Development of decreased susceptibility to daptomycin and vancomycin in a Staphylococcus aureus strain during prolonged therapy

Sir, We document the development of decreased susceptibility to daptomycin and vancomycin in Staphylococcus aureus during a prolonged and complicated therapy with these two antimicrobials. Unlike other reports, the vancomycin MIC value remained at 1 mg/L after several prolonged regimens of vancomycin, but only increased after further prolonged treatment with daptomycin. A 64-year-old man was admitted to the intensive case unit with methicillin-resistant S. aureus (MRSA) bacteraemia and treated with a 17 day course of vancomycin 1 g intravenous (iv) every 12 h. On the 22nd hospital day (HD) the patient became febrile and repeat blood cultures revealed MRSA. A transthoracic-echocardiogram did not reveal evidence of endocarditis. The patient was treated with a 1 month course of vancomycin 1 g iv every 12 h, and blood cultures became negative. On the 60th HD the patient had a repeat febrile episode with blood cultures demonstrating MRSA and was again treated with vancomycin. On the 99th HD, a white blood cell tagged scan showed infection of the right prosthetic hip with an aspiration culture-positive for MRSA, susceptible to vancomycin (MIC 1 mg/L) and daptomycin (MIC 0.5 mg/L). The patient's course was complicated by myocardial infarction and an episode of acute cholecystitis; therefore, surgery was postponed until the 102nd HD and the patient continued to receive vancomycin as suppressive therapy. Intra-operatively the patient developed a disseminated intravascular coagulation further complicated by non-oliguric acute renal failure, and daptomycin 650 mg daily was initiated. The patient's acute medical problems stabilized over the ensuing 4 weeks. On the 150th HD, the patient suddenly developed a fever and MRI demonstrated a 32 cm thigh abscess. The patient was again taken to surgery and an acetabular biopsy grew a vancomycin-intermediate (MIC 4 mg/L), daptomycin-non-susceptible (MIC 8 mg/L) S. aureus, Citrobacter freundii and three species of Candida (Candida albicans, Candida glabrata and Candida parapsilosis). Antimicrobial therapy was changed to dalfopristin/quinupristin 850 mg/day, gatifloxacin 200 mg/day and fluconazole 400 mg/day. The patient subsequently developed a catheter-associated Enterococcus faecalis bacteraemia and expired shortly thereafter. Three strains of S. aureus were isolated from the patient including a blood culture on HD 1, a surgical wound culture from HD 99 and a bone culture from HD 148. The strains were tested by Clinical and Laboratory Standards Institute (CLSI) M7-A7 broth microdilution methods in validated, dry-form panels manufactured by TREK Diagnostics, Inc. (Cleveland, OH, USA).1 Daptomycin susceptibility was tested as recommended in Mueller–Hinton broth supplemented with 50 mg/L calcium.1 Disc diffusion methods were performed according to the CLSI M2-A9 method1 and heteroresistance to vancomycin (hVISA) was evaluated by Etest (AB BIODISK, Solna, Sweden) as previously described by other investigators.2 The three strains tested from this patient exhibited variations in the antimicrobial susceptibility results of daptomycin and vancomycin (Table 1). Strains #1 and #2 showed identical daptomycin (0.5 mg/L) and vancomycin (1 mg/L) MIC results, while strain #3 exhibited a daptomycin MIC of 8 mg/L and a vancomycin MIC of 4 mg/L. Interestingly, dalbavancin MIC values also increased from 0.06 mg/L for strains #1 and #2 to 0.25 mg/L for strain #3 (4-fold increase). Disc diffusion zone diameter results for daptomycin showed a 3–4 mm decrease for strain #3 (15 mm) compared with the first two isolates (18–19 mm), validating observed higher MIC values. The vancomycin disc zone diameter results did not change (16 mm) as the MIC increased from 1 to 4 mg/L. Interestingly, strains #1 and #2 were resistant to penicillin (β-lactamase-positive; MIC at 16 mg/L) and strain #3 was β-lactamase-negative (penicillin MIC at 0.12 mg/L). Conversely, strain #1 was susceptible to rifampicin and strains #2 and #3 were resistant to this antimicrobial. Broth microdilution MIC results (unless noted) for 19 