Influence of the clindamycin administration route on the magnitude of clindamycin-rifampicin interaction: a prospective pharmacokinetic study.

OBJECTIVES: An important clindamycin-rifampicin pharmacokinetic (PK) interaction has been reported, but the potential influence of the clindamycin administration route on that interaction is unknown. This prospective, observational, comparative PK study was undertaken to characterize and analyse the impact of the route, comparing the rifampicin enzyme-inductor effects on clindamycin clearance (CLclin) for oral versus intravenous (IV) administration. METHODS: Patients with bone-and-joint infections (BJIs) were treated with clindamycin monotherapy (n = 20) or clindamycin-rifampicin combination therapy (n = 19). Patients received continuous IV clindamycin infusion for 2-6 weeks, followed by an oral regimen. Liquid chromatography-mass spectrometry was used to measure plasma clindamycin concentrations at the end of IV and after 2 weeks of oral treatment. The ratios of the mean CLclin for the combination and monotherapy groups were calculated for IV (Riv) and oral (Rpo) routes, with the final ratio, Rf = Rpo/Riv, representing the fold change of the rifampicin-inducing effect from the IV to the oral route. RESULTS: Comparing monotherapy with combination-therapy groups, the former's median steady-state concentration was two-fold higher after IV administration (8.49 versus 3.82 mg/L, p < 0.001) and its median AUC0-8h was 12 times higher after oral intake (37.7 versus 3.1 mg.h/L, p < 0.001). Riv, Rpo and Rf were 2.68, 18.8 and 7.0 respectively. CONCLUSION: The magnitude of this interaction was markedly increased by oral intake, questioning the use of oral treatment for difficult-to-treat infections like BJIs. Nevertheless, the clindamycin-rifampicin combination seems possible provided that clindamycin is administered by continuous IV infusion.

Minocycline Combined with Vancomycin for the Treatment of Methicillin-Resistant Coagulase-Negative Staphylococcal Prosthetic Joint Infection Managed with Exchange Arthroplasty.

Introduction: Treatment of methicillin-resistant (MR) staphylococcal prosthetic joint infections (PJIs) remains a matter of discussion, with vancomycin-rifampin combination therapy being the preferred treatment for DAIR and one-stage exchange arthroplasty strategies. This study analyzes the outcomes of patients with chronic methicillin-resistant coagulase-negative staphylococcal PJIs treated with vancomycin-minocycline combination therapy. Methods: This prospective, single center cohort study included all chronic MR coagulase-negative staphylococcal PJIs (01/2004-12/2014) treated with exchange arthroplasty and at least 4 weeks of minocycline-vancomycin. The following endpoints were considered: reinfection including relapse (same microorganism) and a new infection (different microorganism) and PJI-related deaths. Their outcomes were compared with PJIs treated with rifampin-vancomycin during the same period. Results: Thirty-four patients (median age, 69 years) with 22 hip and 12 knee arthroplasty infections were included. Sixteen (47%) had previously been managed in another center. Median vancomycin MIC of strains was 3 mg/L. Nineteen underwent one-stage, 15 two-stage exchange arthroplasty. After a median [IQR] follow-up of 43 [26-68] months, 2 patients relapsed and 6 developed a new PJI. Compared to 36 rifampin-vancomycin treated PJIs, relapse- or reinfection-free survival rates didn't differ, but more new infections developed in the minocycline group (6 vs 3; P 0.3). Conclusions: Minocycline-vancomycin combination therapy for chronic MR coagulase-negative staphylococcal PJIs seems to be an interesting therapeutic alternative.

Activity of fosfomycin alone or combined with cefoxitin in vitro and in vivo in a murine model of urinary tract infection due to Escherichia coli harbouring CTX-M-15-type extended-spectrum ß-lactamase.

The efficacy of fosfomycin alone or combined with cefoxitin was investigated in vitro and in a murine model of urinary tract infection due to susceptible Escherichia coli CFT073-RR and its transconjugant CFT073-RR Tc (pblaCTX-M-15) harbouring a plasmid carrying the blaCTX-M-15 gene. In vitro, the combination of cefoxitin and fosfomycin was synergistic and bactericidal and prevented the emergence of fosfomycin-resistant mutants of CFT073-RR and CFT073-RR Tc (pblaCTX-M-15) that were selected with fosfomycin alone. In vivo, the combination conferred an advantage in terms of kidney sterilisation of mice infected with either strain compared with fosfomycin monotherapy.

