Update in antibiotic therapy in intensive care unit: report from the 2019 Nîmes International Symposium.

The 2019 Nîmes International Symposium in Antibiotic Therapy Optimisation aimed at determining the best approaches of a number of the antibiotic management strategies for critically ill patients. Experts reviewed the latest literature relating to requirements for an optimal antibiotic stewardship program, risks of sub-therapeutic dosing of antibiotics in critically ill patients, persisting issues about efficiency of combination therapy and the value of de-escalation, new perspectives of pharmacokinetics, drug toxicities including collateral damages-associated with antibiotics, the place of nebulisation of antibiotics, management of patients receiving extracorporeal therapies and the place of new antibiotics. In this paper, each of these issues is discussed with key messages presented after a brief review of evidence.

Adjuvant ß-Lactam Therapy Combined with Vancomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: Does ß-Lactam Class Matter?

We analyzed the impact of vancomycin (VAN) combined with adjuvant ß-lactam therapy (Combo) on persistent (≥5 days) methicillin-resistant Staphylococcus aureus bacteremia versus VAN alone by using pooled data from two previously published observational studies (n = 156). Combo was inversely associated with persistent bacteremia (adjusted odds ratio, 0.460; 95% confidence interval, 0.229 to 0.923). Acute kidney injury was more common with Combo than with VAN (18.9% and 7.6%, respectively; P = 0.062).

Multidrug-Resistant Pseudomonas aeruginosa Infection in a Child with Cystic Fibrosis.

We describe a pediatric cystic fibrosis patient who developed a pulmonary exacerbation due to two multidrug-resistant (MDR) Pseudomonas aeruginosa isolates. In addition to these MDR organisms, the case was further complicated by ß-lactam allergy. Despite the MDR phenotype, both isolates were susceptible to an antimicrobial combination.

[Leptospirosis in a family after whitewater rafting in Thailand]. / Leptospirose famitiate apres rafting en Thaïlande.

Leptospirosis is a zoonosis found worldwide, with an incidence that is approximately 10 times higher in the tropics than in temperate regions. The main reservoir of leptospirosis is the rat and human infection usually results from exposure to infected animal urine or tissues. Only 10% of cases are symptomatic. We present here two confirmed and two probable cases of leptospirosis in a family returning from whitewater rafting in Thailand, illustrating the wide variety of the clinical manifestations of this infection. Two of the patients were hospitalized and presented a probable Jarisch-Herxheimer reaction after initiation of beta-lactam therapy. The two others patients were treated empirically with doxycycline. We discuss here some relevant aspects of the epidemiology, clinical manifestations, therapy and the challenge of an early diagnosis of leptospirosis.

Ertapenem usage in cancer patients with and without neutropenia: a report on 97 cases from a comprehensive cancer center.

PURPOSE: Ertapenem is being increasingly utilized in cancer patients, but published data regarding its usage are limited. Our objective was to describe the various indications for ertapenem therapy and its safety and efficacy in cancer patients. METHODS: We conducted a retrospective cohort study of cancer patients who received monotherapy with ertapenem for at least 72 h, between January 2007 and February 2013. RESULTS: Among 97 unique patients who received ertapenem monotherapy, the most common indications were: (1) To facilitate discharge from the hospital of stable patients still requiring antimicrobial therapy (46 %). (2) Primary therapy of various documented infections (bacteremia, pneumonia, urinary tract infection, skin and skin structure infection) with ertapenem (28 %). (3) De-escalation from a different broad-spectrum agent or regimen to ertapenem within the hospital setting in patients not ready for discharge (25 %). The median age of the 97 patients studied was 59 years (range 9-87 years) with 52 % being men. Most patients had underlying hematologic malignancies (54 %), and 7 % were recipients of hematopoietic stem cell transplantation. Twenty-nine patients (30 %) were neutropenic, 26 % were diabetic, and 6 % had chronic lung disease. Primary ertapenem monotherapy was successful in all patients, de-escalation in 95.8 % of patients, and the strategy of discharge on outpatient therapy with ertapenem in 95.6 % of patients. Patients failing de-escalation or early discharge responded to alternative regimens. We documented no significant ertapenem associated toxicity or adverse events. CONCLUSIONS: Ertapenem appears to be safe and effective for several indications in cancer patients.