antimicrobial agents tested against three S. aureus isolates aValue in parentheses represents MIC result when using Etest strips with elevated bacterium inoculum. bβ-Lactamase test negative. Broth microdilution MIC results (unless noted) for 19 antimicrobial agents tested against three S. aureus isolates aValue in parentheses represents MIC result when using Etest strips with elevated bacterium inoculum. bβ-Lactamase test negative. hVISA was observed in strain #3, which showed an MIC value of 12 mg/L for both vancomycin and teicoplanin when tested by Etest using the high inoculum test variation.2 All three S. aureus strains demonstrated an identical molecular typing pattern by automated ribotyping (Riboprinter™ Microbial Characterization System, Qualicon, Wilmington, DE, USA) and PFGE. We describe an in vivo increase of daptomycin and vancomycin MIC values for an MRSA strain causing prosthetic joint infection with MRSA bacteraemia following prolonged therapy with these agents. Isolates taken after several prolonged courses of vancomycin and before institution of daptomycin were found to be susceptible to these two antimicrobials by reference broth microdilution, disc diffusion and Etest methods. However, after prolonged daptomycin therapy the strain developed decreased susceptibility to both daptomycin and vancomycin. Limited information is available on the utility of daptomycin for osteomyelitis. In an experimental rabbit model of MRSA osteomyelitis, treatment success with daptomycin was analogous to that of vancomycin. Eradication was similar for both drugs, and the isolates from the persisting organisms in the model did not demonstrate any antimicrobial resistance.3 Although these antimicrobials have distinctly different mechanisms of action, a recent study from Japan4 demonstrated that staphylococcal cell wall thickness caused by prolonged exposure to vancomycin may act as a common obstacle to daptomycin and vancomycin penetration of the cell and increase the MIC of both antimicrobials. In the case report presented here, however, vancomycin and daptomycin MIC values remained low (1 and 0.5 mg/L, respectively) after prolonged use of vancomycin, but increased (4 and 8 mg/L, respectively) after prolonged use of daptomycin. In addition, the dalbavancin MIC also increased 4-fold (from 0.06 to 0.25 mg/L), since it is a semi-synthetic derivative of the natural glycopeptide produced by a 3,3-dimethylaminopropyl amide substitution on the peptide carboxyl group.5 This agent is similar to other glycopeptides in its mechanism of action by binding to the terminal alanyl-d-alanine of nascent peptidoglycan chains.5 Since extended use of daptomycin resulted in elevated MIC values of these glycopeptides (vancomycin and daptomycin), it is possible that exposure to daptomycin, like vancomycin, may cause thickening of the bacterial cell wall, thus decreasing susceptibility to a number of peptides. Another recent study also showed that prolonged exposure to vancomycin prior to daptomycin treatment increases the risk of emergence of a daptomycin non-susceptible subpopulation.6 Further studies are necessary to better understand the cell wall alterations initiated by prolonged daptomycin exposure and their effect on the activities of structurally related peptides (glycopeptide and lipoglycopeptide agents). Finally, daptomycin seems to offer a bactericidal alternative for treatment of MRSA infections that are unresponsive to vancomycin; however, this case illustrates the adaptability of S. aureus necessitating clinicians to be aware of the possible daptomycin resistance associated with therapy following vancomycin failure. H. S. S. and R. N. J. have received research/education grants in the last 3 years from AB BIODISK, Abbott, AlamX, Arpida, AstraZeneca, Avexa, Basilea, Bayer, Becton Dickinson, Boehringer-Ingelheim, bioMerieux, Bristol-Myers Squibb, Cadence, Cerexa, Chiron, Cognigen, Cubist, Daiichi, Elan, Elanco, Enanta, GlaxoSmithKline, Intrabiotics, Johnson & Johnson, LG Chemicals, Merck, Micrologix, Novartis, Optimer, Ordway, Oscient, Osmotics, Peninsula, Pfizer, Replidyne, Schering-Plough, Sequoia, Serenex, Shionogi, Theravance, TREK Diagnostics, Vicuron, Wyeth.