic brain emboli, meningitisCureMRSA DAP MIC, 1 Leukocytoclastic vasculitis with vancomycin. Rifampin added for CNS disease
       Jugun et al,
      • Jugun K.
      • Vaudaux P.
      • Garbino J.
      • et al.
      The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections.
      2013
      • DAP 8 mg/kg/dose
      • Rifampin 600 mg q 24 h
      Gram-positive osteoarticular infections, N = 16 (staphylococcal, n = 15, streptococcal, n = 1)Successful outcomes at >1-year follow-upMedian duration of treatment was 21 days (range, 10–122 days). Combination therapy well tolerated. Prosthetic device removal in 5 of 16, device exchange in 4 of 16, and device retention in 4 of 16
       Rose et al,
      • Rose W.E.
      • Berti A.D.
      • Hatch J.B.
      • Maki D.G.
      Relationship of in vitro synergy and treatment outcome with daptomycin plus rifampin in patients with invasive methicillin-resistant staphylococcus aureus infections.
      2013
      DAP 4–8 mg/kg/dose Rifampin 300–600 mg/dMRSA (n = 12) Osteoarticular (N = 9) HD catheter infection (1) Prosthetic valve endocarditis (1)Cure in 9 of 12 patientsCheckerboard synergy was seen in 9 of 12 patients and was predictive of therapeutic success. Failure seen in prosthetic joint infection and deep abscess
      Antibiotic combination of DAP + TMP/SMT
       Avery et al,
      • Avery L.M.
      • Steed M.E.
      • Woodruff A.E.
      • et al.
      Daptomycin-nonsusceptible vancomycin-intermediate staphylococcus aureus vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole.
      2012
      DAP 10 mg/kg/dose TMP/SMT IV to oralDNSA, VISA 1. Bacteremia with vertebral osteomyelitis 2. Bacteremia, TV endocarditis, osteomyelitis
      • 1. Cure
      • 2. Clearance of persistent bacteremia
      Suppression with oral TMP/SMT; course complicated by reversible myopathy and renal failure. In vitro combination showed sustained bactericidal activity at 36 to 48 hours
       DiCarlo et al,
      • Di Carlo P.
      • D’Alessandro N.
      • Guadagnino G.
      • et al.
      High dose of trimethoprim-sulfamethoxazole and daptomycin as a therapeutic option for MRSA endocarditis with large vegetation complicated by embolic stroke: A case report and literature review.
      2013
      DAP 8 mg/kg/dose TMP/SMT 15 mg/kg/dMRSA bacteremia MV endocarditis Intracranial hemorrhageCure6 weeks of oral TMP/SMT after 6 weeks of combination IV therapy VAN MIC, 2
      Antibiotic combination of DAP + fosfomycin
       Miro et al,
      • Miro J.M.
      • Entenza J.M.
      • Del Rio A.
      • et al.
      High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant staphylococcus aureus endocarditis.
      2012
      DAP 10 mg/kg/d3 cases of left-sided endocarditisAlive at >6-month follow-upIn vitro activity of combination against (7 MSSA, 5 MRSA, 2 GISA) isolates showed synergy in 79% of isolates and bactericidal activity in 57% of isolates. Combination therapy was well tolerated
      FOS 2 g q 6 h(MRSA, n = 2; MSSA, n = 1)
       Chen et al,
      • Chen L.Y.
      • Huang C.H.
      • Kuo S.C.
      • et al.
      High-dose daptomycin and fosfomycin treatment of a patient with endocarditis caused by daptomycin-nonsusceptible staphylococcus aureus: Case report.
      2011
      DAP 12 mg/kg/d FOS 6 g q 6 hMRSA/DNSA bacteremia, AICD infection, endocarditis, osteomyelitisCureDelayed surgical removal of pacing wire. Eight weeks of intravenous therapy. Combination well tolerated. In vitro additive effect.
       Teng et al,
      • Teng S.
      • Lee W.
      • Ou T.
      Combination therapy of daptomycin and fosfomycin for vancomycin tolerant methicillin-resistant staphylococcus aureus endocarditis complicating metastatic osteomyelitis.
      2012
      DAP 12 mg/kg/dMSSA, VT-MRSACureCombination well tolerated
      FOS 6 g q 6 hBacteremia,
      MV endocarditis, osteomyelitis
      Antibiotic combination of DAP + tigecycline
       Jenkins,
      • Jenkins I.
      Linezolid- and vancomycin-resistant enterococcus faecium endocarditis: Successful treatment with tigecycline and daptomycin.
      2007
      DAP 6 mg/kg/doseE faecium (VRE)Cure at 16-week follow-up
      Tigecycline 50 mg q 12 hMV endocarditis
      × 70 dDAP MIC, 4
       Schutt and Bohm,
      • Schutt A.C.
      • Bohm N.M.
      Multidrug-resistant enterococcus faecium endocarditis treated with combination tigecycline and high-dose daptomycin.
      2009
      DAP 8 mg/kg/dose Tigecycline 50 mg q 12 hE faecium (VRE) Bacteremia Possible TV endocarditis with pulmonary septic emboliRapid clearance of refractory bacteremiaResistant to vancomycin, linezolid. DAP MIC, 3–4
      Antibiotic combination of DAP + linezolid + rifampin
       Kelesidis et al,
      • Kelesidis T.
      • Humphries R.
      • Ward K.
      • et al.
      Combination therapy with daptomycin, linezolid, and rifampin as treatment option for MRSA meningitis and bacteremia.
      2011
      DAP × 6 weeks Linezolid 600 mg q 12 h Rifampin 300 mg q 12 hMRSA prosthetic device infection, bacteremia, meningitis, osteomyelitisCure after removal of shunt and combination antibioticsIn vitro analysis found that combination of linezolid with DAP produced indifference in checkerboard analysis and antagonism in time-kill assays. The addition of rifampin to the combination linezolid + DAP resulted in synergy in the time-kill assays when tested at 0.5 times the MICs for each drug and achieved 99.9% killing significantly quicker than the other combinations
      VRE = vancomycin-resistant enterococci; MV = mitral valve; MRSA = methicillin- resistant Staphylococcus aureus; ASBL = antistaphylococal β-lactam; DNSA = DAP nonsusceptible S aureus; VISA = vancomycin-intermediate S aureus; HD = hemodialysis; CORE = Cubicin Outcomes Registry and Experience; AVR = aortic valve replacement; AV = arteriovenous; CNS = central nervous system; TMP/SXT = trimethoprim/sulfamethoxazole; FOS = fosfomycin; TV = tricuspid valve; MSSA = methicillin-susceptible Staphylococcus aureus; GISA = glycopeptide-intermediate Staphylococcus aureus; AICD = automated implantable cardioverter-defibrillator; VT = vancomycin tolerant.

