Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections.

OBJECTIVES: Oral combination of clindamycin and rifampicin is relevant for the treatment of staphylococcal osteoarticular infection (SOAIs). However, rifampicin induces CYP3A4, suggesting a pharmacokinetic interaction with clindamycin with unknown pharmacokinetic/pharmacodynamic (PK/PD) consequences. This study aimed to quantify clindamycin PK/PD markers before and during rifampicin co-administration in SOAI. METHODS: Patients with SOAI were included. After initial intravenous antistaphylococcal treatment, oral therapy was started with clindamycin (600 or 750 mg t.i.d.), followed by addition of rifampicin 36 h later. Population PK analysis was performed using the SAEM algorithm. PK/PD markers were compared with and without rifampicin co-administration, each patient being his own control. RESULTS: In 19 patients, clindamycin median (range) trough concentrations were 2.7 (0.3-8.9) mg/L and <0.05 (<0.05-0.3) mg/L before and during rifampicin administration, respectively. Rifampicin co-administration increased clindamycin clearance by a factor 16 and reduced the AUC0-8h/MIC by a factor 15 (P < 0.005). Clindamycin plasma concentrations were simulated for 1000 individuals, without and with rifampicin. Against a susceptible Staphylococcus aureus strain (clindamycin MIC 0.0625 mg/L), >80% of individuals would reach all proposed PK/PD targets without co-administration of rifampicin, even with low clindamycin dose. For the same strain, when rifampicin was co-administered, the probability to reach clindamycin PK/PD targets dropped to 1% for %fT>MIC = 100% and to 6% for AUC0-24h/MIC > 60, even with high clindamycin dose. CONCLUSION: Rifampicin co-administration with clindamycin has a high impact on clindamycin exposure and PK/PD targets in SOAI, which could result in clinical failure even for fully susceptible strains.

Genetic, biochemical characterization and mutagenesis of the chromosomal class A ß-lactamase of Raoultella (formerly Klebsiella) terrigena.

BACKGROUND: Chromosomal class A ß-lactamases have been characterized in Raoultella ornithinolytica and Raoultella planticola. The purpose of this study was to characterize that of Raoultella terrigena. MATERIALS AND METHODS: The blaTER-1 gene of R. terrigena strain ATCC33257(T) was cloned (pACter-1) and sequenced. It was then used to detect the bla gene of strains BM 85 01 095 and SB2796. The hypermutable Escherichia coli strain AB1157 mutS::Tn10 was transformed with pACter-1 and mutants growing on plates containing>2mg/L ceftazidime were studied. Notably, the impact of mutations only observed in the promoter region on ß-lactam resistance was assessed by site-directed mutagenesis experiments. RESULTS: R. terrigena strains ATCC33257(T) and BM 85 01 095 had the same bla gene and deduced protein (TER-1) whereas there were 3 substitutions in those of strain SB2796 (TER-2). Class A ß-lactamases TER showed 78%, 69.9% and 38.7% identity with PLA or ORN, TEM-1 and KOXY, respectively. Compared with TEM-1, TER-1 and TER-2 showed 2 particular substitutions, Leu75Pro and Glu240Asn demonstrated to be involved in the inherent ß-lactam resistance profile of R. terrigena. TER-1 (pI of 7.6) had a high activity against penicillin G and a significantly low one against amoxicillin. Substitution G/T observed in the -35 region of the blaTER gene harbored by strains growing in the presence of≥2mg/L ceftazidime was shown to be responsible for this growth. CONCLUSION: TER is a new class A ß-lactamase belonging to functional group 2b.

Faecal carriage of extended-spectrum ß-lactamase (ESBL)-producing enterobacteria in liver disease patients from two hospitals in Egypt and France: a comparative epidemiological study.

