The effect of different antibiotic combinations in calcium sulfate cement on the growth of Cutibacterium acnes and Staphylococcus periprosthetic shoulder infection isolates.

BACKGROUND: Periprosthetic joint infections (PJI) of the shoulder are a devastating complication of shoulder arthroplasty and are commonly caused by Staphylococcus and Cutibacterium acnes. Absorbable calcium sulfate (CS) beads are sometimes used for delivering antibiotics in PJI. This study evaluates the in vitro effect of different combinations of gentamicin, vancomycin, and ertapenem in beads made from CS cement on the growth of C acnes and coagulase-negative Staphylococcus (CNS) strains. METHODS: Three strains of C acnes and 5 strains of CNS from clinically proven shoulder PJI were cultured and plated with CS beads containing combinations of vancomycin, gentamicin, and ertapenem. Plates with C acnes were incubated anaerobically while plates with Staphylococcus were incubated aerobically at 37 °C. Zones of inhibition were measured at intervals of 3 and 7 days using a modified Kirby Bauer technique, and beads were moved to plates containing freshly streaked bacteria every seventh day. This process was run in triplicate over the course of 56 days. Statistical analysis was conducted using SPSS v. 28 with repeated measures analysis of variance (ANOVA) and pairwise comparisons with Tukey correction. RESULTS: In experiments with C acnes, beads containing ertapenem + vancomycin and vancomycin alone formed the largest zones of inhibition over time (P < .001). In experiments with Staphylococcus, beads containing vancomycin alone formed the largest zones of inhibition over time for all 5 strains (P < .001). Zones of inhibition were 1.4x larger for C acnes than for Staphylococcus with beads containing vancomycin alone. For both C acnes and Staphylococcus, beads containing ertapenem had the strongest initial effect, preventing all bacterial growth in C acnes and almost all growth for Staphylococcus during the first week but dropping substantially by the second week. Beads containing gentamicin alone consistently created smaller zones of inhibition than beads containing vancomycin alone, with vancomycin producing zones 5.3x larger than gentamicin in C acnes and 1.3x larger in Staphylococcus (P < .001). DISCUSSION: These data suggest that for both C acnes and Staphylococcal species, CS beads impregnated with vancomycin were most effective at producing a robust antibiotic effect. Additionally, ertapenem may be a viable supplement in order to create a more potent initial antibiotic effect but is not as effective as vancomycin when used alone. Gentamicin alone was not effective in maintaining consistent and long-term antibiotic effects. These results indicate that amongst the antibiotics currently commercially available to be used with CS, vancomycin is consistently superior to gentamicin in the setting of C. acnes and CNS.

From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Antibiotics.

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended.

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

BACKGROUND: To perform a review describing the pharmacokinetic (PK) parameters and covariates of interest of the eight first choice ß-lactams (BL) antibiotics for treatment of severe infections in pediatric population. Pediatric sepsis and septic shock reportedly affect 30% of children admitted to pediatric intensive care units, with a 25% mortality rate. Eight BL are included as first choice antibiotic for severe infections in pediatric population in the World Health Organization model list of essential medicines for children. METHODS: The PubMed/Medline databases was searched and included studies if they described a population PK model of piperacillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cloxacillin, imipenem or meropenem in neonates or children. We compared the PK parameters for each drug. We analysed the used covariates to estimate PK parameters. We compared the pharmacokinetics/pharmacodynamics (PK/PD) targets and the drug dosing recommendations. RESULTS: Thirty-four studies met inclusion criteria with seven studies for piperacillin, five for amoxicillin, three for ampicillin, three for cefotaxime, two for ceftriaxone, two for imipenem and twelve for meropenem. None met inclusion criteria for cloxacillin. Ages ranged from 0-19.1 years with 12 studies including preterm. Body weight, age and renal function were the three major covariates in neonates and children. Different PK/PD targets were observed (between 40% to 100% of the dosing regimen interval of time over which the unbound (or free) drug concentration remains above the minimal inhibitory concentration (MIC) (fT>MIC) or four times the MIC (fT>4xMIC)). Several drug-dosing regimens were fond recommended according to the age and pathogens MIC using intermittent, timed or continuous infusions. CONCLUSIONS: Consensus is lacking on the optimal dosing regimens for these eight first choice antibiotics. A more personalized approach to antibiotic drugs dosing with individual characteristics of patient and pathogen susceptibility is required. According PK/PD targets and used dosing regimens, prospective clinical studies are required to investigate clinical cure, patient survival and emergence of antimicrobial resistance.

