Comparative pharmacodynamics of four different carbapenems in combination with polymyxin B against carbapenem-resistant Acinetobacter baumannii

The objective of this study was to determine the comparative pharmacodynamics of four different carbapenems in combination with polymyxin B (PMB) against carbapenem-resistant Acinetobacter baumannii isolates using time–kill experiments at two different inocula. Two A. baumannii strains (03-149-1 and N16870) with carbapenem minimum inhibitory concentrations (MICs) ranging from 8 to 64 mg/L were investigated in 48-h time–kill experiments using starting inocula of 106 CFU/mL and 108 CFU/mL. Concentration arrays of ertapenem, doripenem, meropenem and imipenem at 0.25×, 0.5×, 1×, 1.5× and 2× published maximum serum concentration (Cmax) values (Cmax concentrations of 12, 21, 48 and 60 mg/L, respectively) were investigated in the presence of 1.5 mg/L PMB. Use of carbapenems without PMB resulted in drastic re-growth. All carbapenem combinations were able to achieve a ≥3 log10 CFU/mL reduction by 4 h against both strains at 106 CFU/mL, whereas maximum reductions against strain 03-149-1 at 108 CFU/mL were 1.0, 3.2, 2.2 and 3.3 log10 CFU/mL for ertapenem, doripenem, meropenem and imipenem, respectively. None of the combinations were capable of reducing 108 CFU/mL of N16870 by ≥2 log10 CFU/mL. Ertapenem combinations consistently displayed the least activity, whereas doripenem, meropenem and imipenem combinations had similar activities that were poorly predicted by carbapenem MICs. As doripenem, meropenem, or imipenem displayed similar pharmacodyanmics in combination, the decision of which carbapenem to use in combination with PMB may be based on toxicodynamic profiles if drastic discordance in MICs is not present

Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens

Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant A. baumannii. Recent reports of polymyxin-resistant A. baumannii highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in A. baumannii AB307-0294 using an in vitro dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log10CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens; partial reversion to susceptibility was observed in 6 of 8 bacterial samples during drug-free passaging. Stable polymyxin-resistant samples contained a mutation in pmrB. The transcriptomes of stable and non-stable polymyxin-resistant samples were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported via integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies

Clinical population pharmacokinetics and toxicodynamics of linezolid

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxico-dynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs o

Substantial impact of altered pharmacokinetics in critically Ill patients on the antibacterial effects of meropenem evaluated via the dynamic hollow-fiber infection model

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharma-cokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum similar to 10(7.5) CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or similar to 10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (5 x MIC) = 56 and 69%, fC(min)/MIC = 32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT >5 x MIC >= 82%, fC(min)/MIC >= 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence

The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 10(8) CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 10(8) to 10(9) CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates

Controlling antibiotic release from mesoporous silica nano drug carriers via self-assembled polyelectrolyte coating

Mesoporous silica nanoparticles (MSNs) have been explored as controlled drug delivery systems since the early 2000s, but many fundamental questions remain for this important application. We sought to design a pH controlled delivery system of gentamicin, an aminoglycoside antibiotic, based on MSNs. Under optimal conditions, MSN was able to load 219 lg gentamicin per mg MSNs. Polymeric networks encompassing gentamicin loaded MSNs were then established to tune the release kinetics. Embedding of drug pre-loaded MSNs was performed by an efficient layer-by-layer (LbL) self-assemble strategy using polystyrene sulfonate (PSS) and poly (allylamine hydrochloride) (PAH). We characterised the release kinetics by nonlinear mixed-effects modelling in the S-ADAPT software. The mean release time from uncoated MSNs was 3.6 days at pH 7.4 and 0.4 days at pH 1.4. A further slower release was achieved by diffusion through one or two PSS/PAH bilayer(s) which had a mean transit time of 6.0 days at pH 7.4 and 3.5 days at pH 1.4. The number of bilayers affected the shape of the release profile. The developed nano-drug carriers combined with the self-assembled polyelectrolyte coating allowed us to tune the release kinetics by pH and the number of bilayers

Chemical processing : the best read magazine in the chemical industry

Herein we report the preparation of antibiotic thin film coatings with excellent stability and well-regulated drug release profile. These films were prepared by pre-loading of the antibiotic gentamicin into mesoporous silica nanoparticles (MSN-G) to form drug nanoreservoirs, which were then coated onto glass substrates followed by adding a polymer (Nafion) protecting layer. Fourier transform infrared (FTIR) spectroscopy and scanning electronic microscopy (SEM) confirmed the successful coating of MSN-G particles on slides. Factors such as the thickness and number of Nafion layers, the thickness of the MSN-G layer, as well as the pH of the surrounding medium were found to affect the stability of the films in solution. A typical film with 7.5 mg MSN-G particles and a thin layer of Nafion coating remained intact more than 80 days in a pH 7.4 simulated body fluid at 37 [degree]C, which is highly promising for further biomedical application. The loaded gentamicin was found to be slowly released from thin films and the release profile could be tuned by varying the pH of the release media. For example, a steady and sustained release of gentamicin (total 95% of the loading amount) was achieved over up to 38 days in a mildly acidic solution (pH 5.5) or 56 days at the physiologic condition (pH 7.4). These films with outstanding stability and controlled release profile are expected to find promising applications in many fields, such as antibiotic coatings for biomedical devices