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Background Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown. Methods MICs of ciprofloxacin (CIP)+/−chlorpromazine, phenylalanine-arginine β naphthylamide (PAβN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147). Exposure ranging experiments were performed initially then fractionation. Changes in bacterial load and population profiles were assessed. Strains recovered after EPI simulations were studied by WGS. Results The CIPMICs for E. coli MG1655 and I1147 were 0.08 and 0.03 mg/L. Chlorpromazine at a concentration of 60 mg/L, PAβN concentrations of 30 mg/L and MBX-4191 concentrations of 0.5–1.0 mg/L reduced CIP MICs for I1147 and enhanced bacterial killing. Using CIP at an AUC of 1.2 mg·h/L, chlorpromazine AUC was best related to reduction in bacterial load at 24 h, however, when the time drug concentration was greater than 25 mg/L (T > 25 mg/L) chlorpromazine was also strongly related to the effect. For PaβN with CIP AUC, 0.6 mg·h/L PaβN AUC was best related to a reduction in bacterial load. MBX-4191T > 0.5–0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacin + EPIs. WGS of recovered strains from simulations with all three EPIs showed mutations in gyrA , gyrB or marR. Conclusions AUC was the pharmacodynamic driver for chlorpromazine and PAβN while T > threshold was the driver for MBX-4191 and important in the activity of chlorpromazine and PAβN. Changes in population profiles did not occur with combinations of ciprofloxacin + EPIs, however, mutations in gyrA , gyrB and marR were detected. [ABSTRACT FROM AUTHOR]

Objectives To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L). Methods An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h. Results Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5–4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin. Conclusions The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint. [ABSTRACT FROM AUTHOR]

Background: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of β-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way.Objectives: To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.Methods: Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu·h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded.Results: Against E. coli and K. pneumoniae meropenem had a maximal ABE at ≥MIC × 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at ≥MIC × 4 and aztreonam at ≥MIC × 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8×/16 × MIC. Other β-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at ≥MIC × 4, concentration changes in population profiles were least apparent with E. coli.Conclusions: β-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of β-lactam to another is not justified. [ABSTRACT FROM AUTHOR]

Objectives: We assessed the antibacterial effect of human simulations of dosing with imipenem/relebactam (with or without amikacin) on Enterobacteriaceae or Pseudomonas aeruginosa over 7 or 14 day antibiotic exposures.Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and population profiles.Results: Imipenem/relebactam produced an initial >4 log drop in viable counts followed by suppression for 7 days for Enterobacteriaceae whether the strain was WT, produced KPC enzymes or produced an AmpC enzyme with porin loss. Similarly, with the P. aeruginosa strains, there was an initial >4 log clearance over the first 24 h irrespective of whether the strain was WT, hyperexpressed AmpC or had OprD mutation with porin loss. However, with three of four strains there was modest regrowth over the 7 days. There were no changes in imipenem/relebactam MICs over the 7 days. Addition of amikacin in 7 day simulations resulted in more suppression of pseudomonal growth. In 14 day simulations with P. aeruginosa there was regrowth to 8 log10 by 14 days with imipenem/relebactam alone and associated increases in MICs. Addition of amikacin resulted in clearance from the model and prevented changes in population profiles.Conclusions: Imipenem/relebactam was highly effective at reducing the bacterial load of Enterobacteriaceae and there was no emergence of resistance. Against P. aeruginosa, the initial bacterial burden was also rapidly reduced, but there was subsequent regrowth, especially after 7 days of exposure. Addition of amikacin increased the clearance of P. aeruginosa and prevented emergence of resistance. [ABSTRACT FROM AUTHOR]

Objectives: To use a pre-clinical infection model to assess the antibacterial effect of human simulations of dosing with ceftolozane/tazobactam (with or without amikacin) or meropenem against Enterobacteriaceae and Pseudomonas aeruginosa.Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and profiles after exposure to mean human serum concentrations over 168 h. Changes in area under the bacterial kill curve (AUBKC; log cfu/mL·h) and growth on 4 × MIC recovery plates were the co-primary outcome measures.Results: Simulations of ceftolozane/tazobactam at 1 g/0.5 g or 2 g/1 g q8h or meropenem 2 g q8h all produced a >4 log reduction in bacterial load of Escherichia coli. Meropenem had smaller AUBKC values, indicating greater reduction in bacterial load than ceftolozane/tazobactam. Meropenem was also more effective than ceftolozane/tazobactam against Klebsiella pneumoniae strains. All regimens were equally effective in reducing P. aeruginosa bacterial load measured by AUBKC but growth on 4 × MIC recovery plates and changes in population profiles were only seen with meropenem. Addition of amikacin at 15 mg/kg q24h or 7.5 mg/kg q12h to 2 g/1 g of ceftolozane/tazobactam produced greater reductions in bacterial load but generated changes in amikacin population profiles with the 7.5 mg/kg q12h amikacin simulation.Conclusions: The doses of ceftolozane/tazobactam simulated were highly effective in reducing the bacterial load of E. coli (MIC ≤0.25 mg/L), but less so for K. pneumoniae (MIC 4 mg/L). For both species, meropenem produced an overall greater reduction in pathogen load. Ceftolozane/tazobactam and meropenem were equally effective as monotherapy against P. aeruginosa but emergence of resistance occurred with meropenem. Addition of amikacin to ceftolozane/tazobactam reduced the bacterial load of P. aeruginosa at the expense of emergence of resistance to amikacin. [ABSTRACT FROM AUTHOR]