Eravacycline for the treatment of intra-abdominal infections.

INTRODUCTION: There has been a dramatic increase in the incidence of multidrug-resistant pathogens over the past few years, which highlights the need for new anti-infective therapeutics. Eravacycline is a novel, broad-spectrum synthetic tetracycline indicated for the treatment of severe infections caused by Gram-positive and Gram-negative bacteria. AREAS COVERED: In this review, the authors report eravacycline's pharmacokinetic characteristics and its microbiological spectrum of activity. Furthermore, the authors also highlight the safety and efficacy data from the recent studies on urinary and intra-abdominal infections. EXPERT OPINION: The profile of eravacycline offers several advantages. Indeed, eravacycline has a broad-spectrum activity toward pathogens involved in complicated urinary tract (cUTIs) and intra-abdominal infections (cIAIs), including extended-spectrum beta-lactamase and carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The availability of an oral formulation supports eravacycline's possible use in sequential therapy. High urinary concentrations favor its use in cUTIs and may reduce the overuse of other antimicrobials that may select resistance, such as carbapenems. Eravacycline efficacy and tolerability have been investigated in a Phase II clinical trial in cIAIs comparing two dosages of eravacycline with ertapenem, showing comparable efficacy among the three arms and a low rate of adverse effects. The results of new Phase III studies are awaited to confirm eravacycline's future applications in severe nosocomial infections.

Analysis on 113 cases of adverse reactions caused by ß-lactam antibiotics.

UNLABELLED: The objectives of this study were to learn about the characteristics and rules of the occurrence of adverse reactions caused by lactam antibiotics and provide a reference for clinical drug use. METHODS: A retrospective study was made to analyse the 113 case reports of adverse reactions caused by ß-lactam antibiotics collected in our hospital between 2007 and 2009. RESULTS: 113 cases of ADR involved 17 kinds of ß-lactam antibiotics, headed by ceftriaxone sodium. The most common manifestation was skin and accessory damage; nervous system and gastrointestinal system damage were also easier to find, and the administration route was mainly intravenous infusion. CONCLUSION: The clinical application of ß-lactam antibiotics should pay attention to adverse reaction monitoring and rational drug use to reduce the incidence of adverse reactions.

Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept.

The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on beta-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a beta-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12h of sampling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5x the minimum inhibitory concentration (MIC) or above 10x MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean+/-standard deviation age was 53.5+/-18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents; 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal beta-lactam pharmacodynamic targets improves clinical outcomes.

Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria.

OBJECTIVE: To describe the rationale, principles, and dosage calculations for continuous-infusion beta-lactam antibiotics to treat multidrug-resistant bacteria in patients undergoing continuous venovenous hemofiltration (CVVH). DATA SOURCES: A MEDLINE search (1968-November 2008) of the English-language literature was performed using the terms continuous infusion and Pseudomonas or Acinetobacter; hemofiltration or CVVH or hemodiafiltration or CVVHDF or continuous renal replacement therapy or pharmacokinetics; and terms describing different beta-lactam antibiotics. STUDY SELECTION AND DATA EXTRACTION: In vitro, in vivo, and human studies were evaluated that used continuous-infusion beta-lactam antibiotics to treat Pseudomonas aeruginosa and Acinetobacter baumannii infections. Studies were reviewed that described the pharmacokinetics of beta-lactam antibiotics during CVVH as well as other modalities of continuous renal replacement therapy. DATA SYNTHESIS: Continuous infusion of beta-lactam antibiotics, maintaining drug concentrations 4-5 times higher than the minimum inhibitory concentration, is a promising approach for managing infections caused by P. aeruginosa and A. baumannii. Safe yet effective continuous infusion therapy is made difficult by the occurrence of acute renal failure and the need for renal replacement therapy. Case series and pharmacokinetic properties indicate that several beta-lactam antimicrobials that have been studied for continuous infusion, such as cefepime, ceftazidime, piperacillin, ticarcillin, clavulanic acid, and tazobactam, are significantly cleared by hemofiltration. Methodology and formulas are provided that allow practitioners to calculate dosage regimens and reach target drug concentrations for continuous beta-lactam antibiotic infusions during CVVH based on a literature review, pharmacokinetic principles, and our experience at the National Institutes of Health Clinical Center. CONCLUSIONS: Continuous infusion of beta-lactam antibiotics may be a useful treatment strategy for multidrug-resistant gram-negative infections in the intensive care unit. Well-established pharmacokinetic and pharmacodynamic principles can be used to safely reach and maintain steady-state target concentrations of beta-lactam antibiotics in critical illness complicated by acute renal failure requiring CVVH.