Efficacy and Therapeutic Drug Monitoring of Continuous Beta-Lactam Infusion for Osteoarticular Infections Caused by Fluoroquinolone-Resistant Pseudomonas aeruginosa: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Osteoarticular infections (OIs) caused by fluoroquinolone-resistant Pseudomonas aeruginosa, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, have poor outcomes. We evaluated the outcomes of an optimized strategy of continuous beta-lactam infusion (BL-CI) guided by therapeutic drug monitoring (TDM) for OIs caused by fluoroquinolone-resistant P. aeruginosa. METHODS: A prospective observational study of patients with P. aeruginosa OIs in a hospital-based BL-CI program (2016-2018) was carried out. TDM targeting free BL concentrations in plasma (fCss) of at least 3-4 × MIC was performed. We compared failure rates between patients with OIs caused by fluoroquinolone-resistant strains who were treated with BL-CI, with or without colistin, and patients with OIs caused by fluoroquinolone-susceptible strains who were treated with ciprofloxacin. RESULTS: Fifty-two patients were included in the study, 19 (36.5%) of whom had OIs caused by fluoroquinolone-resistant P. aeruginosa (13 (68.4%) MDR/XDR strains; 11 (57.9%) device-related infections). The median duration of BL-CI was 36 days; ten patients (52.6%) received BL-colistin combinations. Eighty-two samples were utilized in the TDM, and most patients were found to have a median fCss of 3-10 × MIC; 17 dose adjustments were performed and eight patients needed dose decreases, five of which were due to chronic kidney disease or acute kidney injury (AKI). BL-CI was well tolerated, with the most frequent adverse event being AKI. Failure occurred to 4 patients (21.1%), which was similar to the failure rate of patients with OIs caused by fluoroquinolone-susceptible P. aeruginosa treated with ciprofloxacin (5/30 [16.7%]) (p = 0.699). TDM was also used in the initial BL treatment of patients with OIs caused by susceptible strains before those patients were switched to treatment with ciprofloxacin alone (33 patients, 110 samples, 19 dose adjustments). CONCLUSIONS: BL-CI used with/without colistin and supported by TDM may be an alternative and effective treatment option for OIs caused by fluoroquinolone-resistant P. aeruginosa, where limited available therapeutic options exist, especially in the setting of multidrug resistance. Future research should elucidate whether this strategy can produce outcomes similar to those of patients treated for OIs caused by fluoroquinolone-susceptible strains.

Preserving the Dwindling ß-lactams-Based Empiric Therapy Options for Gram-Negative Infections in Challenging Resistance Scenario: Lessons Learned and Way Forward.

Appropriate empiric therapy reduces mortality and morbidity associated with serious Gram-negative infections. ß-lactams (BLs) owing to their safety, efficacy, and coverage spectrum are the most preferred agents for empiric use. Inappropriate use of older penicillins and cephalosporins led to selection and spread of resistant clones. As a result, these valuable agents have lost their reliability compelling clinicians to often use erstwhile last-line therapies such as carbapenems. Excessive carbapenems use imposed collateral damage by selecting difficult-to-treat carbapenem-resistant organisms. Lack of empiric therapeutic options amenable for use in infections caused by contemporary pathogens was realized by the pharmaceutical industry leading to intensive efforts in discovering novel antibiotics. These efforts led to the approval of newer ß-lactams and ß-lactamase inhibitor (BL-BLI) combination. This review elaborates the past trends in empirical use of BLs and ensuing patterns of resistance emergence in Gram-negatives. Furthermore, a critical appraisal of newer BL-BLIs has been presented to identify the appropriate clinical situations for their use to ensure clinical efficacy coupled with minimal resistance selection. These learning have been derived from past trends of clinical usage of older empiric therapies so that the therapeutic utility of newer agents is preserved for long in light of dwindling global antibiotics pipeline.

