Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis.
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ABSTRACT:
SUBMITTER: Fabre V
PROVIDER: S-EPMC4281789 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We report a case of infective endocarditis (IE) caused by ceftaroline-resistant, daptomycin-tolerant, and heterogeneous vancomycin-intermediate methicillin-resistant S. aureus (MRSA). Resistance to ceftaroline emerged in the absence of drug exposure, and the E447K substitution in the active site of PBP2a previously associated with ceftaroline resistance was identified. Additionally, we present evidence of patient-to-patient transmission of the strain within the same unit. This case illustrates the difficulties in treating MRSA IE in the setting of a multidrug-resistant phenotype.
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Project description:Cefazolin and ertapenem combination therapy was used successfully to salvage 11 cases (6 endocarditis) of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including immediate clearance (≤24 hours) in 8 cases. While in vitro synergy was modest, cefazolin plus ertapenem exhibited synergistic action in a rat model of MSSA endocarditis. The combination of cefazolin and ertapenem provides potent in vivo activity against MSSA beyond what is predicted in vitro and warrants further clinical study in the treatment of refractory MSSA bacteremia and endocarditis.
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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of health care-associated infections. Vancomycin remains an acceptable treatment option. There has been a welcome increase in the number of agents available for the treatment of MRSA infection. These drugs have certain differentiating attributes and may offer some advantages over vancomycin, but they also have significant limitations. These agents provide some alternative when no other options are available.
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Project description:ABSTRACT Trimethoprim-sulfamethoxazole (SXT) is a valuable second-line antimicrobial agent to treat methicillin-resistant Staphylococcus aureus infections. Discrepancies between various antibiotic susceptibility testing (AST) methods for SXT susceptibility in S. aureus have been described. Here, we describe a hemin-inducible heteroresistance phenotype in S. aureus. We compared the results of the Vitek 2 AST on a set of 95 S. aureus clinical isolates with broth microdilution, disk diffusion using standard Mueller-Hinton agar, and disk diffusion using Mueller-Hinton agar supplemented with 5% horse blood (MHF). To investigate the potential clinical relevance of SXT heteroresistance, an in vivoGalleria mellonella infection assay was performed. All Vitek 2 SXT-susceptible (n = 17) isolates were concordant with AST results by other methods applied in this study. In 32/78 (41%) of Vitek 2 SXT-resistant isolates, we observed a heteroresistant growth phenotype on MHF. The heteroresistance phenotype was associated with the presence of dfr genes, encoding trimethoprim resistance. The addition of a hemin-impregnated disk in a double disk diffusion method on standard Mueller-Hinton agar was able to induce growth in the SXT zone of inhibition. An in vivo infection assay with G. mellonella suggested that the SXT heteroresistance phenotype resulted in lethality similar to that of the SXT-resistant phenotype. In this study, we describe a novel hemin-inducible heteroresistance phenotype in S. aureus. This heteroresistance phenotype may be missed by standard AST methods but can be detected by performing disk diffusion using Mueller-Hinton agar supplemented with 5% horse blood, commonly used for AST of fastidious organisms. This phenomenon may partly explain the discrepancies of AST methods in determining SXT resistance in S. aureus. IMPORTANCEStaphylococcus aureus is one of most important pathogens in clinical medicine. Besides its virulence, the acquisition or emergence of resistance toward antibiotic agents, in particular to beta-lactam antibiotics (methicillin-resistant S. aureus [MRSA]), poses a major therapeutic challenge. Trimethoprim-sulfamethoxazole (SXT) is one of the effective antimicrobial agents of last resort to treat MRSA infections. Here, we report the detection of a SXT-heteroresistant phenotype which is inducible by hemin and can be detected using Mueller-Hinton agar supplemented with horse blood. Heteroresistance describes the presence or emergence of resistant subpopulations, which may potentially lead to inaccurate antibiotic susceptibility testing results and influence the success of antibiotic therapy.