      Daptomycin and β-Lactam Combination Therapy

      Daptomycin and β-lactam combinations have been used successfully and increasingly as salvage treatment for refractory or relapsing infections caused by resistant gram-positive organisms (Table II). In addition to the “see-saw” effect,
      • Ortwine J.K.
      • Werth B.J.
      • Sakoulas G.
      • Rybak M.J.
      Reduced glycopeptide and lipopeptide susceptibility in staphylococcus aureus and the “seesaw effect”: Taking advantage of the back door left open?.
      the improved outcomes are based on:
      • Synergy: β-lactam exposure increases the net surface negative charge on the bacterial cell wall leading to increased binding of the positively charged daptomycin Ca2+ complex, resulting in synergy and enhanced killing of resistant gram-positive organisms.
        • Dhand A.
        • Sakoulas G.
        Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
        • Sakoulas G.
        • Okumura C.Y.
        • Thienphrapa W.
        • et al.
        Nafcillin enhances innate immune-mediated killing of methicillin-resistant staphylococcus aureus.
        • Sakoulas G.
        • Bayer A.S.
        • Pogliano J.
        • et al.
        Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant enterococcus faecium.
      • β-lactam–mediated increased killing by various cationic host defense peptides (HDPs): Increased resistance to vancomycin and daptomycin is associated with concomitant resistant to various HDPs that are produced by platelets, leukocytes, and keratinocytes.
        • Mishra N.N.
        • Yang S.J.
        • Chen L.
        • et al.
        Emergence of daptomycin resistance in daptomycin-naive rabbits with methicillin-resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms.
        Antistaphylococal β-lactams sensitize MRSA for augmented clearance by innate immune effectors such as HDP and phagocytes and therefore augment the synergistic activity between these antistaphylococal β-lactams and daptomycin.
        • Dhand A.
        • Sakoulas G.
        Reduced vancomycin susceptibility among clinical staphylococcus aureus isolates (‘the MIC creep’): Implications for therapy.
        • Sakoulas G.
        • Okumura C.Y.
        • Thienphrapa W.
        • et al.
        Nafcillin enhances innate immune-mediated killing of methicillin-resistant staphylococcus aureus.
        • Sakoulas G.
        • Rose W.
        • Nonejuie P.
        • et al.
        Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycin-resistant enterococcus faecium.
      • Prevention of emergence of resistance: β-lactams when used along with daptomycin prevent the emergence of resistance to daptomycin in clinical MRSA isolates and in enterococci.
        • Entenza J.M.
        • Giddey M.
        • Vouillamoz J.
        • Moreillon P.
        In vitro prevention of the emergence of daptomycin resistance in staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin.
        • Mehta S.
        • Singh C.
        • Plata K.B.
        • et al.
        Beta-lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives.
        • Rose W.E.
        • Schulz L.T.
        • Andes D.
        • et al.
        Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible staphylococcus aureus during therapy improves antibacterial activity.
        • Berti A.D.
        • Wergin J.E.
        • Girdaukas G.G.
        • et al.
        Altering the proclivity towards daptomycin resistance in methicillin-resistant staphylococcus aureus using combinations with other antibiotics.

