Purpose of review
Increased emergence of bacterial resistance and the decline in newly developed antibiotics have necessitated the reintroduction of previously abandoned antimicrobial agents active against multidrug-resistant bacteria. Having never been subjected to contemporary drug development procedures, these ‘old’ antibiotics require redevelopment in order to optimize therapy. This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin.
Redevelopment of colistin led to an improved understanding of its chemistry, pharmacokinetics and pharmacodynamics, enabling important steps towards optimizing its clinical use in different patient populations. A scientifically based dosing algorithm was developed for critically ill patients, including those with renal impairment. As nephrotoxicity is a dose-limiting adverse event of colistin, rational combination therapy with other antibiotics needs to be investigated.
The example of colistin demonstrated that state-of-the-art analytical, microbiological and pharmacokinetic/pharmacodynamic methods can facilitate optimized use of ‘old’ antibiotics in the clinic. Similar methods are now being applied to fosfomycin and fusidic acid in order to optimize therapy. To improve and preserve the usefulness of these antibiotics rational approaches for redevelopment need to be followed.
colistin; fosfomycin; fusidic acid; pharmacodynamics; pharmacokinetics
In vitro static concentration time-kill (SCTK) studies are a cornerstone for antibiotic development and designing dosage regimens. However, mathematical approaches to efficiently model SCTK curves are scarce. The currently used model-free, descriptive metrics include the log10 change in CFU from 0 h to a defined time and the area under the viable count versus time curve. These metrics have significant limitations, as they do not characterize the rates of bacterial killing and regrowth and lack sensitivity. Our aims were to develop a novel rate-area-shape modeling approach and to compare, against model-free metrics, its relative ability to characterize the rate, extent, and timing of bacterial killing and regrowth from SCTK studies. The rate-area-shape model and the model-free metrics were applied to data for colistin and doripenem against six Acinetobacter baumannii strains. Both approaches identified exposure-response relationships from 0.5- to 64-fold the MIC. The model-based approach estimated an at least 10-fold faster killing by colistin than by doripenem at all multiples of the MIC. However, bacterial regrowth was more extensive (by 2 log10) and occurred approximately 3 h earlier for colistin than for doripenem. The model-free metrics could not consistently differentiate the rate and extent of killing between colistin and doripenem. The time to 2 log10 killing was substantially faster for colistin. The rate-area-shape model was successfully implemented in Excel. This new model provides an improved framework to distinguish between antibiotics with different rates of bacterial killing and regrowth and will enable researchers to better characterize SCTK experiments and design subsequent dynamic studies.
Although very similar in chemical and microbiological properties, colistin and polymyxin B differ substantially when administered in their parenteral formulations. Overall, polymyxin B has superior clinical pharmacological properties, but both should be made available for specific types of patients and infections.
Colistin and polymyxin B have indistinguishable microbiological activity in vitro, but they differ in the form administered parenterally to patients. Polymyxin B is administered directly as the active antibiotic, whereas colistin is administered as the inactive prodrug, colistin methanesulfonate (CMS). CMS must be converted to colistin in vivo, but this occurs slowly and incompletely. Here we summarize the key differences between parenteral CMS/colistin and polymyxin B, and highlight the clinical implications. We put forth the view that overall polymyxin B has superior clinical pharmacological properties compared with CMS/colistin. We propose that in countries such as the United States where parenteral products of both colistin and polymyxin B are available, prospective studies should be conducted to formally examine their relative efficacy and safety in various types of infections and patients. In the meantime, where clinicians have access to both polymyxins, they should carefully consider the relative merits of each in a given circumstance.
