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.

Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Pneumonia with Ceftaroline Fosamil in a Patient with Inhalational Thermal Injury.

A 48-year-old female, who was found unresponsive and suffered inhalation injury secondary to a house fire, was transferred to our burn center for definitive treatment. Post tracheostomy, the patient became febrile and tachycardic. On hospital day (HD) 5, the patient expressed thick yellow secretions during suctioning and diffuse rhonchi was noted on physical exam. Blood cultures and a culture from the broncheo-alvelolar lavage grew Gram-positive cocci in clusters and the patient was started on empiric vancomycin. Despite aggressive vancomycin dosing (1750 mg intravenously every 6 h), the patient's status continued to deteriorate. The organism was identified as methicillin-resistant Staphylococcus aureus (MRSA) with a vancomycin minimum inhibitory concentration (MIC) of 2 mg/L. Based on the potential for drug-drug interactions with linezolid, the patient was started on ceftaroline fosamil (MIC = 0.5 mg/L) 600 mg intravenously every 8 h with a prolonged 2-h infusion to anticipate suboptimal concentrations secondary to thermal burn injury. Post change in antibiotic therapy, a rapid clinical improvement was observed with the patient becoming afebrile at 48 h after initiation of ceftaroline. The patient completed a total of 14 days of ceftaroline therapy and was subsequently weaned from the ventilator on HD 22 and decannulated 2 days later. To our knowledge, this is the first report of the use of ceftaroline for the treatment of MRSA pneumonia in a patient with thermal injury.

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.