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.

Evolution of fluoroquinolone-resistant Escherichia coli in the gut after ciprofloxacin treatment.

BACKGROUND: Three healthy volunteers carried similar quinolone-resistant E. coli (QREC) (pulsed field gel electrophoresis profiles) in their gut before and after 14 days ciprofloxacin treatment. Given the intensity of the selective pressure and the mutagenic properties of quinolones, we determined whether these strains had evolved at the phenotypic and/or genomic levels. MATERIAL AND METHODS: Commensal QREC from before day-0 (D0), and a month after 14 days of ciprofloxacin (D42) were compared in 3 volunteers. Growth experiments were performed; acetate levels, mutation frequencies, quinolone MICs and antibiotic tolerance were measured at D0 and D42. Genomes were sequenced and single nucleotide polymorphisms (SNPs) between D0 and D42 were analyzed using DiscoSNP and breseq methods. Cytoplasmic proteins were extracted, HPLC performed and proteins identified using X!tandem software; abundances were measured by mass spectrometry using the Spectral Counting (SC) and eXtraction Ion Chromatograms (XIC) integration methods. RESULTS: No difference was found in MICs, growth characteristics, acetate concentrations, mutation frequencies, tolerance profiles, phylogroups, O-and H-types, fimH alleles and sequence types between D0 and D42. No SNP variation was evidenced between D0 and D42 isolates for 2/3 subjects; 2 SNP variations were evidenced in one. At the protein level, very few significant protein abundance differences were identified between D0 and D42. CONCLUSION: No fitness, tolerance, metabolic or genomic evolution of commensal QREC was observed overtime, despite massive exposure to ciprofloxacin in the gut. The three strains behaved as if they had been unaffected by ciprofloxacin, suggesting that gut may act as a sanctuary where bacteria would be protected from the effect of antibiotics and survive without any detrimental effect of stress.

[Characteristics of patients admitted from emergency units in 18 internal medicine departments and organisation of these departments: A cross sectional study from SNFMI (SiFMI study group) in 2015]. / Caractéristiques des patients admis en médecine interne dans 18 hôpitaux français en aval des urgences et organisation de ces services : enquête transversale de la SNFMI (groupe d'étude SiFMI) en 2015.

INTRODUCTION: Patients admitted from emergency units represent a large portion of the population in internal medicine departments. The aim of this study is to identify characteristics of patients and organization of these departments. METHODS: Between June 29th and July 26th 2015, voluntary internal medicine departments from the SiFMI group prospectively filled anonymized internet forms to collect data of each patients admitted in their ward from emergency units, during seven consecutive days. RESULTS: Three hundred and sixty-five patients from emergency departments were admitted in 18 internal medicine inpatients departments, totalling 1100 beds and 33,530 annual stays, 56% of them for emergency units inpatients. Mean age was 68 years, 54% were women, mean Charlson score was 2.6 and 44% of the patients took at least three drugs. Main causes of hospitalization were infectious (29%) and neurological (17%) diseases. Mean length of stay was 9.2 days. The medical team was composed by a median value of 4,5 [2,75-6,25] senior full-time equivalents, 86% were internists. Each department except one received residents, two third of them were from general medicine. CONCLUSION: This study highlights a high organizational variability among internal medicine departments and patients, and sets internal medicine as a specialty with a great capacity to achieve an integrative/comprehensive management of patients and to offer a comprehensive basis for physicians in training.

Dimercaptosuccinic acid in combination with carbapenems against isogenic strains of Escherichia coli producing or not producing a metallo-ß-lactamase in vitro and in murine peritonitis.

BACKGROUND: Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating lead intoxication. OBJECTIVES: To evaluate the activity of carbapenems alone or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model. METHODS: Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time-kill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally for 24 h with imipenem, DMSA or their combination. Bacterial counts in peritoneal fluid and spleen were assessed at 24 h. RESULTS: DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1-producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (P = 0.0006) and spleen (P < 0.0001), as compared with imipenem alone, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose. CONCLUSIONS: DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections.

Expression of CTX-M-15 limits the efficacy of ceftolozane/tazobactam against Escherichia coli in a high-inoculum murine peritonitis model.

OBJECTIVES: Among carbapenem-sparing therapies, ceftolozane/tazobactam has been proposed for the treatment of infections due to CTX-M-15-producing Escherichia coli. However, few data exist on its in vivo activity in infections associated with a high bacterial inoculum. METHODS: We analysed ceftolozane/tazobactam activity against susceptible E. coli CFT073-RR and its CTX-M-15-producing transconjugant E. coli CFT073-RR Tc blaCTX-M-15, in vitro at low and high inocula, and in a high-inoculum murine model of peritonitis. RESULTS: Against E. coli CFT073-RR Tc blaCTX-M-15, ceftolozane/tazobactam bactericidal effect was impaired in vitro with only a minor inoculum effect; this translated into reduced activity compared with imipenem in the mouse peritonitis model. CONCLUSIONS: Combination of extended spectrum ß-lactamase expression and high inoculum size may be a clinical situation at risk of reduced bactericidal activity of ceftolozane/tazobactam.