colistin; polymyxin B; differing clinical pharmacological behaviors; therapeutic implications
There is increasing interest in the optimization of polymyxin B dosing regimens to treat infections caused by multidrug-resistant Gram-negative bacteria. We aimed to develop and validate a liquid chromatography - single quadrupole mass spectrometry (LC-MS) method to quantify polymyxin B in two growth media commonly used in in vitro pharmacodynamic studies, cation-adjusted Mueller-Hinton and tryptone soya broth. Samples were pre-treated with sodium hydroxide (1.0 M) and formic acid in acetonitrile (1:100, v/v) before analysis. The summed peak areas of polymyxin B1 and B2 relative to the summed peak areas of colistin A and B (internal standard) were used to quantify polymyxin B. Quality control samples were prepared and analyzed to assess the intra- and inter-day accuracy and precision. The robustness of the assay in the presence of bacteria and commonly co-administered antibiotics (rifampicin, doripenem, imipenem, cefepime and tigecycline) was also examined. Chromatographic separation was achieved with retention times of approximately 9.7 min for polymyxin B2 and 10.4 min for polymyxin B1. Calibration curves were linear between 0.103 and 6.60 mg/L. Accuracy (% relative error) and precision (% coefficient of variation), pooled for all assay days and matrices (n=84), were −6.85% (8.17%) at 0.248 mg/L, 1.73% (6.15%) at 2.48 mg/L and 1.54% (5.49%) at 4.95 mg/L, and within acceptable ranges at all concentrations examined. Further, the presence of high bacterial concentrations or of commonly co-administered antibiotics in the samples did not affect the assay. The accuracy, precision and cost-efficiency of the assay make it ideally suited to quantifying polymyxin B in samples from in vitro pharmacodynamic models.
Polymyxin B; Liquid chromatography - mass spectrometry; Mueller-Hinton broth; Tryptone soya broth
The purpose of this study was to define the pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following intravenous (i.v.) and inhaled administration in cystic fibrosis (CF) patients. Six CF subjects were administered nebulized CMS doses of 2 and 4 million IU and an i.v. CMS infusion of 150 mg of colistin base activity. Blood plasma, sputum, and urine samples were collected for 12 to 24 h postdose. To assess the tolerability of the drug, lung function tests, blood serum creatinine concentrations, and adverse effect reports were recorded. All doses were well tolerated in the subjects. The pharmacokinetic parameters for CMS following i.v. delivery were consistent with previously reported values. Sputum concentrations of formed colistin were maintained at <1.0 mg/liter for 12 h postdose. Nebulization of CMS resulted in relatively high sputum concentrations of CMS and formed colistin compared to those resulting from i.v. administration. The systemic availability of CMS was low following nebulization of 2 and 4 million IU (7.93% ± 4.26% and 5.37% ± 1.36%, respectively), and the plasma colistin concentrations were below the limit of quantification. Less than 2 to 3% of the nebulized CMS dose was recovered in the urine samples in 24 h. The therapeutic availability and drug targeting index for CMS and colistin following inhalation compared to i.v. delivery were significantly greater than 1. Inhalation of CMS is an effective means of targeting CMS and formed colistin for delivery to the lungs, as high lung exposure and minimal systemic exposure were achieved in CF subjects.
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 toxicodynamics 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 of <100 ×109/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.
Polymyxin is the last-line therapy
against Gram-negative ‘superbugs’;
however, dose-limiting nephrotoxicity can occur in up to 60% of patients
after intravenous administration. Understanding the accumulation and
concentration of polymyxin within renal tubular cells is essential
for the development of novel strategies to ameliorate its nephrotoxicity
and to develop safer, new polymyxins. We designed and synthesized
a novel dual-modality iodine-labeled fluorescent probe for quantitative
mapping of polymyxin in kidney proximal tubular cells. Measured by
synchrotron X-ray fluorescence microscopy, polymyxin concentrations
in single rat (NRK-52E) and human (HK-2) kidney tubular cells were
approximately 1930- to 4760-fold higher than extracellular concentrations.
Our study is the first to quantitatively measure the significant uptake
of polymyxin in renal tubular cells and provides crucial information
for the understanding of polymyxin-induced nephrotoxicity. Importantly,
our approach represents a significant methodological advancement in
determination of drug uptake for single-cell pharmacology.