Background: The pharmacodynamics of inhaled antimicrobials are poorly studied. Amikacin is being developed for inhalational therapy as BAY 41-6551.Objectives: We employed an in vitro pharmacokinetic model to study the pharmacokinetics/pharmacodynamics of amikacin.Methods: A dose-ranging design was used to establish fAUC/MIC and fCmax/MIC targets for static, -1 log drop and -2 log drop effects for strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. We then modelled epithelial lining fluid (ELF) concentration associated with inhaled amikacin (400 mg every 12 h), over 5 days using mean human concentrations.Results: The 24 h static effect fAUC/MIC targets and -1 log drop targets were 51.0 ± 26.7 and 71.6 ± 27.6 for all species of aerobic Gram-negative bacilli. fAUC/MIC targets for static effect, -1 log drop or -2 log drop were smaller than the 24 h values at 12 h and larger at 48 h. Emergence of resistance occurred maximally with E. coli in the fAUC/MIC range 12-60; K. pneumoniae 0-60 (48 h) and P. aeruginosa 12-80. When human ELF concentrations were modelled for strains with MIC ≤8 mg/L, there was rapid clearance and no regrowth. For strains with MIC ≥32 mg/L, there was initial clearance followed by regrowth. If MIC values were related to bacterial clearance then at least a static effect or -1 log drop in count would be expected for bacterial strains with MICs of ≤180 mg/L (static effect) or ≤148 mg/L (-1 log drop effect).Conclusions: An fAUC/MIC amikacin target of 50-80 is appropriate for aerobic Gram-negative bacilli and mean ELF concentrations of BAY 41-6551 would produce a static to -1 log clearance with strains up to 128 mg/L. [ABSTRACT FROM AUTHOR]

Objectives: Dose-ranging experiments were performed to study the pharmacodynamics of ceftaroline against Enterobacteriaceae.Methods: A range of fT>MIC values (0%-100%) were simulated over 96 h using a single-compartment dilutional in vitro pharmacokinetic model using Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter koseri and Serratia marcescens (n = 16). Antibacterial effect was assessed by change in viable count and population profiles by growth on ceftaroline MIC ×2, ×4 and ×8 agar plates. The fT>MIC (%) was related to antibacterial effect using a sigmoid Emax model.Results: The 24 h bacteriostatic effect fT>MIC was 39.7% ± 15.7% and 43.2% ± 15.6% for a -1 log drop for all strains. E. coli required lower exposures than K. pneumoniae, i.e. 24 h fT>MIC for a -3 log drop in viable count was 40.0% ± 9.6% and 84.8% ± 15.2% for K. pneumoniae. Similarly at 96 h, fT>MIC was >100% for K. pneumoniae (for four of five strains), 27.2%-66.2% for E. coli and 16.2%-86.6% for P. mirabilis. Strain-to-strain variation within species in the fT>MIC for static and cidal effect was marked; the 24 h bacteriostatic range was 14.1%-73.4% for P. mirabilis, 34.2%-44.6% for E. coli and 42.2%-62.5% for K. pneumoniae. Changes in ceftaroline population analysis profiles were observed with E. coli, K. pneumoniae and C. koseri, especially at fT>MIC values just below the bacteriostatic effect exposures.Conclusions: The pharmacodynamics of ceftaroline against the species within the Enterobacteriaceae group are different. K. pneumoniae requires higher drug exposures than E. coli, and P. mirabilis strains are highly variable, which may have important clinical correlates. Translational extrapolations from preclinical observations using E. coli to other Enterobacteriaceae species may not be optimal. [ABSTRACT FROM AUTHOR]

Objectives Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI. Methods MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations. Results Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing. Conclusions Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid. [ABSTRACT FROM PUBLISHER]

Objectives: To compare the antibacterial effects (ABEs) of the free (f) drugs daptomycin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), using high and low inocula in a pharmacokinetic in vitro model. To determine the daptomycin fAUC/MIC ratio for a static effect and 3 log reduction in viable count and relate this target to the clinical breakpoint. [ABSTRACT FROM PUBLISHER]