[Beta-lactam antibiotics]. / Antibióticos betalactámicos.

Beta-lactam drugs, whose mechanism of action is inhibition of the last stage of bacterial cell wall synthesis, are the largest family of antimicrobial agents and the most widely used in current clinical practice. These drugs have a slow, time-dependent bactericidal action, generally good distribution in the body, and low toxicity. Modifications of the original molecule have led to new compounds with a greater antimicrobial spectrum and activity; nonetheless, the use and efficacy of beta-lactams is limited in some clinical settings, owing to the increasing emergence of antimicrobial resistance. Despite this problem, penicillin remains the treatment of choice in a large number of infections, cephalosporins have a wide range of indications, carbapenems are used in nosocomially-acquired infection and infection caused by multiresistant microorganisms, and beta-lactam inhibitors restore the spectrum of activity of their companion penicillins (aminopenicillins, ureidopenicillins) when resistance is caused by beta lactamase production.

Efficacy and safety of faropenem in eradication therapy of Helicobacter pylori.

AIMS: While triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin is the standard therapy for Helicobacter pylori eradication, it is ineffective against clarithromycin-resistant strains. To seek a better regimen for eradication therapy, we assessed the sensitivity of clinical strains seen in Japan to faropenem and then evaluated the efficacy and safety of eradication therapy containing this antibiotic. METHODS: Minimum inhibitory concentrations (MICs) of faropenem were determined in 78 Japanese clinical H. pylori isolates using the agar dilution method. H. pylori-positive patients were consecutively assigned to a 7-day eradication therapy protocol with LAF (lansoprazole 60 mg/day, amoxicillin 2000 mg/day, and faropenem 600 mg/day), and then to a 14-day protocol. The outcomes of the therapies were assessed by (13)C-urea breath tests. RESULTS: All 78 strains showed MICs of faropenem that were equal to or less than 0.2 microg/mL. The eradication rates according to intention-to-treat analyses were 46.5% with the 7-day therapy (n = 43) and 62.5% with the 14-day therapy (n = 32). No special measures were required to treat the adverse events observed in approximately one-third of the patients. CONCLUSIONS: Faropenem was found to have good antimicrobial action against H. pylori in vitro. The 14-day LAF therapy successfully eradicated H. pylori in about two-thirds of the patients although the incidence of adverse events was high.

Efficacy of ertapenem in the treatment of early ventilator-associated pneumonia caused by extended-spectrum beta-lactamase-producing organisms in an intensive care unit.