Colistin, administered intravenously as its inactive prodrug colistin methanesulfonate (CMS), is increasingly used as last-line therapy to combat multidrug-resistant Gram-negative bacteria. CMS dosing needs to be adjusted for renal function. The impact of continuous ambulatory peritoneal dialysis (CAPD) on the pharmacokinetics of both CMS and colistin has not been studied. No CMS dosing recommendations are available for patients receiving CAPD. Eight CAPD patients received a single intravenous CMS dose (150 mg colistin base activity [CBA]) over 30 min. Serial blood and dialysate samples, and cumulative urine where applicable, were collected over 25 h. CMS and colistin concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations were conducted. The total body clearance of CMS (excluding CAPD clearance) was 1.77 liters/h (44%) [population mean (between-subject variability)], while CAPD clearance was 0.088 liter/h (64%). The population mean terminal half-life of CMS was 8.4 h. For colistin, the total clearance/fraction of CMS metabolized to colistin (fm) (excluding CAPD clearance) was 2.74 liters/h (50%), the CAPD clearance was 0.101 liter/h (34%), and the mean terminal half-life was 13.2 h. Monte Carlo simulations suggested a loading dose of 300 mg CBA on day 1 and a maintenance dose of either 150 mg or 200 mg CBA daily to achieve a target average steady-state plasma colistin concentration of 2.5 mg/liter. Clearance by CAPD was low for both CMS and formed colistin. Therefore, CMS doses should not be increased during CAPD. Modeling and simulation enabled us to propose the first evidence-based CMS dosage regimen for CAPD patients.
Polymyxin combination therapy is increasingly used clinically. However, systematic investigations of such combinations are a relatively recent phenomenon. The emerging pharmacodynamic (PD) and pharmacokinetic (PK) data on CMS/colistin and polymyxin B suggest that caution is required with monotherapy. Given this situation, polymyxin combination therapy has been suggested as a possible way to increase bacterial killing and reduce the development of resistance. Considerable in vitro data have been generated in support of this view, particularly recent studies utilizing dynamic models. However, most existing animal data are of poor quality with major shortcomings in study design, while clinical data are generally limited to retrospective analysis and small, low-power, prospective studies. This article provides an overview of clinical and preclinical investigations of CMS/colistin and polymyxin B combination therapy.
Colistin; Colistin methanesulfonate; Combination; Pharmacodynamic; Polymyxins; Polymyxin B
The dry antibiotic development pipeline
coupled with the emergence
of multidrug resistant Gram-negative ‘superbugs’ has
driven the revival of the polymyxin lipopeptide antibiotics. Polymyxin
resistance implies a total lack of antibiotics for the treatment of
life-threatening infections. The lack of molecular imaging probes
that possess native polymyxin-like antibacterial activity is a barrier
to understanding the resistance mechanisms and the development of
a new generation of polymyxin lipopeptides. Here we report the regioselective
modification of the polymyxin B core scaffold at the N-terminus with the dansyl fluorophore to generate an active probe
that mimics polymyxin B pharmacologically. Time-lapse laser scanning
confocal microscopy imaging of the penetration of probe (1) into Gram-negative bacterial cells revealed that the probe initially
accumulates in the outer membrane and subsequently penetrates into
the inner membrane and finally the cytoplasm. The implementation of
this polymyxin-mimetic probe will advance the development of platforms
for the discovery of novel polymyxin lipopeptides with efficacy against
Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼106 and ∼108 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [Cmax] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 106-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 108-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log10 CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii.
The antimicrobial lipopeptides polymyxin
B and E (colistin) are
being used as a ‘last-line’ therapy for infections caused
by multidrug-resistant Gram-negative pathogens. Polymyxin resistance
implies a total lack of antibiotics for the treatment of life-threatening
infections caused by the Gram-negative ‘superbugs’.
This report details the structure–activity relationships (SAR)
based design, in toto synthesis, and preclinical
evaluation of a series of novel polymyxin lipopeptides with better
antibacterial activity against polymyxin-resistant Gram-negative bacteria.
Purpose of review
Colistin is a 50 year-old antibiotic that is being used increasingly as a ‘last-line’ therapy to treat infections caused by MDR Gram-negative bacteria, when essentially no other options are available. Despite its age, or because of its age, there has been a dearth of knowledge on its pharmacological and microbiological properties. This review focuses on recent studies aimed at optimizing the clinical use of this old antibiotic.
