β-lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis

BackgroundCombining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice.ObjectiveTo determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy.MethodsA systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity.ResultsFour randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63–1.08, P = 0.10, I² 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64–0.99, P = 0.04, I² 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83–2.09, P = 0.40, I² 0%).ConclusionsThe existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.     

The pharmacokinetics of ampicillin–sulbactam in anuric patients: dosing optimization for prophylaxis during cardiovascular surgery

Background The administration of antibiotic prophylaxis during cardiothoracic surgery can reduce the rate of surgical site infections. Trials of cardiothoracic antibiotic prophylaxis have found it to be beneficial in preventing postoperative wound infections. Objective To determine the more appropriate timing of repeated doses of ampicillin–sulbactam to maintain adequate antibiotic concentrations during cardiovascular surgery in anuric patients. Method Five adult anuric dialysis patients who received ampicillin–sulbactam during cardiovascular surgery at Kagoshima University Hospital, the total plasma concentrations of ampicillin and sulbactam were monitored after ampicillin (1 g)–sulbactam (0.5 g) administration. Pharmacokinetic parameters were estimated and used to predict the free plasma concentrations of ampicillin and sulbactam. Results The mean values for the volume of distribution, total clearance, elimination rate constant and the elimination half-life for ampicillin were 8.9 ± 2.4 L, 1.69 ± 0.93 L/h, 0.180 ± 0.059 h^?1 and 4.23 ± 1.48 h, respectively. The pharmacokinetic parameters were similar to those of sulbactam. When ampicillin (1 g)–sulbactam (0.5 g) was intravenously administered at 8, 12 and 24 h intervals, the predicted free trough plasma concentrations of ampicillin were 28.72, 12.06 and 1.25 μg/mL, respectively. Conclusion We suggest that ampicillin (1 g)–sulbactam (0.5 g) should be intravenously administered every 12 h in order to maintain a free ampicillin concentration of more than 12 μg/mL in anuric patients during cardiovascular surgery.     

Individualized dosing regimens in children based on population PKPD modelling: are we ready for it?

Despite profound differences in response between children and adults, and between children of different ages, drugs are still empirically dosed in mg/kg in children. Since maturation of expression and function is typically a non-linear dynamic process which differs between biotransformation routes and pharmacological targets, paediatric dosing regimens should be based on the changing pharmacokinetic-pharmacodynamic (PKPD) relationship in children. In this respect, the population approach is essential, allowing for sparse sampling in each individual child. An example is presented on morphine glucuronidation, for which two covariates were identified and subsequently used to derive a model-based dosing algorithm for a prospective clinical trial in children. Using this novel dosing algorithm, similar morphine concentrations are expected while, depending on age, lower and higher morphine dosages are administered compared to mg/kg/h dosing. As the covariate functions may reflect system-specific information on the maturation of a specific drug-disposition pathway, its use for other drugs that share the same pathway is explored. For this purpose, prospective clinical trials and cross-validation studies are urgently needed. In conclusion, PKPD modelling and simulation studies are important to develop evidence-based and individualized dosing schemes for children, with the ultimate goal to improve drug safety and efficacy in this population.     

Cyclodextrin-accelerated degradation of β-lactam antibiotics in aqueous solutions

The catalytic effect of heptakis(2,6-di-O-methyl)-β-cyclodextrin, 2-hydroxypyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin and glucose on the degradation of aztreonam and phenoxymethylpenicillin in aqueous buffer solutions has been studied. All three cyclodextrin derivatives and glucose increased the rate of degradation of aztreonam. The two hydroxyprophyl cyclodextrin derivatives also accelerated the degradation of phenoxymethylpenicillin. This effect of cyclodextrins on β-lactam antibiotics will limit their usage in pharmaceutical preparations containing these drugs.     

PK-PD modeling of β-lactam antibiotics: in vitro or in vivo models?

A modified E(max)-pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of β-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20?h(-1), maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20?h(-1) and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27?μg?ml(-1), respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.     

Characterisation of the β-lactam resistance enzyme in Acanthamoeba castellanii

β-Lactams are well known as the best antibiotics for inhibiting the cross-linking between adjacent polysaccharide chains and peptides in the peptidoglycan layer of bacterial cell walls, causing bacterial cell lysis. There are no reports on the action of and resistance mechanisms to β-lactams in protozoa. Acanthamoeba castellanii is a free-living protozoan pathogen capable of causing blinding keratitis and fatal granulomatous encephalitis. When Acanthamoeba is exposed to harsh conditions, it differentiates into the cyst stage to avoid environmental stresses, such as drug treatment. In this study, it was shown that the mature encystation rate of A. castellanii is decreased by treatment with cefotaxime (CTX) and clavulanic acid (CLA); however, the drugs do not kill the amoeba. We hypothesise that β-lactam antibiotics may disturb synthesis of the double cell wall during the encystation process of Acanthamoeba. Interestingly, CTX is considered a powerful β-lactam, whereas CLA is considered a weak β-lactam but an efficient β-lactamase inhibitor. It was demonstrated that Acanthamoeba expresses β-lactamases to prevent inhibition of the encystation process by β-lactams. To reveal the functions of Acanthamoeba β-lactamases, a recombinant Acanthamoeba β-lactamase was produced in Escherichia coli that conferred resistance to β-lactams such as CTX, cefuroxime, penicillin and meropenem. Consequently, we suggest that Acanthamoeba produces enzymes similar to β-lactamases to avoid interference from the environment. Here we provide a new point of view on an important gene responsible for drug resistance and advocate for the development of more efficient treatment against Acanthamoeba infection.     

Which dosing scheme is suitable for the taxanes? An in vitro model

The discovery and development of the taxane class of antitumor compounds represent significant advances in the treatment of patients with a variety of malignancies. These drugs are effectively used in the treatment of breast cancer. In this study we evaluated the efficacy of fractionated usage of both paclitaxel and docetaxel as a single agent in the breast cancer cell line MCF-7. It has been shown that the cytotoxic effect of paclitaxel was increased when the divided IC50 concentrations were used sequentially and in contrast to paclitaxel, cytotoxic effect of docetaxel was decreased with the same schema and the single dose of IC50 concentration was optimal. The cause of the difference between the cytotoxic effects of two agents with this schedule is obscure. Demonstrating mechanisms, which are responsible for these differences, will be important for more rational use of taxoids and to provide basis for the following clinical trials.     

Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis

The clinical advantages of prolonged (extended/continuous) infusion remain controversial. Previous studies and reviews have failed to show consistent clinical benefits of extending the infusion time. This meta-analysis sought to determine whether prolonged β-lactam infusions were associated with a reduction in mortality and improvement in clinical success. A search of PubMed, EMBASE and The Cochrane Library for randomised controlled trials (RCTs) and observational studies comparing prolonged infusion with intermittent bolus administration of the same antibiotic in hospitalised adult patients was conducted. Primary outcomes evaluated were mortality and clinical success. A total of 29 studies with 2206 patients (18 RCTs and 11 observational studies) were included in the meta-analysis. Compared with intermittent boluses, use of prolonged infusion appeared to be associated with a significant reduction in mortality [pooled relative risk (RR) = 0.66, 95% confidence interval (CI) 0.53–0.83] and improvement in clinical success (RR = 1.12, 95% CI 1.03–1.21). Statistically significant benefit was supported by non-randomised studies (mortality, RR = 0.57, 95% CI 0.43–0.76; clinical success, RR = 1.34, 95% CI 1.02–1.76) but not by RCTs (mortality, RR = 0.83, 95% CI 0.57–1.21; clinical success, RR = 1.05, 95% CI 0.99–1.12). The positive results from observational studies, especially in the face of increasing antibiotic resistance, serve to justify the imperative need to conduct a large-scale, well-designed, multicentre RCT involving critically ill patients infected with high minimum inhibitory concentration pathogens to clearly substantiate this benefit.     

Synthesis and antimicrobial evaluation of novel benzo[b]thiophenes comprising β-lactam nucleus

Synthesis, structural characterization, and biological activity studies of benzo[b]thiophene derivatives containing β-lactam nucleus are described. Cycloaddition of azomethines (4a–j) to in situ-generated ketenes from 2,4-dichlorophenoxyacetic acid, in the presence of triethylamine and benzenesulfonyl chloride afforded the title compounds (5a–j). The stereochemical course of reaction depends on both the substituents on the ketenes as well as on the imines. The mechanism for the formation of cis/trans derivative is presented.     

Fluoroquinolone-based versus β-lactam-based regimens for complicated intra-abdominal infections: a meta-analysis of randomised controlled trials

Complicated intra-abdominal infections (cIAIs) are common and confer significant morbidity, mortality and costs. In this era of evolving antimicrobial resistance, selection of appropriate empirical antimicrobials is paramount. This systematic review and meta-analysis of randomised controlled trials compared the effectiveness and safety of fluoroquinolone (FQ)-based versus β-lactam (BL)-based regimens for the treatment of patients with cIAIs. Primary outcomes were treatment success in the clinically evaluable (CE) population and all-cause mortality in the intention-to-treat (ITT) population. Subgroup analyses were performed based on specific antimicrobials, infection source and isolated pathogens. Seven trials (4125 patients) were included. FQ-based regimens included moxifloxacin (four studies) or ciprofloxacin/metronidazole (three studies); BL-based regimens were ceftriaxone/metronidazole (three studies), carbapenems (two studies) or piperacillin/tazobactam (two studies). There was no difference in effectiveness in the CE (2883 patients; RR = 1.00, 95% CI 0.95–1.04) or ITT populations (3055 patients; RR = 0.97, 95% CI 0.94–1.01). Mortality (3614 patients; RR = 1.04, 95% CI 0.75–1.43) and treatment-related adverse events (2801 patients; RR = 0.97, 95% CI 0.70–1.33) were also similar. On subset analysis, moxifloxacin was slightly less effective than BLs in the CE (1934 patients; RR = 0.96, 95% CI 0.93–0.99) and ITT populations (1743 patients; RR = 0.94, 95% CI 0.91–0.98). Although FQ- and BL-based regimens appear equally effective and safe for the treatment of cIAIs, limited data suggest slightly inferior results with moxifloxacin. Selection of empirical coverage should be based on local bacterial epidemiology and patterns of resistance as well as antimicrobial stewardship protocols.     

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

The aim of the present study was to provide a “proof of concept” of colon delivery of β-lactamases by pectin beads aiming to degrade residual β-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 β-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 β-lactamases induced, as expected, the antibiotic inactivation. Finally, after oral administration of loaded-beads to CD1 mice, β-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 β-lactamases to the colon in order to hydrolyse antibiotic residues during treatment and prevent their impact on colonic microflora.     

Design, synthesis, and biological evaluation of β-lactam antibiotic-based imidazolium- and pyridinium-type ionic liquids

We herein report the preparation and investigation of antibacterial activity of biocidal ionic liquids (ILs) consisting of cationic imidazolium or pyridinium and an anionic β‐lactam antibiotic. The antibacterial properties were quantified by measuring the minimum inhibitory concentration and minimum bactericidal concentration against Escherichia coli O157:H7, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus faecium. In general, the ILs had improved antibacterial activity than their parent materials, whether individually or in combination. In 83% of the experiments, the ampicillin ILs (Amp‐ILs) had better antibacterial activities than their quaternary halide parent materials, whereas in 92% of the experiments, Amp‐ILs outperformed the commercially available sodium ampicillin salt. Amp‐ILs had up to 43 times improved antibacterial activity than sodium ampicillin. Overall, when normalized for ampicillin content, ILs had greater antimicrobial activity against E. coli O157:H7, K. pneumoniae, S. aureus, and E. faecium than sodium ampicillin alone.     

Prolonging β-lactam infusion: A review of the rationale and evidence,and guidance for implementation

Given the sparse antibiotic pipeline and the increasing prevalence of resistant organisms, efforts should be made to optimise the pharmacodynamic exposure of currently available agents. Prolonging the infusion duration is a strategy used to increase the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT > MIC), the pharmacodynamic efficacy driver for time-dependent antibiotics such as β-lactams. β-Lactams, the most commonly prescribed class of antibiotics owing to their efficacy and safety profile, have been the mainstay of therapy since the discovery of penicillin over 60 years ago. Mounting evidence, including the use of population pharmacokinetic modelling and Monte Carlo simulation, suggests that prolonging the infusion time of β-lactam antibiotics may have advantages over standard infusion techniques, including an enhanced probability of achieving requisite fT > MIC exposures, lower mortality and potentially reductions in infection/antibiotic-related costs. As a result of these favourable attributes, clinical practice guidelines support the use of prolonged-infusion β-lactams in the treatment of many severe infections. This article discusses the rationale and evidence for prolonging the infusion of β-lactam antibiotics and provides guidance for the implementation of a prolonged-infusion programme.     

Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing

Purpose

We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data.

Methods

PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation).

Results

The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]?=?target AUC[mg?×?h/L]?×?3.04L/h?×?(ABW/16.1)^0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients.

Conclusions

We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.     

Chick chorioallantoic membrane model for in ovo evaluation of timolol maleate–brimonidine tartrate ocular inserts

Abstract

The main aspire of this study was to develop ocular drug delivery system for dual drug glaucoma therapy by timolol maleate–brimonidine tartrate and endeavor the possibility of biocompatibility studies by in ova studies. Matrix type, both hydrophilic and lipophilic polymers, and reservoir-type ocular inserts of timolol maleate were prepared using hydrophilic polymers like polyvinyl alcohol, hydroxyl propyl methyl cellulose K4M and lipophilic polymers like ethylcellulose and eudragit S100 and were optimized. Based on the optimized formulation, triple-layered ocular inserts (reservoir type) of dual drug were prepared by solvent casting technique with an objective of reducing the frequency of administration, obtaining controlled release and greater therapeutic efficacy, preservative free dosage form for the treatment of glaucoma. FTIR spectral studies revealed no pharmaceutical incompatibility and no drug polymer interactions. Maximum drug release (99.18?±?1.7) was achieved when PVP and HPMC K4M in 1:1 ratio with PEG 400 (0.3?ml) drug reservoir layer was sandwiched between ethyl cellulose as rate control membrane up to 32?h in a controlled fashion. Drug release was by non-Fickian diffusion mechanism for single drug formulation. But in dual drug insert, timolol maleate best fit into zero order and for brimonidine tartrate to Higuchi model and diffusion of drugs from this by non-Fickian diffusion mechanism. In ovo studies suggested that the optimized formulation was found to be sterile, biocompatible and physicochemically stable and support us to claim that the developed formulation was biocompatible.     

Cognitive evaluation of disease-modifying efficacy of donepezil in the APP23 mouse model for Alzheimer’s disease

Rationale The interest for acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease has been greatly renewed owing to the discovery of a broad range of additional cholinergic and non-cholinergic effects, exploitable to maximize the efficacy of these drugs beyond merely improving intellectual functions at the symptomatic level. Objectives The age-dependent cognitive decline in the valid APP23 transgenic mouse model for Alzheimer’s disease was employed to evaluate disease-modifying efficacy of chronic treatment with donepezil. Materials and methods At age 6 weeks, heterozygous APP23 mice and control littermates were subcutaneously implanted with osmotic pumps delivering saline or donepezil (0.27 or 0.58 mg/kg per day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects before cognitive evaluation in the Morris water maze commenced. Results Donepezil (0.27 mg/kg per day)-treated APP23 mice performed significantly better than their sham-treated counterparts during the Morris water maze acquisition phase and the subsequent probe or retention trial. Chronic donepezil (0.27 mg/kg per day) treatment improved spatial accuracy in APP23 mice as to reach the same level of performance as wild-type control animals on this complex visual–spatial learning task. Conclusion This is the first study reporting disease-modifying efficacy of donepezil at the level of cognitive performance in transgenic mice modeling Alzheimer’s disease. Van Dam Debby and Coen Katrien equally contributed to this publication.