      Unique Role of Ceftaroline

      Unlike other β-lactams, ceftaroline has activity against MRSA, heterogeneous VISA, VISA, vancomycin-resistant strains, and daptomycin-nonsusceptible S aureus, which is mediated by binding to PBP2a with 128 times greater affinity than any other clinically available β-lactam.
      • Kosowska-Shick K.
      • McGhee P.L.
      • Appelbaum P.C.
      Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from staphylococcus aureus and streptococcus pneumoniae.
      Because PBP2a on the cell surface decreases with reduced glycopeptide and lipopeptide susceptibility, the enhanced activity of daptomycin mediated by ceftaroline is likely a result of synergistic activity as well. Ceftaroline has been used in combination with daptomycin to eradicate resistant S aureus and enterococcal infections and offers an attractive and potent therapeutic option for the treatment of resistant gram-positive infections.
      • Rose W.E.
      • Schulz L.T.
      • Andes D.
      • et al.
      Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible staphylococcus aureus during therapy improves antibacterial activity.
      • Sakoulas G.
      • Nonejuie P.
      • Nizet V.
      • et al.
      Treatment of high-level gentamicin-resistant enterococcus faecalis endocarditis with daptomycin plus ceftaroline.
      • Sakoulas G.
      • Rose W.
      • Nonejuie P.
      • et al.
      Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycin-resistant enterococcus faecium.
      • Werth B.J.
      • Sakoulas G.
      • Rose W.E.
      • et al.
      Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate staphylococcus aureus in a pharmacokinetic/pharmacodynamic model.

      Is the Synergistic Activity of All β-Lactams With Daptomycin the Same?

      While nafcilln and oxacillin enhance daptomycin and killing of MRSA, b-lactam antibiotics with penicillin-binding protein-1 (PBP1) binding demonstrate enhance the activity of daptomycin compared to those with relatively less PBP1 binding (cefoxitin, and cefaclor).
      • Berti A.D.
      • Sakoulas G.
      • Nizet V.
      • et al.
      Beta-lactam antibiotics targeting PBP1 selectively enhance daptomycin activity against methicillin-resistant staphylococcus aureus.
      The mechanism for this specificity is unknown. However, given that PBP1 is a critical component of cell divisome formation that may be a compensatory response to daptomycin membrane insertion for initiation of surface repair, PBP1 inhibition or interference by β-lactam antibiotics that bind it may result in cell death with fewer daptomycin molecules inserted per cell (G.S., unpublished observations).
      • Pogliano J.
      • Pogliano N.
      • Silverman J.A.
      Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins.

      Conclusions

      A severe limitation in the treatment of S aureus bacteremia is that it takes several days for “complicated” versus “uncomplicated” situations to be determined.

      Kullar R, McKinnell JA, Sakoulas G. Avoiding the perfect storm: The biologic and clinical case for reevaluating the 7-day expectation for methicillin-resistant staphylococcus aureus bacteremia before switching therapy. Clin Infect Dis. 2014. http://dx.doi.org/ciu583 [pii].

      In the meantime, however, under current first-line monotherapy treatment approaches frequently used with vancomycin, complicated infections are exacerbated by selection of drug resistance and consequent treatment failure. Currently, there is no way to risk-stratify the complicated versus uncomplicated cases early-on, although some research points to potential use of biomarkers to predict treatment failure and patient death. In light of the positive data that are emerging with combination therapy, particularly with daptomycin plus β-lactams in MRSA bacteremia, it may be reasonable to initiate combination therapy for 3 to 5 days and then de-escalate treatment based on clinical and microbiologic responses. Although much remains to be determined, including questions such as which β-lactam to use in the early empiric approach and the role of vancomycin in combination therapy schemes, the current data indicating such poor outcomes in MRSA bacteremia suggest that an alternative approach is required. There is insufficient clinical data using the combination of daptomycin with other antibiotics such as fosfomycin, linezolid, tigecycline, gentamicin, and trimethoprim-sulfamethoxazole in the treatment of MRSA bacteremia; further clinical studies are required to assess their efficacy and long-term tolerability. Early consultation with infectious diseases has increasingly been shown to improve mortality and other outcomes in S aureus bacteremia.
      • Honda H.
      • Krauss M.J.
      • Jones J.C.
      • et al.
      The value of infectious diseases consultation in staphylococcus aureus bacteremia.
      • Schmitt S.
      • McQuillen D.P.
      • Nahass R.
      • et al.
      Infectious diseases specialty intervention is associated with decreased mortality and lower healthcare costs.
      The early use of combination therapy for treatment of MRSA bacteremia, especially in clinical settings in which emergence of resistance during treatment is known to occur, may be an additional benefit that infectious diseases clinicians can offer to these patients with the goal of improving outcomes.

      Conflicts of Interest

      Dr. Dhand is a member of a speaker’s bureau and has received speaking honoraria from Cubist Pharmaceuticals; he is also a consultant for Astellas and Theravance. Dr. Sakoulas is a member of a speaker’s bureau and has received speaking honoraria from Cubist, Forest, Astellas, and Pfizer Pharmaceuticals; he has also received grant support and consulting fees from Cubist Pharmaceuticals.

      Acknowledgments

      Both authors contributed equally to the literature search, data interpretation, figure creation, and writing of the manuscript.

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