The role of extended infusion ß-lactams in the treatment of bloodstream infections in patients with liver cirrhosis.

INTRODUCTION: Bloodstream infections (BSIs) in patients with liver cirrhosis are associated with significant morbidity and mortality. Early appropriated antibiotic treatment is essential for the correct management of these patients. Areas covered: This review covers several aspects of how the pharmacokinetic/pharmacodynamic behavior of antimicrobials may change in patients with liver cirrhosis. Common features of cirrhosis, including hypoproteinemia, third space expansion and impairment of renal function may alter drug distribution in patients receiving hydrophilic drugs like ß-lactams, which are often frontline agents. ß-lactams exhibit time-dependent pharmacodynamics and achieve maximal bacterial killing when serum drug and tissue concentrations exceed a multiple of the minimal inhibitory concentration (MIC) during the dosing interval (%fT>MIC). Administration of ß-lactams by extended infusion strategies improves the rate of this pharmacodynamic target attainment and has been associated with improved outcomes in several randomized trials in critically-ill patients. Expert commentary: Observational studies have suggested that cirrhotic patients have improved outcomes when beta-lactam therapy is administered by extended or continuum infusion. Given the multiple pathophysiological features of liver cirrhosis that impact antimicrobial behavior and the high incidence of multidrug resistance in this population, additional studies are needed to understand how cirrhosis affects the pharmacokinetics and pharmacodynamics of antibacterial therapy.

Benzylpenicillin versus wide-spectrum beta-lactam antibiotics as empirical treatment of Haemophilus influenzae-associated lower respiratory tract infections in adults; a retrospective propensity score-matched study.

There is consensus that definitive therapy for infections with H. influenzae should include antimicrobial agents with clinical breakpoints against the bacterium. In Scandinavia, benzylpenicillin is the recommended empirical treatment for community-acquired pneumonia (CAP) except in very severe cases. However, the effect of benzylpenicillin on H. influenzae infections has been debated. The aim of this study was to compare the outcomes of patients given benzylpenicillin with patients given wide-spectrum beta-lactams (WSBL) as empirical treatment of lower respiratory tract H. influenzae infections requiring hospital care. We identified 481 adults hospitalized with lower respiratory tract infection by H. influenzae, bacteremic and non-bacteremic. Overall, 30-day mortality was 9% (42/481). Thirty-day mortality, 30-day readmission rates, and early clinical response rates were compared in patients receiving benzylpenicillin (n = 199) and a WSBL (n = 213) as empirical monotherapy. After adjusting for potential confounders, empirical benzylpenicillin treatment was not associated with higher 30-day mortality neither in a multivariate logistic regression (aOR 2.03 for WSBL compared to benzylpenicillin, 95% CI 0.91-4.50, p = 0.082), nor in a propensity score-matched analysis (aOR 2.14, 95% CI 0.93-4.92, p = 0.075). Readmission rates did not significantly differ between the study groups, but early clinical response rates were significantly higher in the WSBL group (aOR 2.28, 95% CI 1.21-4.31, p = 0.011), albeit still high in both groups (84 vs 81%). In conclusion, despite early clinical response rates being slightly lower for benzylpenicillin compared to WSBL, we found no support for increased mortality or readmission rates in patients empirically treated with benzylpenicillin for lower respiratory tract infections by H. influenzae.

Beta-lactams in continuous infusion for Gram-negative bacilli osteoarticular infections: an easy method for clinical use.