OBJECTIVES: Ventilator-associated pneumonia (VAP) is a frequent complication of patients admitted to intensive care units (ICUs). Ertapenem is a newer carbapenem with good in vitro activity against extended-spectrum beta-lactamase (ESBL)-producing organisms. However, there are no clinical data to support the use of ertapenem in VAP. Our purpose is to evaluate the usefulness and safety of ertapenem in the treatment of VAP caused by susceptible ESBL strains. METHODS: Ertapenem 1 g daily intravenously was given to adult patients with signs and symptoms of VAP beginning within 7 days of mechanical ventilation and caused by ESBL-producing Gram-negative organisms. RESULTS: From June 2005 to June 2006, we enrolled 20 adult patients hospitalized in an ICU and diagnosed with VAP due to Gram-negative ESBL strains. Causative organisms identified as ESBL producers susceptible to ertapenem were Klebsiella pneumoniae (alone in 10 cases and with methicillin-resistant Staphylococcus aureus in 4 cases), Enterobacter cloacae (2), Proteus mirabilis (2) and Citrobacter freundii (2). Clinical success was achieved in 16/20 (80%) of the clinically evaluable patients and in 15/20 (75%) of the microbiologically evaluable patients. The drug was well-tolerated; one patient presented a transient increase in liver enzymes. CONCLUSIONS: We believe this is one of the first reports to demonstrate that ertapenem has clinical utility in treating serious infections caused by ESBL-producing organisms. Ertapenem appears to be suitable for ESBL VAP therapy. This pilot study suggests subsequent controlled randomized trials in this indication.

Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy.

BACKGROUND: We developed a clinical pathway to optimize the use of antimicrobials by decreasing vancomycin use in preoperative patients with a history of penicillin allergy. OBJECTIVE: To decrease the use of vancomycin in surgical patients with a self-reported penicillin allergy. METHODS: In June 2002, same-day allergy consultation and penicillin skin testing were made available for preoperative patients with self-reported penicillin allergy at the preoperative evaluation (POE) clinic. We reviewed the penicillin allergy skin test results, recommendations, and beta-lactam antibiotic administration outcomes from July 1, 2002, to September 16, 2003. RESULTS: A total of 1,204 of 11,819 patients were evaluated for beta-lactam allergy at the POE clinic. Of these, 1,120 were approved by the institutional review board for inclusion in the study and 9 were excluded from the study. Of the remaining 1,111 patients, 1,030 (93%) underwent skin testing for penicillin allergy. Forty-three (4%) had a positive skin test result to penicillin. A total of 947 (85%) of the 1,111 patients with a history of beta-lactam allergy were advised to use a beta-lactam antibiotic, and 164 (15%) were advised to avoid beta-lactams. A total of 955 patients (86%) actually received preoperative antibiotics. Of these 955 patients, 716 (75%) received cefazolin, and only 149 (16%) received vancomycin compared with 30% historical controls (P < .01). Among the patients with a negative penicillin skin test result who received a cephalosporin, 5 (0.7%) of 675 experienced an adverse drug reaction to a cephalosporin. CONCLUSIONS: Establishment of a clinical pathway in a preoperative clinic that includes allergy consultation and penicillin skin testing reduced vancomycin use to only 16% in surgical patients with a history of beta-lactam allergy.

Cutaneous adverse drug reactions seen at a university hospital department of dermatology.

Patients with suspected cutaneous adverse drug reactions are often referred to allergy clinics or departments of dermatology for evaluation. These patients are selected compared with patients identified in prospective and cross-sectional studies of hospital populations. This explains the observed variation in prevalence of specific reactions and of eliciting drugs. This study investigated the prevalence of cutaneous adverse drug reactions in a university hospital department of dermatology that is specially focused on allergy. An 8-month survey was carried out during the period April-December 2003. Consecutive patients suspected of having cutaneous adverse drug reactions during this period were examined by dermatologists and investigated. Drug imputability was assessed in the 194 patients included; 33.5% had an exanthema with certain or likely drug imputability. Urticaria and local reactions at injection sites were the most frequent reactions (25% and 18.8%, respectively). Beta-lactam antibiotics, extracts for desensitization and insulins were the main drug groups involved, and accounted for 22.8%, 17.1% and 14.2%, respectively, of the reactions. Extracts for desensitization and insulins elicited more reactions than expected. This probably reflects the referral pattern to an allergy clinic.

Ciprofloxacin/metronidazole versus beta-lactam-based treatment of intra-abdominal infections: a meta-analysis of comparative trials.