Ten-year decrease of acquired methicillin-resistant Staphylococcus aureus (MRSA) bacteremia at a single institution: the result of a multifaceted program combining cross-transmission prevention and antimicrobial stewardship.

BACKGROUND: In France, the proportion of MRSA has been over 25% since 2000. Prevention of hospital-acquired (HA) MRSA spread is based on isolation precautions and antibiotic stewardship. At our institution, before 2000, the Infection Disease and the Infection Control teams had failed to reduce HA-MRSA rates. OBJECTIVES AND METHODS: We implemented a multifaceted hospital-wide prevention program and measured the effects on HA-MRSA colonization and bacteremia rates between 2000 and 2009. From 2000 to 2003, active screening and decontamination of ICU patients, hospital wide alcohol based hand rubs (ABHR) use, control of specific classes of antibiotics, compliance audits, and feed-backs to the care providers were successively implemented. The efficacy of the program was assessed by HA-MRSA colonized and bacteremic patient rates per 1000 patient-days in patients hospitalized for more than twenty-four hours. RESULTS: Compliance with the isolation practices increased between 2000 and 2009. Consumption of ABHR increased from 6.8 L to 27.5 L per 1000 patient-days. The use of antibiotic Defined Daily Doses (DDD) per 1000 patient-days decreased by 31%. HA-MRSA colonization decreased by 84% from 1.09 to 0.17 per 1000 patient-days and HA-MRSA bacteremia by 93%, from 0.15 to 0.01 per 1000 patient-days (p < 10-7 for each rate). CONCLUSIONS: In an area highly endemic for MRSA, a multifaceted prevention program allows for sustainable reduction in HA-MRSA bacteremia rates.

Effect of moxifloxacin combined with cefotaxime compared to cefotaxime-gentamicin combination on prevention of white matter damage associated with Escherichia coli sepsis in neonatal rats.

Relative to the cefotaxime-gentamicin combination, the moxifloxacin-cefotaxime combination significantly reduced microglial activation and immature oligodendrocyte cell death and delayed myelination in the developing white matter of neonatal rats with experimental Escherichia coli sepsis. These neuroprotective effects were not due to differences in in vivo bactericidal activities or in the systemic inflammatory responses and could be related to the intrinsic immunomodulatory properties of moxifloxacin. Molecular mechanisms underlying the neuroprotective effect of moxifloxacin remain to be elucidated.

Ciprofloxacin prevents myelination delay in neonatal rats subjected to E. coli sepsis.

OBJECTIVE: Perinatal infections and the systemic inflammatory response to them are critical contributors to white matter disease (WMD) in the developing brain despite the use of highly active antibiotics. Fluoroquinolones including ciprofloxacin (CIP) have intrinsic anti-inflammatory effects. We hypothesized that CIP, in addition to its antibacterial activity, could exert a neuroprotective effect by modulating white matter inflammation in response to sepsis. METHODS: We adapted an Escherichia coli sepsis model to 5-day-old rat pups (P5), to induce white matter inflammation without bacterial meningitis. We then compared the ability of CIP to modulate inflammatory-induced brain damage compared with cefotaxime (CTX) (treatment of reference). RESULTS: Compared with CTX, CIP was associated with reduced microglial activation and inducible nitric oxide synthase (iNOS) expression in the developing white matter in rat pups subjected to E. coli sepsis. In addition to reducing microglial activation, CIP was able to prevent myelination delay induced by E. coli sepsis and to promote oligodendroglial survival and maturation. We found that E. coli sepsis altered the transcription of the guidance molecules semaphorin 3A and 3F; CIP treatment was capable of reducing semaphorin 3A and 3F transcription levels to those seen in uninfected controls. Finally, in a noninfectious white matter inflammation model, CIP was associated with significantly reduced microglial activation and prevented WMD when compared to CTX. INTERPRETATION: These data strongly suggest that CIP exerts a beneficial effect in a model of E. coli sepsis-induced WMD in rat pups that is independent of its antibacterial activity but likely related to iNOS expression modulation.

Development of ertapenem resistance in a patient with mediastinitis caused by Klebsiella pneumoniae producing an extended-spectrum beta-lactamase.