Continuous infusion (CI) of beta-lactams could optimize their pharmacokinetic/pharmacodynamic indices, especially in difficult-to-treat infections. PURPOSE: To validate an easy-to-use method to guide beta-lactams dosage in CI (formula). METHODS: A retrospective analysis was conducted of a prospectively collected cohort (n = 24 patients) with osteoarticular infections caused by Gram-negative bacilli (GNB) managed with beta-lactams in CI. Beta-lactams dose was calculated using a described formula (daily dose = 24 h × beta-lactam clearance × target "steady-state" concentration) to achieve concentrations above the MIC. We correlated the predicted concentration (Cpred = daily dose/24 h × beta-lactam clearance) with the patient's observed concentration (Cobs) measured by UPLC-MS/MS (Spearman's coefficient). RESULTS: The most frequent microorganism treated was P. aeruginosa (21 cases; 9 MDR). Beta-lactams in CI were ceftazidime (n = 14), aztreonam (7), and piperacillin/tazobactam (3), mainly used in combination (12 with colistin, 5 with ciprofloxacin) and administered without notable side effects. The plasma Cobs was higher overall than Cpred; the Spearman correlation between both concentrations was rho = 0.6 (IC 95%: 0.2-0.8) for all beta-lactams, and rho = 0.8 (IC 95%: 0.4-1) for those treated with ceftazidime. CONCLUSIONS: The formula may be useful in clinical practice for planning the initial dosage of beta-lactams in CI, while we await a systematic therapeutic drug monitoring. The use of beta-lactams in CI was safe.

Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus ß-lactams.

Enterobacteriaceae bloodstream infections (EB-BSIs) are a common manifestation of Gram-negative sepsis and are initially managed with empirical intravenous antibiotics. Upon stabilisation and source control, patients are often transitioned to an oral agent. Fluoroquinolones (FQs) plays a prominent role in stepdown therapy for severe infections owing to favourable pharmacokinetic parameters; however, serious adverse events (AEs) have been documented with their use. A total of 224 adults with EB-BSI initiated on empirical intravenous antibiotics with stepdown to oral ß-lactam (BLM) (n = 84) or FQ (n = 140) were studied to compare clinical success and identify risk factors for treatment failure. Subgroups of early versus late oral stepdown and short versus extended duration of therapy (DOT) were assessed. Stepdown therapy with oral BLM was non-inferior to oral FQ (86.9% vs. 87.1%; mean difference 0.2%, 97.5% CI -10.3 to 10.7). Microbiological success (94.0% vs. 97.9%; P > 0.05) and 30-day re-admission (14.3% vs. 14.3%; P > 0.05) were similar. Patients were more likely to complete their BLM course without an AE compared with FQs (91.7% vs. 82.1%; P = 0.049). Clinical success was comparable between early and late stepdown (86.7% vs. 87.5%; P > 0.05) and short versus extended DOT (88.2% vs. 86.7%; P > 0.05). Negative predictors of clinical success identified by logistic regression were complicated diabetes (OR = 0.35, 95% CI 0.15-0.83) and urinary abnormality (OR = 0.39, 95% CI 0.16-0.94). These findings suggest that oral BLMs were non-inferior to FQs as stepdown therapy for EB-BSI, with less AEs.

Impact of ß-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of ß-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). ß-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered ß-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of ß-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of ß-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. ß-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive ß-lactam concentrations.

Comparison of ß-lactam plus aminoglycoside versus ß-lactam plus fluoroquinolone empirical therapy in serious nosocomial infections due to Gram-negative bacilli.

