Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients

Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model-informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill

Decline in Clostridium difficile-associated disease rates in Singapore public hospitals, 2006 to 2008

<p>Abstract</p> <p>Background</p> <p><it>Clostridium difficile </it>is the major cause of pseudomembranous colitis associated with antibiotic use, and the spread of the hypervirulent epidemic ribotype 027/NAP-1 strain across hospitals worldwide has re-focused attention on this nosocomial pathogen. The overall incidence and trend of <it>C. difficile</it>-associated disease (CDAD) in Singapore is unknown, and a surveillance program to determine these via formal laboratory-based reporting was established.</p> <p>Findings</p> <p>Laboratory and pharmacy data were collated from one tertiary and two secondary hospitals on a quarterly basis between 2006 and 2008. All hospitals tested for <it>C. difficile </it>using Immunocard Toxins A&B (Meridian Bioscience Inc., Cincinnati, OH) during this period. Duplicate positive <it>C. difficile </it>results within a 14-day period were removed. The CDAD results were compared with trends in hospital-based prescription of major classes of antibiotics.</p> <p>Overall CDAD incidence-density decreased from 5.16 (95%CI: 4.73 - 5.62) cases per 10,000 inpatient-days in 2006 to 2.99 (95%CI: 2.67 to 3.33) cases per 10,000 inpatient-days in 2008 (<it>p </it>< 0.001), while overall rates for <it>C. difficile </it>testing increased significantly (<it>p </it>< 0.001) within the same period. These trends were mirrored at the individual hospital level. Evaluation of antibiotic prescription data at all hospitals showed increasing use of carbapenems and fluoroquinolones, while cephalosporin and clindamycin prescription remained stable.</p> <p>Conclusions</p> <p>Our results demonstrate a real decline of CDAD rates in three large local hospitals. The cause is unclear and is not associated with improved infection control measures or reduction in antibiotic prescription. Lack of <it>C. difficile </it>stool cultures as part of routine testing precluded determination of the decline of a major clone as a potential explanation. For more accurate epidemiological trending of CDAD and early detection of epidemic clones, data collection will have to be expanded and resources set in place for reference laboratory culture and typing.</p

Prevalence of invasive fungal disease in hematological patients at a tertiary university hospital in Singapore

<p>Abstract</p> <p>Background</p> <p>The use of newer azoles as prophylaxis in hematological patients undergoing stem cell transplantation or immunosuppressive chemotherapy has been shown to decrease the risk of developing invasive fungal disease (IFD). However, the cost-effectiveness of such a strategy is dependent on the local epidemiology of IFD. We conducted an audit of hematological patients with IFD in our institution in order to derive the prevalence and types of IFD that occur locally.</p> <p>Findings</p> <p>We conducted a retrospective chart review of all hematological patients who developed possible, probable or definite IFD according to EORTC/MSG criteria in the period from Oct 2007 to Apr 2010. The prevalence of IFD was determined via correlation with institutional database records of all hematological patients treated at our institution over the same time period.</p> <p>There were 39 cases of IFD diagnosed during the study period, with 8 (20.5%) possible, 19 (48.7%) probable and 12 (30.8%) definite cases of IFD. <it>Aspergillus </it>spp. accounted for 83.9% of all probable and definite infections. There was 1 case each of <it>Rhinocladelia </it>spp., <it>Coprinopsis cinerea</it>, <it>Exserohilum </it>spp. sinusitis and <it>Rhizopus </it>spp. sinusitis. IFD occurred in 12 of 124 (9.7%) AML and 4 of 103 (3.9%) ALL patients treated at our institution respectively. There were 10 (16.1%) infections among 62 allogeneic HSCT recipients, six of whom were having concurrent graft-versus-host disease (GVHD). Five other cases occurred after allogeneic HSCT failure, following salvage chemotherapy for disease relapse. The prevalence of IFD during induction chemotherapy was 8.9% (11 of 124 cases) for AML and 1.0% (1 of 103 cases) for ALL. Fluconazole prophylaxis had been provided for 28 out of the 39 (71.8%) cases, while 4 (10.3%) were on itraconazole prophylaxis. The in-hospital mortality was 28.2% (11 of 39 cases), of which 5 (12.8%) deaths were attributed to IFD.</p> <p>Conclusions</p> <p>The burden of IFD is high in our institution, especially in allogeneic HSCT recipients and patients on induction chemotherapy for AML. A prophylactic strategy directed against invasive mould infections for local high-risk patients may be considered as the comparative costs of treatment, prolonged hospitalisation and subsequent delayed chemotherapy favours such an approach.</p

In-Vitro Activity of Polymyxin B, Rifampicin, Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii in Singapore

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. METHODS: AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. RESULTS: 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. CONCLUSION: Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations

ACORN (A Clinically-Oriented Antimicrobial Resistance Surveillance Network) II: protocol for case based antimicrobial resistance surveillance

Background: Antimicrobial resistance surveillance is essential for empiric antibiotic prescribing, infection prevention and control policies and to drive novel antibiotic discovery. However, most existing surveillance systems are isolate-based without supporting patient-based clinical data, and not widely implemented especially in low- and middle-income countries (LMICs). Methods: A Clinically-Oriented Antimicrobial Resistance Surveillance Network (ACORN) II is a large-scale multicentre protocol which builds on the WHO Global Antimicrobial Resistance and Use Surveillance System to estimate syndromic and pathogen outcomes along with associated health economic costs. ACORN-healthcare associated infection (ACORN-HAI) is an extension study which focuses on healthcare-associated bloodstream infections and ventilator-associated pneumonia. Our main aim is to implement an efficient clinically-oriented antimicrobial resistance surveillance system, which can be incorporated as part of routine workflow in hospitals in LMICs. These surveillance systems include hospitalised patients of any age with clinically compatible acute community-acquired or healthcare-associated bacterial infection syndromes, and who were prescribed parenteral antibiotics. Diagnostic stewardship activities will be implemented to optimise microbiology culture specimen collection practices. Basic patient characteristics, clinician diagnosis, empiric treatment, infection severity and risk factors for HAI are recorded on enrolment and during 28-day follow-up. An R Shiny application can be used offline and online for merging clinical and microbiology data, and generating collated reports to inform local antibiotic stewardship and infection control policies. Discussion: ACORN II is a comprehensive antimicrobial resistance surveillance activity which advocates pragmatic implementation and prioritises improving local diagnostic and antibiotic prescribing practices through patient-centred data collection. These data can be rapidly communicated to local physicians and infection prevention and control teams. Relative ease of data collection promotes sustainability and maximises participation and scalability. With ACORN-HAI as an example, ACORN II has the capacity to accommodate extensions to investigate further specific questions of interest

Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: The PASSPORT Program—Asia-Pacific Region

Due to escalating antimicrobial resistance amongst Gram-negative organisms, the choice of effective empirical antimicrobial regimens has become challenging. Monte Carlo simulations were conducted for conventional and prolonged infusion regimens of doripenem, imipenem and meropenem using pharmacokinetic data from adult patients with conserved renal function. Minimum inhibitory concentration data against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were incorporated from the COMPACT surveillance programme in the Asia-Pacific region of the world. The cumulative fraction of response (CFR) was determined for each regimen against each bacterial population. All simulated carbapenem regimens achieved an optimal CFR against E. coli and K. pneumoniae (94.5-100% CFR). Against P. aeruginosa, doripenem achieved 78.7-92.6% CFR, imipenem achieved 60.4-79.0% CFR and meropenem achieved 73.0-85.1% CFR. The only dosing regimen to achieve >= 90% CFR against P. aeruginosa was doripenem 1000 mg and 2000 mg every 8 h (4-h infusion). Carbapenem CFRs against A. baumannii were much lower (29.2-54.4% CFR). CFRs for non-fermenting isolates were ca. 10% lower for isolates collected in the Intensive Care Unit. Carbapenem resistance amongst Enterobacteriaceae remains low in the Asia-Pacific region and thus standard carbapenem dosing regimens had a high likelihood of achieving pharmacodynamic exposures. However, larger doses combined with prolonged infusion will be required to increase the CFR for these carbapenems against resistant non-fermenting Gram-negatives that are common in these countries. The safety and efficacy of these high dosing regimens will need to be confirmed in the clinical setting. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved

Pharmacodynamics of Polymyxin B against Pseudomonas aeruginosa

Despite limited data, polymyxin B (PB) is increasingly used clinically as the last therapeutic option for multidrug-resistant (MDR) gram-negative bacterial infections. We examined the in vitro pharmacodynamics of PB against four strains of Pseudomonas aeruginosa. Clonal relatedness of the strains was assessed by random amplification of polymorphic DNA. Time-kill studies over 24 h were performed with approximately 10(5) and 10(7) CFU/ml of bacteria, using PB at 0, 0.25, 0.5, 1, 2, 4, 8, and 16× MIC. Dose fractionation studies were performed using an in vitro hollow-fiber infection model (HFIM) against a wild-type and a MDR strain. Approximately 10(5) CFU/ml of bacteria were exposed to placebo and three regimens (every 8 h [q8h], q12h, and q24h) simulating the steady-state unbound PB pharmacokinetics resulting from a daily dose of 2.5 mg/kg of body weight and 20 mg/kg (8 times the clinical dose). Samples were obtained over 4 days to quantify PB concentrations, total bacterial population, and subpopulation with reduced PB susceptibility (>3× MIC). The bactericidal activity of PB was concentration dependent, but killing was significantly reduced with a high inoculum. In HFIM studies, a significant reduction in bacterial load was seen at 4 h in all active regimens, but selective amplification of the resistant subpopulation(s) was apparent at 24 h with the clinical dose (both strains). Regrowth was eventually observed in all dosing regimens with the MDR strain, but its occurrence was prevented in the wild-type strain by using 8 times the clinical dose (regardless of dosing intervals). Our results suggested that the bactericidal activity of PB was concentration dependent and appeared to be related to the ratio of the area under the concentration-time curve to the MIC