Mortality in Escherichia coli bloodstream infections: antibiotic resistance still does not make it.

BACKGROUND: Escherichia coli bloodstream infections (BSIs) account for high mortality rates (5%-30%). Determinants of death are unclear, especially since the emergence of ESBL producers. OBJECTIVES: To determine the relative weight of host characteristics, bacterial virulence and antibiotic resistance in the outcome of patients suffering from E. coli BSI. METHODS: All consecutive patients suffering from E. coli BSI in seven teaching hospitals around Paris were prospectively included for 10 months. E. coli isolates were sequenced using Illumina NextSeq technology to determine the phylogroup, ST/ST complex (STc), virulence and antimicrobial resistance gene content. Risk factors associated with death at discharge or Day 28 were determined. RESULTS: Overall, 545 patients (mean ± SD age 68.5 ±âŸ16.5 years; 52.5% male) were included. Mean Charlson comorbidity index (CCI) was 5.6 (± 3.1); 19.6% and 12.8% presented with sepsis and septic shock, respectively. Portals of entry were mainly urinary (51.9%), digestive (41.9%) and pulmonary (3.5%); 98/545 isolates (18%) were third-generation cephalosporin resistant (3GC-R), including 86 ESBL producers. In-hospital death (or at Day 28) was 52/545 (9.5%). Factors independently associated with death were a pulmonary portal of entry [adjusted OR (aOR) 6.54, 95% CI 2.23-19.2, P = 0.0006], the iha_17 virulence gene (aOR 4.41, 95% CI 1.23-15.74, P = 0.022), the STc88 (aOR 3.62, 95% CI 1.30-10.09, P = 0.014), healthcare-associated infections (aOR 1.98, 95% CI 1.04-3.76, P = 0.036) and high CCI (aOR 1.14, 95% CI 1.04-1.26, P = 0.006), but not ESBL/3GC-R. CONCLUSIONS: Host factors, portal of entry and bacterial characteristics remain major determinants associated with mortality in E. coli BSIs. Despite a high prevalence of ESBL producers, antibiotic resistance did not impact mortality. (ClinicalTrials.gov identifier: NCT02890901.).

[Association between psychiatric comorbidities and hospital length of stay in post-emergency internal medicine patients]. / Association des comorbidités psychiatriques avec la durée de séjour des patients en médecine interne d'aval des urgences.

INTRODUCTION: Patients with psychiatric disorders suffer from a higher rate of somatic disorders than those without psychiatric disorder, often inappropriately managed. Our study aimed to describe patients with psychiatric comorbidity in post-emergency internal medicine units and to compare their length of hospital stay to patients without psychiatric disease. METHODS: This French cross sectional study used the data warehouse of the greater Paris hospitals. It included, all patients hospitalized through the emergency department in 9 internal medicine departments during the year 2017. Psychiatric disorders and the burden of somatic disorders (Charlson score) were determined through diagnostic coding. Charlson score and hospital length of stay were compared between patients with and without psychiatric comorbidity. RESULTS: In total, 8981 hospital stays (8001 patients) were included, 1867 (21%) with psychiatric comorbidity. After adjusting for age, gender, hospital and main diagnosis, the Charlson score was on average 0.68 higher in the psychiatric comorbidity group (P<0.001) and the length of hospital stay was 30% higher after further adjustment on the Charlson score (P<0.001). These differences were consistent for each main diagnosis. CONCLUSION: Patients with psychiatric comorbidity are frequent in post-emergency internal medicine wards. They experience longer hospital stays, only partly related with a higher burden of somatic disorders. Special attention should be paid to this vulnerable population.

The inoculum effect of Escherichia coli expressing mcr-1 or not on colistin activity in a murine model of peritonitis.