We sought to compare clinical cure on day 7 and a 28-day all-cause mortality in patients who received an anti-pseudomonal ß-lactam with a fluoroquinolone or an aminoglycoside for treatment of nosocomial bacteremia or pneumonia due to Gram-negative bacilli while in the ICU. This retrospective cohort study was conducted in critically ill patients at an academic medical centre from January 2005 to August 2011. A total of 129 patients (83 receiving aminoglycoside and 46 receiving fluoroquinolone combinations) were included. Seven-day clinical cure rates were 74% and 72% for fluoroquinolone and aminoglycoside groups, respectively (p = 0.84). There was no significant difference in the odds of clinical cure with a fluoroquinolone as compared to an aminoglycoside combination (adjusted odds ratio 2.4, 95% confidence interval [CI] 0.7-9.0). There was no significant difference in 28-day mortality in patients who received a fluoroquinolone or an aminoglycoside combination (22% vs. 18%, adjusted hazard ratio 0.82, 95% CI 0.29-2.28).

Application of Pharmacodynamic Profiling for the Selection of Optimal ß-lactam Regimens in a Large University Hospital.

BACKGROUND: Infections caused by drug-resistant Gram-negative bacteria (GNB) are increasing worldwide and as a result, the selection of appropriate empiric antibiotics (ATBs) has been made increasingly difficult. The present study aimed to identify optimized dosing regimens of intravenous (IV) ATBs, defined by cumulative fraction response (CFR), against E. coli (EC), K. pneumoniae (KP), P. aeruginosa (PA), and A. baumannii (AB) at 2,300-bed University Hospital. MATERIALS AND METHODS: The minimum inhibitory concentrations (MIC) of EC, KP, PA, and AB from clinical specimens, 250 each, were determined. Pharmacodynamic profiling using Monte Carlo Simulation was performed for standard, high dosage, and prolonged infusions (PI) of ceftriaxone, cefepime, ceftazidime, imipenem, meropenem, and doripenem. A CFR of ≥90% was targeted as providing a sufficiently high ATB exposure. RESULTS: When considering the Enterobacteriaceae, the % susceptible for the cephalosporins ranged from 60% for ceftriaxone to 86% for cefepime, as a result only the 2g q8h regimens of ceftazidime and cefepime provided high CFRs. In contrast, all the carbapenems had % susceptible and CFRs ≥90% for EC and KP. While cefepime and ceftazidime demonstrated higher % susceptibility (82-83%) for PA relative to that of the carbapenems (61-69%) only doripenem 2g q8h (4h PI) achieved an optimal CFR (92%) against this organism. Due to the MIC profiles and dismal susceptibilities of AB (16-22%), none of the regimens studied achieved CFRs > 65%. CONCLUSIONS: The pharmacodynamic profiling undertaken in the current study provides insights that allow prescribers to select more appropriate empirical antibiotic regimens for the treatment of infection caused by these common GNB pathogens at this Thai hospital. While higher doses and PI of ß-lactams improve exposures against EC, KP and PA, this approach will not sufficiently enhance their potency against AB, thus alternative therapies should be considered for this organism.

Short article: Successful faecal coliform sensitivity-based oral ertapenem therapy for chronic antibiotic-refractory pouchitis: a case series.

Pouchitis is a common complication of restorative proctocolectomy for ulcerative colitis, and a proportion of patients develop a refractory course. The treatment of chronic antibiotic-refractory pouchitis (CARP) is challenging, and treatment failure is often a cause of pouch excision. We report on a series of three patients with CARP who were treated with oral ertapenem following faecal coliform sensitivity testing. There was an improvement in the pouchitis disease activity index in all three patients [pretreatment pouch disease activity index, median 13 (range: 10-14); post-treatment pouch disease activity index, median 1 (range: 1-3)]. Identification of faecal coliform sensitivity and treatment with oral ertapenem might be helpful in patients with CARP.

Even high-dose extended infusions may not yield desired concentrations of ß-lactams: the value of therapeutic drug monitoring.

A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2-4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with ß-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize ß-lactam therapy in a difficult-to-treat critically ill patient.

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.

Mechanisms of ß-lactam killing and resistance in the context of Mycobacterium tuberculosis.

ß-Lactams are one of the most useful classes of antibiotics against many common bacterial pathogens. One exception is Mycobacterium tuberculosis. However, with increasing incidence of multidrug-resistant tuberculosis and a need for new agents to treat it, the use of ß-lactams, specifically the combination of carbapenem and clavulanate, is now being revisited. With this attention, comes the need to better understand both the mechanisms of action of ß-lactams against M. tuberculosis as well as possible mechanisms of resistance, within the context of what is known about the ß-lactam action in other bacteria. M. tuberculosis has two major mechanisms of intrinsic resistance: a highly active ß-lactamase and a poorly permeable outer membrane. Within the cell wall, ß-lactams bind several enzymes with differing peptidoglycan-synthetic and -lytic functions. The inhibition of these enzymes may lead to cell death through several mechanisms, involving disruption of the balance of synthetic and lethal activities. Currently, all known means of resistance to the ß-lactams rely on diminishing the proportion of peptidoglycan-synthetic proteins bound and inhibited by ß-lactams, through either exclusion or destruction of the antibiotic, or through replacement or supplementation of target enzymes. In this review, we discuss possible mechanisms for ß-lactam activity in M. tuberculosis and the means by which it may acquire resistance, within the context of what is known in other bacterial species.

Risk factors for target non-attainment during empirical treatment with ß-lactam antibiotics in critically ill patients.

PURPOSE: Risk factors for ß-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment. METHODS: This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 % and 100 % of the dosing interval respectively (50 % and 100 % f T (>MIC)). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure. RESULTS: A total of 343 critically ill patients receiving eight different ß-lactam antibiotics were included. The median (interquartile range) age was 60 (47-73) years, APACHE II score was 18 (13-24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 % and 100 % of the dosing interval in 66 (19.2 %) and 142 (41.4 %) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100 % f T( >MIC) target. CONCLUSIONS: This study found that-in empirical dosing and considering a worst--case scenario--19 % and 41 % of the patients would not achieve antibiotic concentrations above the MIC during 50 % and 100 % of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets; increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.

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.

Susceptibility to antibiotics of aerobic bacteria isolated from community acquired secondary peritonitis in children: therapeutic guidelines might not always fit with and everyday experience.

Appendicitis is a frequent clinical condition in normal children that may be complicated by community-acquired secondary peritonitis (CASP). We evaluated the potential efficacy of different drugs for initial treatment of this condition, as recommended by recent Consensus Conference and Guidelines for paediatric patients. Susceptibility to ampicillin-sulbactam, ertapenem, gentamycin, piperacillin, piperacillin-tazobactam, vancomycin, and teicoplanin was evaluated according to EUCST 2012 recommendations in aerobic bacteria isolated from peritoneal fluid in CASP diagnosed from 2005 to 2011 at 'Istituto Giannina Gaslini', Genoa, Italy. A total of 114 strains were analysed: 83 E. coli, 15 P. aeruginosa, 6 Enterococci, and 10 other Gram-negatives. Resistance to ampicillin-sulbactam was detected in 37% of strains, while ertapenem showed a potential resistance of 13% (all P. aeruginosa strains). However, the combination of these drugs with gentamicin would have been increased the efficacy of the treatment to 99 and 100%, respectively. Resistance to piperacillin-tazobactam was 3%, while no strain was resistant to meropenem. Our data suggest that monotherapy with ampicillin-sulbactam or ertapenem for community-acquired secondary peritonitis would present a non-negligible rate of failure, but the addition of gentamycin to these drugs could reset to zero this risk. On the contrary, monotherapy with piperacillin-tazobactam or meropenem is highly effective.

Efficacy of humanized carbapenem exposures against New Delhi metallo-ß-lactamase (NDM-1)-producing enterobacteriaceae in a murine infection model.

Enterobacteriaceae producing the novel carbapenemase New Delhi metallo-ß-lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels of in vitro resistance to multiple antibiotics, in vivo efficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-type K. pneumoniae and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed the in vitro maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was ≤ 8 µg/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producing Enterobacteriaceae under certain conditions, and this warrants further in vivo exploration.