The aim was to study the clinical and microbiological features associated with a carbapenem-resistant Klebsiella pneumoniae isolate that had been selected in vivo by an ertapenem-containing regimen in a patient with mediastinitis despite high blood and mediastinal levels of ertapenem. Carbapenem resistance was characterized by conjugation, PCR, DNA sequencing and analysis of outer-membrane proteins. The isolates susceptible and resistant to the carbapenems were compared by ribotyping and PFGE. Resistance to all available beta-lactams was most probably due to combined production of extended-spectrum beta-lactamase (ESBL) CTX-M-15 and loss of OmpK36 porin. The results of ribotyping and PFGE suggest that the carbapenem-resistant strain was a derivative of the original mediastinal isolate rather than a superinfecting isolate. This observation stresses the risk of selection of pan-penem resistant strains of enterobacteria when ertapenem is used for the treatment of severe infections due to ESBL-producing enterobacteria.

Continuous clindamycin infusion, an innovative approach to treating bone and joint infections.

The feasibility, safety, and efficacy of prolonged, continuous, intravenous clindamycin therapy were retrospectively evaluated for 70 patients treated for bone and joint infections, 40% of whom were treated as outpatients. The median treatment duration was 40 days, the median daily clindamycin dose was 2,400 mg, and three moderate-grade adverse events occurred. The median serum clindamycin concentrations on days 3 to 14 and days 8 to 28 were 5 and 6.2 mg/liter, respectively; the median concentration was significantly lower (P < 0.02) in patients treated with rifampin (5.3 mg/liter) than in those not treated with rifampin (8.9 mg/liter). Among 53 patients with a median follow-up of 30 months (range, 24 to 53 months), 49 (92%) were considered cured (1 patient had a relapse, and 3 patients had reinfections).

Drug-to-drug interaction between dapsone and minocycline: an unusual cause of relapse of toxoplasmic encephalitis in an HIV-infected patient.

HIV-infected patients with opportunistic infections receive therapeutic regimens that often contain numerous drugs and are then exposed to potential drug-to-drug interactions. We report here an unusual case of relapse of toxoplasmic encephalitis in an HIV-infected patient, possibly due to a drug-to-drug interaction between dapsone and minocycline.

Continuous cefazolin infusion to treat bone and joint infections: clinical efficacy, feasibility, safety, and serum and bone concentrations.

Cefazolin has been used for many years to treat bone and joint infections. Because of its time-dependent antimicrobial activity, continuous infusion would potentially be beneficial. We report on the feasibility, safety, and efficacy of prolonged continuous intravenous cefazolin therapy in a cohort of 100 patients, their serum cefazolin levels, and the concomitant bone cefazolin concentrations in 8 of them. This retrospective cohort study included all the patients treated for bone or joint infection with a continuous cefazolin infusion administered over a 12-h period twice daily for >or=2 weeks. Drug monitoring was performed at least twice for all the patients. Serum and bone cefazolin concentrations were determined by standardized disk diffusion microbiological assays. The absence of clinical, biological, and radiological signs of infection after 2 years of follow-up and the same criteria after 1 year of follow-up defined cures and probable cures, respectively. The median treatment duration was 42 days, and the median daily cefazolin dose was 6 g. Half of the patients received parenteral antibiotic therapy on an outpatient basis. Two moderate-grade adverse events were observed. The median serum cefazolin concentrations were 63 microg/ml (range, 13 to 203 microg/ml) and 57 microg/ml (range, 29 to 128 microg/ml) on days 2 to 10 and days 11 to 21, respectively. The median bone cefazolin concentration reached 13.5 microg/g (range, 3.5 to 29 microg/g). The median bone concentration/serum concentration ratio was 0.25 (range, 0.06 to 0.41). Among 88 patients with a median follow-up of 25 months (range, 12 to 53 months), 52 were considered cured and 29 were considered probably cured. Thus, the treatment of bone and joint infections with a prolonged continuous intravenous cefazolin infusion was feasible, effective, well-tolerated, safe, and convenient, making it a strong candidate for home therapy.

Identification and phenotypic characterization of a beta-lactam-dependent, methicillin-resistant Staphylococcus aureus strain.