| S-EPMC8549745 | biostudies-literature
Project description:BACKGROUND/AIMS:Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in hospitals, and has recently emerged in the community. The impact of methicillin-resistance on mortality and medical costs for patients with S. aureus bacteremia (SAB) requires reevaluation. METHODS:We searched studies with SAB or endocarditis using electronic databases including Ovid-Medline, Embase-Medline, and Cochrane Library, as well as five local databases for published studies during the period January 2000 to September 2011. RESULTS:A total of 2,841 studies were identified, 62 of which involved 17,563 adult subjects and were selected as eligible. A significant increase in overall mortality associated with MRSA, compared to that with methicillin-susceptible S. aureus (MSSA), was evidenced by an odds ratio (OR) of 1.95 (95% confidence interval [CI], 1.73 to 2.21; p < 0.01). In 13 endocarditis studies, MRSA increased the risk of mortality, with an OR of 2.65 (95% CI, 1.46 to 4.80). When three studies, which compared mortality rates between CA-MRSA and CA-MSSA, were combined, the risk of methicillin-resistance increased 3.23-fold compared to MSSA (95% CI, 1.25 to 8.34). The length of hospital stay in the MRSA group was 10 days longer than that in the MSSA group (95% CI, 3.36 to 16.70). Of six studies that reported medical costs, two were included in the analysis, which estimated medical costs to be $9,954.58 (95% CI, 8,951.99 to 10,957.17). CONCLUSION:MRSA is still associated with increased mortality, longer hospital stays and medical costs, compared with MSSA in SAB in studies published since the year 2000.
| S-EPMC6823568 | biostudies-literature
Project description:Vancomycin (VAN) and daptomycin (DAP) are approved as a monotherapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. A regimen of daptomycin plus ceftaroline (DAP+CPT) has shown promise in published case series of MRSA salvage therapy, but no comparative data exist to compare up-front DAP+CPT head-to-head therapy versus standard monotherapy as an initial treatment. In a pilot study, we evaluated 40 adult patients who were randomized to receive 6 to 8 mg/kg of body weight per day of DAP and 600 mg intravenous (i.v.) CPT every 8 h (q8h) (n = 17) or standard monotherapy (n = 23) with vancomycin (VAN; dosed to achieve serum trough concentrations of 15 to 20 mg/liter; n = 21) or 6 to 8 mg/kg/day DAP (n = 2). Serum drawn on the first day of bacteremia was sent to a reference laboratory post hoc for measurement of interleukin-10 (IL-10) concentrations and correlation to in-hospital mortality. Sources of bacteremia, median Pitt bacteremia scores, Charlson comorbidity indices, and median IL-10 serum concentrations were similar in both groups. Although the study was initially designed to examine bacteremia duration, we observed an unanticipated in-hospital mortality difference of 0% (0/17) for combination therapy and 26% (6/23) for monotherapy (P = 0.029), causing us to halt the study. Among patients with an IL-10 concentration of >5 pg/ml, 0% (0/14) died in the DAP+CPT group versus 26% (5/19) in the monotherapy group (P = 0.057). Here, we share the full results of this preliminary (but aborted) assessment of early DAP+CPT therapy versus standard monotherapy in MRSA bacteremia, hoping to encourage a more definitive clinical trial of its potential benefits against this leading cause of infection-associated mortality. (The clinical study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT02660346.).
| S-EPMC6496065 | biostudies-literature
Project description:BackgroundWe aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis.MethodsA randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy.ResultsOf 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018).ConclusionsDaptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.Clinical trials registrationNCT01898338.