A number of factors, including the diversity in the pharmaceutical products available, have hindered the optimal use of colistin. Recent advances in understanding of the pharmacokinetics and pharmacodynamics of colistin, and the emerging knowledge on the relationship between the pharmacokinetics and pharmacodynamics, providing a solid base for optimization of dosage regimens. The potential for nephrotoxicity has been a lingering concern, but recent studies provide useful new information on the incidence, severity and reversibility of this adverse effect. Recent approaches to the use of other antibiotics in combination with colistin hold promise for increased antibacterial efficacy with less potential for emergence of resistance.
Because few, if any, new antibiotics with activity against MDR Gram-negative bacteria will be available within the next several years, it is essential that colistin is used in ways that maximize its antibacterial efficacy and minimize toxicity and development of resistance. Recent developments have improved use of colistin in the 21st century.
colistin; approaches to optimizing therapy; Gram-negative infections
To investigate the effect of P-gp inhibition on the maternal to foetal transfer of indinavir.
Term human placentae (n = 12) were from non-HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P-gp inhibitors PSC833 (n = 7) or ritonavir (n = 5), in the perfused human placenta. Antipyrine and [3H]-vinblastine were included as markers of passive diffusion and P-gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0 min; PSC833 or ritonavir was added at 25 min. Steady-state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index).
Indinavir clearance index increased between the control (0.25 ± 0.03) and PSC833 phases (0.37 ± 0.14) (95% CI of the difference −0.23, −0.002). Vinblastine clearance index increased from (0.25 ± 0.08) to (0.34 ± 0.06) in the control and PSC833 phases, respectively (95% CI of difference −0.14, −0.05). Indinavir clearance index was unchanged between control (0.34 ± 0.14) and ritonavir phases (0.39 ± 0.13) (95% CI of the difference −0.19, 0.08). Vinblastine clearance index increased from (0.24 ± 0.12) to (0.32 ± 0.12) in the control and ritonavir phases, respectively (95% CI of the difference −0.15, −0.009).
Maternal to foetal transfer clearance of indinavir and vinblastine increased following P-gp inhibition. The potential role for co-administration of P-gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTWe have shown previously using the dually perfused isolated human placenta model that the maternal to foetal transfer of the antiviral protease inhibitor drug indinavir is substantially lower than the transfer in the opposite direction.This finding is not consistent with passive diffusion and indicates that a carrier-mediated mechanism is involved in retarding the movement in the maternal to foetal direction.The efflux transporter P-gp located in the apical membrane domain of the placental trophoblast cells has been implicated as the likely cause of the differential bi-directional transport.
WHAT THIS STUDY ADDSThe present study also utilizes the human perfused human isolated placenta to investigate the possible inhibitory effects of the P-gp inhibitor PSC833 and the P-gp substrate/inhibitor ritonavir on the maternal to foetal transfer clearance of indinavir.The studies, which were conducted such that each placenta served as its own control, demonstrated a statistically significant increase in the maternal to foetal transfer of indinavir in the presence of PSC833 but not in the presence of ritonavir, a protease inhibitor that is often used in combination with other protease inhibitors in dual therapy.The lack of effect of ritonavir is most likely related to the relatively low inhibitory activity at the clinically relevant concentration used in this study.
HIV protease inhibitors; indinavir; P-glycoprotein; placental transfer
The impact of under-acylation of lipid A on the interaction between Klebsiella pneumoniae LPS and polymyxins B and E was examined with fluorometric and calorimetric methods, and by 1H NMR, using a paired wild type (WT) and the Δ6lpxM mutant strains B5055 and B5055 ΔlpxM, which predominantly express LPS with hexa- and penta-acylated lipid A structures respectively. LPS from B5055 ΔlpxM displayed a fourfold increased binding affinity for polymyxins B and E compared with the B5055 WT LPS. EC50 values were consistent with polymyxin minimum inhibitory concentration (MIC) values for each strain. Accordingly, polymyxin exposure considerably enhanced the permeability of the B5055 ΔlpxM OM. Analysis of the melting profiles of isolated LPS aggregates suggested that bactericidal polymyxin activity may relate to the acyl chains’ phase of the outer membrane (OM). The enhanced polymyxin susceptibility of B5055 Δ6lpxM may be attributable to the favorable insertion of polymyxins into the more fluid OM compared with B5055. Molecular models of the polymyxin B–lipid A complex illuminate the key role of the lipid A acyl chains for complexation of polymyxin. The data provide important insight into the molecular basis for the increased polymyxin susceptibility of K. pneumoniae strains with under-acylated lipid A. Under-acylation appears to facilitate the integration of the N-terminal fatty-acyl chain of polymyxin into the OM resulting in an increased susceptibility to its antimicrobial activity/activities.
