Daptomycin, Fosfomycin, or Both for Treatment of Methicillin-Resistant Staphylococcus aureus Osteomyelitis in an Experimental Rat Model

c Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBC log values were 32/>512 g/ml for fosfomycin, 4/>64 g/ml for rifampin, 1/2 g/ml for ampicillin, 2/>256 g/ml for linezolid, 16/32 g/ml for gentamicin, 1/>64 g/ml for vancomycin, and 1/5 g/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8؋ and 16؋ MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by Ϸ4 log 10 CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Activities of Fosfomycin and Rifampin on Planktonic and Adherent Enterococcus faecalis Strains in an Experimental Foreign-Body Infection Model

Oliva

Tafin

Maiolo

et al. 2014

“…Of particular interest, combinations of DAP ϩ OXA and DAP ϩ CLR appear to significantly reduce the emergence of DAP resistance over 28 days of treatment, which is often a minimum recommended therapy duration for complicated infections, as was the case in the patient from whom the test strain was isolated. Published reports on the combination of DAP and FOF are few and have not addressed the effect of FOF on DAP resistance development (6,31,33). More data are available on the addition of RIF, which has been shown previously to delay the emergence of DAP resistance (12,20) and can significantly enhance clearance of complex MRSA infection when given in combination with DAP (1,38), possibly by suppressing the emergence of resistance to both agents (15).…”

Section: Discussionmentioning

confidence: 99%

Altering the Proclivity towards Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Using Combinations with Other Antibiotics

Berti

Wergin

Girdaukas

et al. 2012

ABSTRACTDaptomycin (DAP) is increasingly used as a part of combination therapy, particularly in complex methicillin-resistantStaphylococcus aureus(MRSA) infections. While multiple studies have reported the potential for synergy between DAP and adjunctive anti-infectives, few have examined the influence of adjunctive therapy on the emergence of DAP resistance. This study examined eight adjunctive antimicrobial combinations with DAPin vitroand the emergence of DAP resistance over time (up to 4 weeks) using clinical isolates of DAP-susceptible MRSA (MIC, 0.5 μg/ml) in which DAP resistance subsequently developed during patient therapy (MIC, 3 μg/ml). In addition to DAP susceptibility testing, selected strains were examined for phenotypic changes associated with DAP resistance, including changes to cell wall thickness (CWT) and cell membrane alterations. The addition of either oxacillin or clarithromycin in medium containing DAP significantly inhibited the development of DAP resistance through the entirety of the 4-week exposure (10- to 32-fold MIC reduction from that of DAP alone). Combinations with rifampin or fosfomycin were effective in delaying the emergence of DAP resistance through the end of week one only (week one MIC, 0.5 μg/ml; week four MIC, 24 μg/ml). Cell wall thickening was observed for all antibiotic combinations regardless of their effect on the DAP MIC (14 to 70% increase in CWT), while changes in cell membrane fluidity were variable and treatment dependent. DAP showed reduced activity against strains with DAP MICs of 1 to 12 μg/ml, but cell membrane integrity was still disrupted at concentrations achieved with doses greater than 10 mg/kg of body weight. The emergence of DAP resistance in MRSA is strongly influenced by the presence of subinhibitory concentrations of adjunctive antimicrobials. These data suggest that combining DAP with oxacillin or clarithromycin may delay the development of DAP resistance in cases requiring prolonged antibiotic therapy.

“…All antimicrobial agents were administered every 12 h intraperitoneally for 4 days, i.e., a total of eight doses, as previously reported (28). The dosing regimens for all tested antimicrobials were chosen according to pharmacokinetic studies performed in mice, rats, and rabbits, mimicking concentrations achievable in humans (33)(34)(35)(36)(37)(38)(39)(40).…”

Section: Methodsmentioning

confidence: 99%

Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model

Corvec

Tafin

Bétrisey

et al. 2013

105

Limited antimicrobial agents are available for the treatment of implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli. We compared the activities of fosfomycin, tigecycline, colistin, and gentamicin (alone and in combination) against a CTX-M15-producing strain of Escherichia coli (Bj HDE-1) in vitro and in a foreign-body infection model. The MIC and the minimal bactericidal concentration in logarithmic phase (MBC log ) and stationary phase (MBC stat ) were 0.12, 0.12, and 8 g/ml for fosfomycin, 0.25, 32, and 32 g/ml for tigecycline, 0.25, 0.5, and 2 g/ml for colistin, and 2, 8, and 16 g/ml for gentamicin, respectively. In time-kill studies, colistin showed concentration-dependent activity, but regrowth occurred after 24 h. Fosfomycin demonstrated rapid bactericidal activity at the MIC, and no regrowth occurred. Synergistic activity between fosfomycin and colistin in vitro was observed, with no detectable bacterial counts after 6 h. In animal studies, fosfomycin reduced planktonic counts by 4 log 10 CFU/ml, whereas in combination with colistin, tigecycline, or gentamicin, it reduced counts by >6 log 10 CFU/ml. Fosfomycin was the only single agent which was able to eradicate E. coli biofilms (cure rate, 17% of implanted, infected cages). In combination, colistin plus tigecycline (50%) and fosfomycin plus gentamicin (42%) cured significantly more infected cages than colistin plus gentamicin (33%) or fosfomycin plus tigecycline (25%) (P < 0.05). The combination of fosfomycin plus colistin showed the highest cure rate (67%), which was significantly better than that of fosfomycin alone (P < 0.05). In conclusion, the combination of fosfomycin plus colistin is a promising treatment option for implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli.