Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model.

Daptomycin (DAP) is being used more frequently to treat infections caused by vancomycin-resistant enterococcus (VRE). DAP tends to be less active against enterococci than staphylococci and may require high doses or combination therapy to be bactericidal. Fosfomycin (FOF) has activity against VRE and has demonstrated synergistic bactericidal activity with DAP in vitro The objective of this study was to evaluate the activity of DAP alone and in combination with FOF against VRE in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activity of DAP at 8 and 12 mg/kg of body weight/day (DAP 8 and DAP 12, respectively) and FOF of 40 mg/kg intravenously every 8 h, alone and in combination, were evaluated against 2 vancomycin-resistant Enterococcus faecium strains (8019 and 5938) and 2 vancomycin-resistant E. faecalis strains (V583 and R7302) in an in vitro PK/PD model over 72 h. Cell surface charge in the presence and absence of FOF was evaluated by zeta potential analysis. Daptomycin-boron-dipyrromethene (bodipy) binding was assessed by fluorescence microscopy. The addition of FOF to DAP 8 and DAP 12 resulted in significantly increased killing over DAP alone at 72 h for 8019, V583, and R7302 (P < 0.05). Therapeutic enhancement was observed with DAP 12 plus FOF against 8019, V583, and R7302. Cell surface charge became more negative after exposure to FOF by ∼2 to 8mV in all 4 strains. Daptomycin-bodipy binding increased by 2.6 times in the presence of fosfomycin (P < 0.0001). The combination of DAP plus FOF may provide improved killing against VRE (including DAP-resistant strains) through modulation of cell surface charge. Further studies to clarify the role of intravenous FOF are warranted.

Risk Factors and Outcomes for Carbapenem-Resistant Klebsiella pneumoniae Isolation, Stratified by Its Multilocus Sequence Typing: ST258 Versus Non-ST258.

A "high risk" clone of carbapenem-resistant Klebsiella pneumoniae (CRKP) identified by multilocus sequence typing (MLST) as sequence type (ST) 258 has disseminated worldwide. As the molecular epidemiology of the CRE pandemic continues to evolve, the clinical impact of non-ST258 strains is less well defined. We conducted an epidemiological investigation of CRKP based on strains MLST. Among 68 CRKP patients, 61 were ST258 and 7 belonged to non-ST258. Klebsiella pneumoniae ST258 strains were significantly associated with bla KPC production and with resistance to an increased number of antimicrobials. Clinical outcomes were not different. Based on this analysis, one cannot rely solely on the presence of bla KPC in order to diagnose CRKP.

Human Bocavirus 1 Primary Infection and Shedding in Infants.

BACKGROUND: Human bocavirus 1 (HBoV-1) is frequently detected in young children. The role of HBoV-1 in respiratory illness is unclear, owing to frequent detection in asymptomatic children. METHODS: Weekly oral fluid samples from a longitudinal cohort of infants were tested by quantitative polymerase chain reaction for HBoV-1 DNA. Symptoms during HBoV-1 primary shedding events were compared to those during 14-day control periods occurring 1 month prior to and following the primary event. Eight single-nucleotide polymorphisms were analyzed to assess HBoV-1 variants. RESULTS: Sixty-six of 87 children (76%), followed for at least 18 months from birth, had a primary HBoV-1 infection. HBoV-1 was consistently detected for >1 month (maximum duration, 402 days) following 42 of 66 primary shedding events. Children were more likely to experience new cough symptoms (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.4-5.5) and to visit a healthcare provider (OR, 2.8; 95% CI, 1.02-7.7) during the 14 days surrounding the time of initial detection of HBoV-1. Recurrent HBoV-1 shedding events were found in 33 children (50%). Twelve of 48 children with HBoV-1 variant data had multiple viral allelic patterns over time. CONCLUSIONS: HBoV-1 primary shedding events are associated with mild respiratory illness with subsequent prolonged detection of HBoV-1 DNA for up to a year. HBoV-1 reinfection contributes to long-term shedding.

Evaluation of High-Dose Daptomycin Versus Vancomycin Alone or Combined with Clarithromycin or Rifampin Against Staphylococcus aureus and S. epidermidis in a Novel In Vitro PK/PD Model of Bacterial Biofilm.

INTRODUCTION: Medical device infections are associated with significant morbidity and mortality. These difficult-to-treat infections often result in antibiotic failure and resistance. Combination therapy is often required, however, the most optimal combination is unknown. We evaluated the in vitro activity of daptomycin (DAP) or vancomycin (VAN) alone and in combination with rifampin (RIF) or clarithromycin (CLA) against strains of Staphylococcus aureus and S. epidermidis grown in biofilm on 3 prosthetic device materials. METHODS: One methicillin-resistant S. aureus (MRSA R5266), one heteroresistant vancomycin-intermediate S. aureus (hVISA R3640), and one methicillin-resistant S. epidermidis (MRSE R461) strain was evaluated in a CDC biofilm reactor with titanium, Teflon®, and steel coupons. Regimens simulated included DAP 10 mg/kg/day, and VAN 1 g q12h alone or in combination with RIF 600 mg q24h or CLA 250 mg q12h. Additional regimens including DAP 12 mg/kg/day or VAN ± RIF 450 mg q12h were evaluated against the hVISA strain. RESULTS: DAP + RIF or VAN + RIF demonstrated enhanced activity against R3640 in embedded biofilm (EB) cells in all materials versus DAP or VAN alone (P ≤ 0.040). Only DAP + RIF demonstrated sustained bactericidal activity (≥3.80 log10 CFU/cm2 reduction from baseline) against EB and planktonic cells of R5266 and EB cells of R461 in all 3 materials. Of interest, CLA did not appear to enhance DAP or VAN killing activities, and the addition of RIF prevented the emergence of resistance to DAP or VAN in all organisms. CONCLUSION: Using an in vitro bacterial biofilm model containing three common prosthetic device materials, DAP + RIF and VAN + RIF were the most effective regimens. DAP + RIF displayed the greatest activity and represents a promising combination to evaluate for treatment of biofilm-associated staphylococcal infections.

A novel approach utilizing biofilm time-kill curves to assess the bactericidal activity of ceftaroline combinations against biofilm-producing methicillin-resistant Staphylococcus aureus.

Medical device infections frequently require combination therapy. Beta-lactams combined with glycopeptides/lipopeptides are bactericidal against methicillin-resistant Staphylococcus aureus (MRSA). Novel macrowell kill-curve methods tested synergy between ceftaroline or cefazolin plus daptomycin, vancomycin, or rifampin against biofilm-producing MRSA. Ceftaroline combinations demonstrated the most pronounced bacterial reductions. Ceftaroline demonstrated greatest kill with daptomycin (4.02 ± 0.59 log10 CFU/cm(2)), compared to combination with vancomycin (3.36 ± 0.35 log10 CFU/cm(2)) or rifampin (2.68 ± 0.61 log10 CFU/cm(2)). These data suggest that beta-lactam combinations are useful against MRSA biofilms.