This study aimed to assess and compare the epidemiology of faecal carriage of extended spectrum ß-lactamase-producing enterobacteria (ESBL-E) in Hepatology departments of two hospitals specializing in liver diseases, Theodor Bilharz Research Institute (TBRI) in Cairo (Egypt) and Beaujon Hospital (Bj) in Clichy (France). CTX-M groups were identified by PCR, and TEM and SHV derivatives with the check-point system. Phylogenetic groups of E. coli were determined by multiplex PCR, and clone ST131 by PCR of gene pabB. Prevalence of ESBL-E was 77·6% (45/58) in TBRI and 6·5% (13/199) in Bj (P < 10-7). Previous hospitalization was more common (P = 0·003) in Bj patients (93%) than in TBRI patients (45%) suggesting high prevalence of ESBL-E in the Egyptian community. The presence of E. coli B2 ST131 among ESBL-E faecal E. coli in Egypt confirms its pervasiveness in the community and raises concern regarding this highly virulent and resistant clone.

Clinical spectrum of urine cultures positive for ESBL-producing Escherichia coli in hospitalized patients and impact on antibiotic use.

OBJECTIVE: We wanted to describe the clinical features associated with urinalysis positive for ESBL-producing Escherichia coli and their impact on antibiotic use. METHODS: We performed a prospective observational study in 13 French hospitals of the Paris area for 3 consecutive months. We included all patients with urine cultures positive for ESBL-producing E. coli. RESULTS: One hundred and seventeen of the 218 patients (54%) presented with asymptomatic bacteriuria, 31 (14%) with cystitis, and 70 (32%) with a parenchymal infection. Nineteen patients with asymptomatic bacteriuria (16%) received antibiotics. Forty-one with parenchymal infections (59%) received a carbapenem. A carbapenem alternative could have been used in every patient treated with a carbapenem, according to antibiotic susceptibility testing results. CONCLUSIONS: Urinary tract infections accounted for 46% of E. coli ESBL positive urinalysis. Fifty percent of parenchymal infections were treated with a carbapenem.

Frequency and epidemiology of extended-spectrum ß-lactamase-producing Enterobacteriaceae isolates susceptible to third-generation cephalosporins or to aztreonam.

OBJECTIVE: We evaluated among 400 strains of extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBLE) the rate of strains categorized as intermediate or resistant to 3rd generation cephalosporins or aztreonam according to the 2011 guidelines of the French Society of Microbiology Antibiogram Committee. MATERIAL AND METHODS: MICs of cefotaxime, ceftazidime, cefepime or aztreonam were determined by the E-test method for isolates with susceptible zones to these antibiotics. RESULTS: Overall, 109/400 (27.3%) isolates were susceptible to at least one of these 4 agents. Notably, 21.8% of Escherichia coli isolates were susceptible to ceftazidime, and 21.1% of Klebsiella pneumoniae isolates were susceptible to cefepime. Discrepancies between categorization by disk diffusion and MIC determination were observed for aztreonam and cefepime. CONCLUSION: These results indicate alternatives to carbapenems for treating infections caused by ESBLE.

The emergence of multidrug-resistant Klebsiella pneumoniae of international clones ST13, ST16, ST35, ST48 and ST101 in a teaching hospital in the Paris region.

Despite infection control measures, an important increase in the extended-spectrum ß-lactamase (ESBL)-producing Klebsiella pneumoniae incidence density occurred in our hospital from 2006 onwards. This study, focusing on the 2005-2007 period, was performed in an attempt to explain this increase. ESBLs were characterized, isolates were typed by ERIC2-PCR, and sequence type (ST) of clustered isolates was determined. Temporal-spatial relationships of patients were analysed to assess possible cross-contamination. Of the 74 ESBL-producing isolates, 30 (40%) were detected at admission, 53 (71∙5%) produced CTX-M enzymes, 40 displayed unique ERIC2-PCR profiles and 34 were assigned into six clusters: ST16 (n=21), ST101, ST48, ST35, ST13, and ST436. Relationships were identified in 22 of the 34 patients harbouring clustered isolates. This study highlights the complex epidemiology of ESBL-producing K. pneumoniae in the mid-2000s with potential cross-contamination for only 30% of the 74 patients in our hospital, and the emergence of clones that are currently spreading worldwide.