Intra-abdominal infections are polymicrobial and result in substantial morbidity and mortality. The combination of ciprofloxacin/metronidazole as well as several beta-lactam-based regimens are among the commonly used regimens for the treatment of patients with such infections. Thus, we sought to review the evidence from available comparative clinical trials studying ciprofloxacin/metronidazole versus broad-spectrum beta-lactam-based regimens in the treatment of intra-abdominal infections. Studies for the meta-analysis were retrieved from searches of the PubMed database. Five available comparative trials (four randomised controlled trials and one non-randomised comparative trial) including 1431 patients with intra-abdominal infections were included in the meta-analysis. There was a statistically significant difference between the compared arms with regard to cure in favour of the ciprofloxacin/metronidazole combination (odds ratio (OR)=1.69, 95% confidence interval (CI) 1.20-2.39). There was no statistically significant difference between the compared arms with regard to total mortality (OR=1.10, 95% CI 0.71-1.69), mortality attributable to infection (OR=1.42, 95% CI 0.66-3.06) and toxicity (OR=1.25, 95% CI 0.66-2.35). In conclusion, pooled data from the available comparative trials suggest that the ciprofloxacin/metronidazole combination may be superior to beta-lactam-based therapeutic regimens in the treatment of intra-abdominal infections with regard to cure of infections, although no difference in mortality was found.

In vitro and in vivo evaluation of pectin beads for the colon delivery of beta-lactamases.

The aim of the present study was to provide a "proof of concept" of colon delivery of beta-lactamases by pectin beads aiming to degrade residual beta-lactam antibiotics, in order to prevent the emergence of resistant bacterial strains. Pectin beads were prepared according to ionotropic gelation method using CaCl2 as a gelling agent. Particles were then washed and soaked in polyethylenimine (PEI). Coating beads with PEI considerably improved their stability in simulated intestinal medium. In vitro studies showed that beta-lactamases were released from pectin beads in colonic medium due to the action of pectinolytic enzymes. When ampicillin was added to this medium, the release of beta-lactamases induced, as expected, the antibiotic inactivation. Finally, after oral administration of loaded-beads to CD1 mice, beta-lactamases were retrieved in high concentrations in faeces. Observation by SEM of beads extracted from mice intestinal tracts concluded the core degradation of beads without any modification of the PEI coating layer. This study demonstrates that a multiparticulate system with suitable characteristics for site-specific colonic delivery can be prepared. This system could be used to target beta-lactamases to the colon in order to hydrolyse antibiotic residues during treatment and prevent their impact on colonic microflora.

beta-Lactam drug allergens: fine structural recognition patterns of cephalosporin-reactive IgE antibodies.

Lack of experimental findings on the spectrum of cephalosporin allergenic determinants has hindered diagnosis of adverse reactions to these drugs and retarded understanding of allergenic cross-reactions between cephalosporins and between cephalosporins and penicillins. Subjects allergic to the widely used cephalosporin antibiotic cefaclor have serum immuno globulin (Ig) E antibodies that react with the drug. Quantitative hapten inhibition studies employing sera from subjects allergic to cefaclor revealed fine structural recognition differences between the combining site specificities of cefaclor-reactive IgE antibodies in the sera of different subjects. Unlike penicillins, where discrete side chain or thiazolidine ring determinants alone may be recognized, IgE binding determinants on cefaclor encompassed the entire molecule. Fine structural recognition specificity differences at positions R1 (side-chain) and R2 (substituent attached to dihydrothiazine ring) were detected between IgE antibodies in different sera. Some antibodies showed clear preferential recognition of the aminobenzyl group at position R1 and Cl at R2 while with others, a greater degree of recognition tolerance was seen at R1 where, for example, the aminohydroxybenzyl or aminodihydrobenzyl groups were recognized, and at R2 where a methyl or even an ester group was tolerated. As with the penicillins, cephalosporins as allergens cannot simply be considered as a group of compounds with a common allergenic determinant structure. IgE antibodies that bind to cefaclor show great heterogeneity indicated by clear, fine structural differences in recognition of the R1 and R2 groups on the drug.