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Project description:Ceftaroline (CPT) is a novel cephalosporin with in vitro activity against Staphylococcus aureus. Ceftaroline exhibits a level of binding affinity for PBPs in S. aureus including PBP2a of methicillin-resistant S. aureus (MRSA). The aims of this study were to investigate the morphological, physiological and molecular responses of MRSA clinical strains and MRSA biofilms to sub-MICs (1/4 and 1/16 MIC) of ceftaroline by using transmission, scanning and confocal microscopy. We have also used quantitative Real-Time PCR to study the effect of sub-MICs of ceftaroline on the expression of the staphylococcal icaA, agrA, sarA and sasF genes in MRSA biofilms. In one set of experiments, ceftaroline was able to inhibit biofilm formation in all strains tested at MIC, however, a strain dependent behavior in presence of sub-MICs of ceftaroline was shown. In a second set of experiments, destruction of preformed biofilms by addition of ceftaroline was evaluated. Ceftaroline was able to inhibit biofilm formation at MIC in all strains tested but not at the sub-MICs. Destruction of preformed biofilms was strain dependent because the biofilm formed by a matrix-producing strain was resistant to a challenge with ceftaroline at MIC, whereas in other strains the biofilm was sensitive. At sub-MICs, the impact of ceftaroline on expression of virulence genes was strain-dependent at 1/4 MIC and no correlation between ceftaroline-enhanced biofilm formation and gene regulation was established at 1/16 MIC. Our findings suggest that sub-MICs of ceftaroline enhance bacterial attachment and biofilm formation by some, but not all, MRSA strains and, therefore, stress the importance of maintaining effective bactericidal concentrations of ceftaroline to fight biofilm-MRSA related infections.
| S-EPMC4723258 | biostudies-literature
Project description:Novel therapies for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are needed in the setting of reduced antibiotic susceptibilities and therapeutic failure. Ceftaroline is a cephalosporin antibiotic with MRSA activity. Although not FDA approved for MRSA BSI, ceftaroline has generated much interest as a potential treatment option. However, detailed descriptions of its use in this setting remain limited. To address this, we conducted a retrospective, multicenter, observational study of adult patients with MRSA BSI treated with at least 72 h of ceftaroline from 2011 to 2015. Safety outcomes were examined in the overall cohort, while efficacy outcomes were examined among patients who had not cleared their BSI prior to ceftaroline initiation. Data were also stratified by ceftaroline monotherapy or combination therapy. Predictors of clinical failure on ceftaroline treatment were also sought. Overall, 211 patients were included in the safety population; Clostridium difficile infection, rash, and neutropenia occurred in 6 patients (2.8%), 7 patients (3.3%), and 3 patients (1.4%), respectively. Clinical success was observed in 86 (68.3%) of the 126 patients included in the efficacy population. The monotherapy and combination therapy subgroups had similar proportions of patients experiencing success (69.7 and 64.9%, respectively). The median BSI durations post-ceftaroline treatment were 2 days (interquartile range, 1 to 4 days) for monotherapy and 3 days (interquartile range, 1.5 to 5 days) for combination therapy. Higher acute physiology and chronic health evaluation II scores and comorbid malignancy independently predicted treatment failure. Ceftaroline appears effective for MRSA BSI as both monotherapy and combination therapy. However, comparative studies are needed to further delineate the role of ceftaroline in MRSA BSI treatment.
| S-EPMC5278749 | biostudies-literature
Project description:Approximately 3% of Staphylococcus aureus strains that, according to results of conventional phenotypic methods, are highly susceptible to methicillin-like antibiotics also have polymerase chain reaction (PCR) results positive for mecA. The genetic nature of these mecA-positive methicillin-susceptible S. aureus (MSSA) strains has not been investigated. We report the first clearly defined case of reversion from methicillin susceptibility to methicillin resistance among mecA-positive MSSA within a patient during antibiotic therapy. We describe the mechanism of reversion for this strain and for a second clinical isolate that reverts at a similar frequency. The rates of reversion are of the same order of magnitude as spontaneous resistance to drugs like rifampicin. When mecA is detected by PCR in the clinical laboratory, current guidelines recommend that these strains be reported as resistant. Because combination therapy using both a ?-lactam and a second antibiotic suppressing the small revertant population may be superior to alternatives such as vancomycin, the benefits of distinguishing between mecA-positive MSSA and MRSA in clinical reports should be evaluated.
| S-EPMC4760414 | biostudies-literature