Polymyxin; Klebsiella pneumoniae; lipopolysaccharide
This study examines the interaction of polymyxin B and colistin with the surface and outer membrane components of a susceptible and resistant strain of Klebsiella pneumoniae. The interaction between polymyxins and bacterial membrane and isolated LPS from paired wild type and polymyxin-resistant strains of K. pneumoniae were examined with N-phenyl-1-naphthylamine (NPN) uptake, fluorometric binding and thermal shift assays, lysozyme and deoxycholate sensitivity assays, and by 1H NMR. LPS from the polymyxin-resistant strain displayed a reduced binding affinity for polymyxins B and colistin in comparison with the wild type LPS. The outer membrane NPN permeability of the resistant strain was greater compared with the susceptible strain. Polymyxin exposure enhanced the permeability of the outer membrane of the wild type strain to lysozyme and deoxycholate, whereas polymyxin concentrations up to 32 mg/ml failed to permeabilize the outer membrane of the resistant strain. Zeta potential measurements revealed that mid-logarithmic phase wild type cells exhibited a greater negative charge than the mid-logarithmic phase-resistant cells. Taken together, our findings suggest that the resistant derivative of K. pneumoniae can block the electrostatically driven first stage of polymyxin action, which thereby renders the hydrophobically driven second tier of polymyxin action on the outer membrane inconsequential.
Polymyxin; colistin; Klebsiella pneumoniae; lipopolysaccharide; surface
Antibiotics; Polymyxins; Colistin; RNA; Translation
To determine whether lower umbilical cord than maternal binding of indinavir and saquinavir contributed to the low cord : maternal (C : M) total concentration ratios reported previously.
Indinavir and saquinavir unbound fraction (fu) was determined using equilibrium dialysis. Buffer solutions of human serum albumin (HSA) (20.0, 30.0, 40.0 g l−1) and α1-acid glycoprotein (AAG) (0.20, 0.60, 2.00 g l−1) were spiked with indinavir (1.00 and 8.00 mg l−1) or saquinavir (0.15 and 1.50 mg l−1). Matched maternal and umbilical cord plasma was spiked with 1.00 mg l−1 indinavir (n = 12) or 0.15 mg l−1 saquinavir (n = 20). Spiked protein/plasma solutions were dialyzed against isotonic phosphate buffer, at 37 °C. At equilibrium, indinavir and saquinavir concentrations were quantified, and the fu determined.
Indinavir and saquinavir demonstrated protein concentration-dependent binding in buffer solutions of HSA and AAG. Indinavir fu was significantly higher in umbilical cord (0.53 ± 0.12) compared with maternal (0.36 ± 0.11) plasma (95% CI of the difference −0.26, −0.097). Similarly, saquinavir fu was different between umbilical cord (0.0090 ± 0.0046) and maternal plasma (0.0066 ± 0.0039) (95% CI of the difference −0.0032, −0.0016). The transplacental AAG concentration gradient contributed significantly to the binding differential of both drugs.
The differential plasma binding of both drugs, which was largely the result of the transplacental AAG concentration gradient, would contribute to the low C : M total plasma concentration ratios observed previously. Unbound concentrations of indinavir and saquinavir are likely to be substantially lower in umbilical cord than maternal plasma.
HIV protease inhibitors; indinavir; pharmacokinetics; pregnancy; protein binding; saquinavir
Very different labelling conventions are employed by different products of colistimethate (CMS), an inactive prodrug of colistin that is used as a last-line defence against Gram-negative ‘superbugs’. This study examined the chemical composition and pharmacokinetics in rats of four commercial parenteral products of CMS.