OBJECTIVES: Colistin often remains the last resort antibiotic active against carbapenemase-producing Enterobacteriaceae. However, while in vitro inoculum effect has been reported, therapeutic relevance of this phenomenon remains questioned. METHODS: Ten E. coli strains were used that included the wild-type CFT073 and its transconjugant CFT073-MCR-1 and eight susceptible clinical isolates. Mice with peritonitis were treated for 24 h with colistin sulfate. Bacterial loads were determined in peritoneal fluid (PF) and spleen and colistin-resistant mutants were detected. RESULTS: MICs of colistin against the eight susceptible clinical strains and CFT073 ranged from 0.125 to 0.5 mg/L with an inoculum of 105 CFU/mL and from 2 to 4 mg/L with a 107 CFU/mL inoculum; 5/9 strains with an MIC of 4 mg/L were considered resistant according to EUCAST breakpoint (resistance, > 2 mg/L). When the bacterial load of wild-type CFT073 inoculated in mice increased from 107 to 108 CFU: i) mean log10 CFU reduction generated by colistin in PF and spleen decreased from 5.8/mL and 3.1/g, respectively, (p < 0.01) to 0.9/mL and 0.8/g, respectively (NS); ii) mice survival rate decreased from 15/15 (100%) to 6/15 (40%) (p = 0.017); and iii) proportion of mice with selection of colistin-resistant mutants increased from 4/15 to 15/15 (p < 0.01). These results were comparable to those obtained when peritonitis was produced with a 107 CFU bacterial load of E. coli CFT073 expressing mcr-1, for which the mean log10 CFU reductions were 3.5/mL and 0.6/g in PF and spleen, respectively (NS), and survival rate was 8/15 (53%) (p < 0.01 versus survival of mice infected with wild-type CFT073). CONCLUSIONS: Phenotypic colistin resistance in wild-type E. coli due to an increase in inoculum size had a therapeutic impact in mice with peritonitis that was comparable to that observed when the mcr-1 gene was expressed.

Acute cholangitis: Diagnosis and management.

Acute cholangitis is an infection of the bile and biliary tract which in most cases is the consequence of biliary tract obstruction. The two main causes are choledocholithiasis and neoplasia. Clinical diagnosis relies on Charcot's triad (pain, fever, jaundice) but the insufficient sensitivity of the latter led to the introduction in 2007 of a new score validated by the Tokyo Guidelines, which includes biological and radiological data. In case of clinical suspicion, abdominal ultrasound quickly explores the biliary tract, but its diagnostic capacities are poor, especially in case of non-gallstone obstruction, as opposed to magnetic resonance cholangiopancreatography and endoscopic ultrasound, of which the diagnostic capacities are excellent. CT scan is more widely available, with intermediate diagnostic capacities. Bacteriological sampling through blood cultures (positive in 40% of cases) and bile cultures is essential. A wide variety of bacteria are involved, but the main pathogens having been found are Escherichia coli and Klebsiella spp., justifying first-line antimicrobial therapy by a third-generation cephalosporin. Systematic coverage of Enterococcus spp. and anaerobic infections remains debated, and is usually recommended, in case of severity criteria for Enterococcus severity levels, or anaerobic bilio-digestive anastomosis for anaerobes. Presence of a biliary stent is the only identified risk-factor associated with infections by multidrug-resistant pathogens. Along with antimicrobial therapy, endoscopic or radiological biliary drainage is a crucial management component. Despite improved management, mortality in cases of acute cholangitis remains approximately 5%.

Lyme borreliosis and other tick-borne diseases. Guidelines from the French scientific societies (II). Biological diagnosis, treatment, persistent symptoms after documented or suspected Lyme borreliosis.

The serodiagnosis of Lyme borreliosis is based on a two-tier strategy: a screening test using an immunoenzymatic technique (ELISA), followed if positive by a confirmatory test with a western blot technique for its better specificity. Lyme serology has poor sensitivity (30-40%) for erythema migrans and should not be performed. The seroconversion occurs after approximately 6 weeks, with IgG detection (sensitivity and specificity both>90%). Serological follow-up is not recommended as therapeutic success is defined by clinical criteria only. For neuroborreliosis, it is recommended to simultaneously perform ELISA tests in samples of blood and cerebrospinal fluid to test for intrathecal synthesis of Lyme antibodies. Given the continuum between early localized and disseminated borreliosis, and the efficacy of doxycycline for the treatment of neuroborreliosis, doxycycline is preferred as the first-line regimen of erythema migrans (duration, 14 days; alternative: amoxicillin) and neuroborreliosis (duration, 14 days if early, 21 days if late; alternative: ceftriaxone). Treatment of articular manifestations of Lyme borreliosis is based on doxycycline, ceftriaxone, or amoxicillin for 28 days. Patients with persistent symptoms after appropriate treatment of Lyme borreliosis should not be prescribed repeated or prolonged antibacterial treatment. Some patients present with persistent and pleomorphic symptoms after documented or suspected Lyme borreliosis. Another condition is eventually diagnosed in 80% of them.

Lyme borreliosis and other tick-borne diseases. Guidelines from the French Scientific Societies (I): prevention, epidemiology, diagnosis.