[Intermittent prolonged fever triggered by efforts]. / Fièvre prolongée intermittente survenant à l'effort.

INTRODUCTION: Fever of unknown origin is a common reason for care in internal medicine. The wide variety of possible etiologies makes it difficult to standardize the diagnostic work-up that has to be primarily guided by the interview and physical examination. CASE REPORT: We report a case of prolonged fever having as main characteristics to be intermittent and triggered by efforts. The diagnosis of cerebrospinal fluid shunt infection with Propionibacterium acnes was finally made. In reaching this conclusion, many tests were needed, including renal explorations with biopsy showing an aspect of shunt nephritis. CONCLUSION: Prolonged fever of unknown origin in a patient having prosthetic material should raise the suspicion of prosthesis infection (especially if the fever is associated with efforts).

[Totally implanted access port-related infections: features and management]. / Complications infectieuses liées aux chambres implantables: caractéristiques et prise en charge.

Totally implanted access port-related infections are responsible for their own morbidity and mortality. Main risk factors of totally implanted access port-related infections are total parenteral nutrition, young age, difficulties during insertion, poor general status and neutropenia. Recent guidelines defined intravascular catheter-related infections. This relies on a strict clinical and microbiological work-up including simultaneous culture of blood drawn from the catheter and a peripheral vein. The search for local or general complications is mandatory: clinical and possibly echographic assessments are therefore needed. Depending on the context and the type of microorganism, this evaluation may include transoesophageal echocardiography and search for suppurative thrombosis in case of catheter-related bloodstream infection caused by Staphylococcus aureus. Indeed, intravascular complications in this setting are frequent. Catheter removal is mandatory in case of local complication (tunnel infection or port pocket abscess), septic thrombosis, infective endocarditis, osteomyelitis, septic shock or infection related to specific pathogens (S. aureus, Candida spp., Pseudomonas aeruginosa). Otherwise, retention of the catheter might be proposed given results from recent studies including antibiotic lock therapy associated with systemic antibiotic. Future studies must focus on defining more precisely the factors associated with salvage therapy failure including host, pathogens virulence factors and biofilm formation.

[Emergence of vancomycin-dependent enterococci following glycopeptide therapy: case report and review]. / Emergence d'entérocoque dépendant de la vancomycine à la suite d'un traitement par glycopeptide: cas clinique et revue.

INTRODUCTION: Outbreaks of vancomycin-resistant enterococci have been increasingly reported in France over the last three years. We report here, the emergence of a vancomycin-dependent enterococci isolate following glycopeptide therapy. PATIENTS AND METHODS: An Enterococcus faecium isolate that required vancomycin for growth was cultured from the stools of a liver transplant recipient who was colonised with vancomycin-resistant enterococci and who received vancomycin treatment for methicillin-resistant Staphylococcus aureus infection. The resistant isolate and the dependent isolate were typed by pulsed-field gel electrophoresis. The sequence of the ddl gene coding for the D-Ala: D-Ala ligase was analysed. RESULTS: The dependent isolate was primary cultured onto a vancomycin-containing screening medium and could not be subcultured in the absence of vancomycin. Both the resistant and dependent isolates harboured the vanA gene and they had the same DNA restriction pattern after pulsed-field gel electrophoresis. Dependence on vancomycin was associated with a 1-bp deletion in the D-Ala: D-Ala ligase gene leading to an early stop odon. CONCLUSION: Cultures onto vancomycin-containing media are warranted for clinical specimens from patients, who are known to carry vancomycin-resistant enterococci and receive vancomycin therapy.

Imipenem resistance in Salmonella enterica serovar Wien related to porin loss and CMY-4 beta-lactamase production.