Contents per vial of four brands of CMS from three different continents were weighed (n = 3). Elemental analysis and HPLC examination were conducted. The pharmacokinetics of CMS and formed colistin were investigated for each product after intravenous administration in rats (28.1 mg/kg CMS; n = 4). Blood was collected over 180 min, and concentrations of CMS and colistin were measured followed by pharmacokinetic analysis.
X-GEN, Paddock and Atlantic products, labelled with 150 mg ‘colistin base activity’, contained 366.8 ± 0.80, 340.6 ± 0.08 and 380.0 ± 5.97 mg CMS (sodium) per vial, respectively; while the Forest product (labelled with 2 000 000 IU) contained 159.3 ± 1.75 mg CMS (sodium). The elemental compositions of the four products were similar; however, the HPLC profile of the Atlantic CMS was different from those of the other three products. The pharmacokinetics of CMS were generally comparable across brands; however, the molar ratios (%) of the AUC0–180min of colistin to CMS (1.68% ± 0.35% to 3.29% ± 0.43%) were significantly different (P = 0.0157).
This is the first study to demonstrate that although different brands of CMS from various parts of the world have similar elemental compositions, they lead to different exposures to the microbiologically active formed colistin. The study has significant implications for the interpretation of pharmacological studies of CMS conducted in different parts of the world.
elemental analysis; HPLC; intravenous administration; colistin base activity
Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (108 CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n = 5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n = 14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.
Polymyxin B and colistin were examined for their ability to inhibit the type II NADH-quinone oxidoreductases (NDH-2) of three species of Gram-negative bacteria. Polymyxin B and colistin inhibited the NDH-2 activity in preparations from all of the isolates in a concentration-dependent manner. The mechanism of NDH-2 inhibition by polymyxin B was investigated in detail with E. coli inner membrane preparations and conformed to a mixed inhibition model with respect to ubiquinone-1 and a non-competitive inhibition model with respect to NADH. These suggest inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins.
type II NADH-quinone oxidoreductase; polymyxin B; colistin; Escherichia coli; Klebsiella pneumoniae; Acinetobacter baumannii
Enterococci are a major cause of healthcare-associated infection. In Australia, vanB vancomycin-resistant enterococci (VRE) is the predominant genotype. There are limited data on the factors linked to vanB VRE bacteraemia. This study aimed to identify factors associated with vanB VRE bacteraemia, and compare them with those for vancomycin-susceptible enterococci (VSE) bacteraemia.
A case-case-control study was performed in two tertiary public hospitals in Victoria, Australia. VRE and VSE bacteraemia cases were compared with controls without evidence of enterococcal bacteraemia, but may have had infections due to other pathogens.
All VRE isolates had vanB genotype. Factors associated with vanB VRE bacteraemia were urinary catheter use within the last 30 days (OR 2.86, 95% CI 1.09-7.53), an increase in duration of metronidazole therapy (OR 1.65, 95% CI 1.17-2.33), and a higher Chronic Disease Score specific for VRE (OR 1.70, 95% CI 1.05-2.77). Factors linked to VSE bacteraemia were a history of gastrointestinal disease (OR 2.29, 95% CI 1.05-4.99) and an increase in duration of metronidazole therapy (OR 1.23, 95% CI 1.02-1.48). Admission into the haematology/oncology unit was associated with lower odds of VSE bacteraemia (OR 0.08, 95% CI 0.01-0.74).
This is the largest case-case-control study involving vanB VRE bacteraemia. Factors associated with the development of vanB VRE bacteraemia were different to those of VSE bacteraemia.
Enterococci; Vancomycin-resistant; Vancomycin-susceptible; Bacteraemia
Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections.
Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these ‘superbugs’ in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure–activity relationships and pharmacokinetics/pharmacodynamics. In the ‘Bad Bugs, No Drugs’ era, we must pursue structure–activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative ‘superbugs’. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
colistin; lipid A; lipopolysaccharide; pharmacokinetic/pharmacodynamic; polymyxin; resistance; structure–activity relationship