Lyme borreliosis is transmitted en France by the tick Ixodes ricinus, endemic in metropolitan France. In the absence of vaccine licensed for use in humans, primary prevention mostly relies on mechanical protection (clothes covering most parts of the body) that may be completed by chemical protection (repulsives). Secondary prevention relies on early detection of ticks after exposure, and mechanical extraction. There is currently no situation in France when prophylactic antibiotics would be recommended. The incidence of Lyme borreliosis in France, estimated through a network of general practitioners (réseau Sentinelles), and nationwide coding system for hospital stays, has not significantly changed between 2009 and 2017, with a mean incidence estimated at 53 cases/100,000 inhabitants/year, leading to 1.3 hospital admission/100,000 inhabitants/year. Other tick-borne diseases are much more seldom in France: tick-borne encephalitis (around 20 cases/year), spotted-fever rickettsiosis (primarily mediterranean spotted fever, around 10 cases/year), tularemia (50-100 cases/year, of which 20% are transmitted by ticks), human granulocytic anaplasmosis (<10 cases/year), and babesiosis (<5 cases/year). The main circumstances of diagnosis for Lyme borreliosis are cutaneous manifestations (primarily erythema migrans, much more rarely borrelial lymphocytoma and atrophic chronic acrodermatitis), neurological (<15% of cases, mostly meningoradiculitis and cranial nerve palsy, especially facial nerve) and rheumatologic (mostly knee monoarthritis, with recurrences). Cardiac and ophtalmologic manifestations are very rarely encountered.

A 5-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: a randomized clinical trial.

OBJECTIVES: Intestinal carriage with extended spectrum ß-lactamase Enterobacteriaceae (ESBL-E) and carbapenemase-producing Enterobacteriaceae (CPE) can persist for months. We aimed to evaluate whether oral antibiotics followed by faecal microbiota transplantation (FMT) can eradicate intestinal carriage with ESBL-E/CPE. METHODS: Randomized, open-label, superiority trial in four tertiary-care centres (Geneva (G), Paris (P), Utrecht (U), Tel Aviv (T)). Non-immunocompromised adult patients were randomized 1: 1 to either no intervention (control) or a 5-day course of oral antibiotics (colistin sulphate 2 × 106 IU 4×/day; neomycin sulphate 500 mg 4×/day) followed by frozen FMT obtained from unrelated healthy donors. The primary outcome was detectable intestinal carriage of ESBL-E/CPE by stool culture 35-48 days after randomization (V4). ClinicalTrials.govNCT02472600. The trial was funded by the European Commission (FP7). RESULTS: Thirty-nine patients (G = 14; P = 16; U = 7; T = 2) colonized by ESBL-E (n = 36) and/or CPE (n = 11) were enrolled between February 2016 and June 2017. In the intention-to-treat analysis 9/22 (41%) patients assigned to the intervention arm were negative for ESBL-E/CPE at V4 (1/22 not receiving the intervention imputed as positive) whereas in the control arm 5/17 (29%) patients were negative (one lost to follow up imputed as negative) resulting in an OR for decolonization success of 1.7 (95% CI 0.4-6.4). Study drugs were well tolerated overall but three patients in the intervention group prematurely stopped the study antibiotics because of diarrhoea (all received FMT). CONCLUSIONS: Non-absorbable antibiotics followed by FMT slightly decreased ESBL-E/CPE carriage compared with controls; this difference was not statistically significant, potentially due to early trial termination. Further clinical investigations seem warranted.

[Insights on the management of Lyme disease]. / Actualités sur la prise en charge de la maladie de Lyme.

Lyme disease is currently a hot topic in France due to a high incidence in some areas. Its clinical polymorphism can lead to misdiagnosis on one hand and to unjustified treatment on the other hand. Clinical symptoms vary considerably according to involved organs (skin, central and/or peripheral nervous system, joints, heart, eyes) and may be limited to or associated with general non-specific signs. Biological exams must be guided by clinical symptoms to help diagnosis and treatment decision according to clinical history, presentation, time of onset and duration of symptoms. However, to date, no serologic test can discriminate between past and active disease. The role of the internist is two-fold: make a diagnosis when faced with general or focal symptoms and avoid inappropriate attribution to Lyme disease of symptoms related to alternate diagnoses.

Activity of fosfomycin alone or combined with temocillin in vitro and in a murine model of peritonitis due to KPC-3- or OXA-48-producing Escherichia coli.

Background: Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance is a major limitation. Our aim was to determine whether the association of temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections. Methods: Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected. Results: Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P < 0.001) and inhibited growth of resistant mutants in all cases. Conclusions: The combination of fosfomycin and temocillin demonstrated a benefit in vitro and in vivo against E. coli strains producing KPC-3 or OXA-48-type carbapenemases. This combination prevented the emergence of fosfomycin resistance and proved to be more bactericidal than fosfomycin alone.