Methicillin resistance in Staphylococcus aureus is primarily mediated by the acquired penicillin-binding protein PBP 2a, which is encoded by mecA. PBP 2a acts together with native PBP 2 to mediate oxacillin resistance by contributing complementary transpeptidase and transglycosylase activities, respectively. In this study, we have investigated a phenotype of beta-lactam dependence in a clinical methicillin-resistant S. aureus strain (strain 2884D) obtained by in vitro selection with ceftobiprole. 28884D, which grew very poorly in blood agar, required the presence of the beta-lactam antibiotics to grow. On the basis of this observation, we hypothesized that a gene or genes essential for growth were dependent on oxacillin induction. Identification and analysis of genes regulated by oxacillin were performed by both real-time reverse transcription-PCR and spotted microarray analysis. We found that mecA was constitutively expressed in strain 2884D and that the constitutive expression resulted from perturbations in the two systems involved in its regulation, i.e., MecI/MecR1 (staphylococcal chromosome cassette mec type I) and BlaI/BlaR1 (nonfunctional penicillinase operon). PBP 2 appeared to be poorly induced by oxacillin in 2884D. Further analysis of the PBP 2 two-component VraSR regulatory system showed that it was nonfunctional, accounting for the lack of response to oxacillin. Together, these results support the notion that limited PBP 2 availability may have led 2884D to become dependent on oxacillin-mediated mecA induction as a required survival mechanism.

Hip arthroplasty infection with heterogeneous vancomycin-resistant Staphylococcus aureus.

We report a case of heterogeneous vancomycin-resistant Staphylococcus aureus hip arthroplasty infection. Apparent cure was obtained by excision of infected tissues and removal of prosthetic material combined with optimal and closely monitored prolonged intravenous antibiotic therapy including continuous high-dose vancomycin.

Highly sensitive and efficient computer-assisted system for routine surveillance for surgical site infection.

OBJECTIVES: Surveillance of surgical site infections (SSIs) is effective in reducing the rates of these complications, but it is extremely time-consuming and, consequently, underused. We determined the sensitivity and specificity of a computer-assisted surveillance system, compared with a conventional method involving review of medical records, and the time saved with the computer-assisted system. METHOD: A prospective study was conducted from January 1 to December 31, 2001. With the computer-assisted method, screening for SSIs relied on identification in the laboratory database of positive results of microbiological tests of surgical-site specimens; confirmation was obtained via computer-generated questionnaires completed by the surgeon in charge of the patient. In the conventional method, SSIs were identified by exhaustive chart review. The time spent on surveillance was recorded for both methods. SETTING: A 25-bed gastrointestinal surgery unit in a tertiary care hospital. PATIENTS: A total of 766 consecutive patients who underwent gastrointestinal surgery. RESULTS: The sensitivity of the computer-assisted method was 84.3% (95% confidence interval, 0.66-0.94); the specificity was 99.9%. For the 807 surgical procedures in the study, 197 had an SSI identified by culture of a surgical-site specimen. After elimination of 63 duplicate cultures with positive results, 134 questionnaires were sent to the surgeons, who confirmed 27 SSIs. The conventional method identified 32 SSIs. The computer-assisted method required 60% less time than the conventional method (90 hours vs 223 hours). CONCLUSION: Surveillance for SSIs using computer-assisted, laboratory-based screening and case confirmation by surgeons is as efficient as and far less time-consuming than the conventional method of chart review. This method permits routine surveillance for SSIs with reliable accuracy.

In vitro bactericidal activities of linezolid in combination with vancomycin, gentamicin, ciprofloxacin, fusidic acid, and rifampin against Staphylococcus aureus.

The in vitro activities of linezolid were determined alone and in combination with vancomycin, ciprofloxacin, gentamicin, fusidic acid, or rifampin against five methicillin-susceptible Staphylococcus aureus (MSSA) and five methicillin-resistant S. aureus (MRSA) strains. Similar responses were obtained against MSSA and MRSA. When combined with fusidic acid, gentamicin, or rifampin, linezolid prevented selection of resistant mutants but showed no synergy. When linezolid was combined with vancomycin and ciprofloxacin, a slight antagonism was observed. While the combination with linezolid may reduce the emergence of mutants resistant to the associated drugs, the absence of synergy, especially in the case of vancomycin and ciprofloxacin, does not argue in favor of such combinations.