Two multidrug-resistant Salmonella enterica serovar Wien strains (SW468 and SW1107) were isolated in 2001 in Tunis. Both strains produced the beta-lactamases TEM-1, SHV-2a, and CMY-4, whereas strain SW1107 also produced the beta-lactamase CTX-M-3. The imipenem-resistant strain (SW468) was totally devoid of the OmpF-immunorelated porin. Imipenem resistance was shown as being related to porin loss and CMY-4 beta-lactamase production.

Updated sequence information and proposed nomenclature for bla(TEM) genes and their promoters.

The nucleotide sequences of 59 bla(TEM) genes encoding inhibitor-resistant TEM enzymes showed great genetic variability and were associated with different types of promoters. These findings led us to suggest an updated bla(TEM) gene nomenclature based on the origin of the bla(TEM) gene (bla(TEM-1A), bla(TEM-1B), bla(TEM-1C), bla(TEM-1D), bla(TEM-1E), and bla(TEM-1F)) and the promoter type.

Epidemiological survey of amoxicillin-clavulanate resistance and corresponding molecular mechanisms in Escherichia coli isolates in France: new genetic features of bla(TEM) genes.

Amoxicillin-clavulanate resistance (MIC >16 microg/ml) and the corresponding molecular mechanisms were prospectively studied in Escherichia coli over a 3-year period (1996 to 1998) in 14 French hospitals. The overall frequency of resistant E. coli isolates remained stable at about 5% over this period. The highest frequency of resistant isolates (10 to 15%) was observed, independently of the year, among E. coli isolated from lower respiratory tract samples, and the isolation rate of resistant strains was significantly higher in surgical wards than in medical wards in 1998 (7.8 versus 2.8%). The two most frequent mechanisms of resistance for the 3 years were the hyperproduction of the chromosomal class C beta-lactamase (48, 38.4, and 39.7%) and the production of inhibitor-resistant TEM (IRT) enzymes (30.4, 37.2, and 41.2%). By using the single-strand conformational polymorphism-PCR technique and sequencing methods, we determined that 59 IRT enzymes corresponded to previously described IRT enzymes whereas 8 were new. Three of these new enzymes derived from TEM-1 by only one amino acid substitution (Ser130Gly, Arg244Gly, and Asn276Asp), whereas three others derived by two amino acid substitutions (Met69Leu and Arg244Ser, Met69Leu and Ile127Val, and Met69Val and Arg275Gln). The two remaining new IRTs showed three amino acid substitutions (Met69Val, Trp165Arg, and Asn276Asp and Met69Ile, Trp165Cys, and Arg275Gln). New genetic features were also found in bla(TEM) genes, namely, bla(TEM-1B) with either the promoters Pa and Pb, P4, or a promoter displaying a C-->G transversion at position 3 of the -35 consensus sequence and new bla(TEM) genes, notably one encoding TEM-1 but possessing the silent mutations originally described in bla(TEM-2) and then in some bla(TEM)-encoding IRT enzymes.

Typing of Clostridium perfringens strains by use of Random Amplified Polymorphic DNA (RAPD) system in comparison with zymotyping.

The definition of strain clonality postulates that strains showed identical phenotypic and genetic traits are likely to descend from a common ancestor even if they were isolated from different sources and locations. Regarding this definition, non-epidemiologically linked strains might be clonal strains. To overcome this ambiguity, the discriminatory capability of RAPD typing was assessed firstly on eight Clostridium perfringens strains proven to be chromosomally different with one being the mutant of another one. Thirteen primers were tested but only two were able to differentiate seven of the eight strains. With none of the used primers it was possible to differentiate the parental strain and its mutant harboring an insertion of 180 kb. The four most discriminant primers were retained to determine the RAPD fingerprints of a further 20 previously zymotyped strains from which seventeen were unrelated. To compare the two typing systems, the zymotype of the eight chromosomally different strains was determined. Thus, the discriminatory index was calculated on the basis of 25 unrelated C. perfringens strains. This was 0.97 with RAPD typing and 0.99 with zymotyping. From these results we conclude that the RAPD typing which is less fastidious than zymotyping can be used as an epidemiological marker for C. perfringens.