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ABSTRACTCeftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitropotency against a range of clinically important β-lactamase-producing bacteria, including most extended-spectrum-β-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of β-lactam–β-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coliand Pseudomonas aeruginosausing an in vitropharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC β-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coliwere 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. colistrains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosawere 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coliand P. aeruginosaand is more similar to the fT>MIC reported for carbapenems.

ABSTRACTAn in vitrosingle-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus(both methicillin-susceptible S. aureus[MSSA] and methicillin-resistant S. aureus[MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureusstrains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 μg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fTMIC) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a −1-log-unit drop, and one of 32.1% ± 8.1% was associated with a −2-log-unit drop. The MSSA and MRSA strains had similar fTMICvalues. fTMICvalues increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fTMIC. fTMICs of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureusstrains with MICs of ≤2 μg/ml. An fTMICof 25 to 30% would make a suitable pharmacodynamic index target, but fTMICvalues of ≥50% are needed to suppress the emergence of resistance and require clinical evaluation.

ABSTRACTAn in vitrodilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosaor Acinetobacter baumanniiand also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMICs) required for doripenem to produce a 24-h bacteriostatic effect and a −2-log-unit reduction in viable count were 25% ± 11% and 35% ± 13%, respectively, for P. aeruginosa(MIC range, 0.24 to 3 mg/liter) and 20% ± 11% and 33% ± 12%, respectively, for Acinetobacterspp. (MIC range, 0.45 to 3.0 mg/liter). A TMICof >40 to 50% produced a maximum response with both species at 24 h or 48 h of exposure. After 24 h of exposure to doripenem at a TMICin the range of 12.5 to 37.5%, P. aeruginosaand A. baumanniipopulation profiles revealed mutants able to grow on 4× MIC-containing medium; such changes were further amplified by 48 h of exposure. Dose-fractionation experiments targeting TMICs of 12.5%, 25%, or 37.5% as six exposures, two exposures, or a single exposure over 48 h with a single strain of P. aeruginosaindicated that changes in population profiles were greatest with multiple exposures at TMICtargets of 12.5 or 25%. In contrast, multiple exposures at 37.5% TMICmost effectively suppressed total bacterial counts and changes in population profiles. Simulations of human doses of doripenem of 500 mg, 1,000 mg, 2,000 mg, and 3,000 mg every 8 h over 96 h showed marked initial killing up to 6 h but growback thereafter. Changes in population profiles occurred only in the regimen of 500 mg every 8 h against P. aeruginosabut occurred with all dose regimens for A. baumanniistrains. A doripenem TMICof ≥40 to 50% is maximally effective in killing P. aeruginosaor A. baumanniiand suppressing changes in population profiles in short-term experiments for up to 48 h; however, a TMICof 12.5 to 25% amplifies population changes, especially with exposures every 8 h. In longer-term experiments, up to 96 h, even doripenem doses of 4 to 6 times those used in human studies proved incapable of pathogen eradication and prevention of changes in population profiles. The association of a TMICof 25 to 37.5% with changes in population profiles has implications in terms of future clinical breakpoint setting.

ABSTRACTThe antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureusstrains (1 methicillin-susceptible S. aureus[MSSA] strain, 4 methicillin-resistant S. aureus[MRSA] strains, and 1 vancomycin-intermediate S. aureus[VISA] strain) and three Enterococcussp. strains (1 Enterococcus faecalisstrain, 1 Enterococcus faeciumstrain, and 1 vancomycin-resistant E. faecium[VREF] strain) were compared using an in vitropharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible S. aureus(VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC24) and 48 h (AUBKC48) in comparison to vancomycin or teicoplanin (P< 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P< 0.05). Against the three Enterococcusspp. tested, telavancin was superior to vancomycin in terms of its AUBKC24, AUBKC48, and greater early bactericidal effect (P< 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3 Enterococcusstrains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the Enterococcusspp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with S. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against Enterococcusspp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for both S. aureusand Enterococcusspp.

ABSTRACTFree drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus(MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log10-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (P< 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with r2of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and −1-log-unit, −2-log-unit, and −3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.

ABSTRACTThe antibacterial effect of amoxicillin-clavulanate in two formulations, pharmacokinetically enhanced 16:1 amoxicillin-clavulanate twice a day (b.i.d.) and standard 7:1 amoxicillin-clavulanate b.i.d., were studied in an in vitro pharmacokinetic model of infection. Five strains of Streptococcus pneumoniaeand two of Haemophilus influenzae, all associated with raised MICs (2 to 8 mg/liter), were used. The antibacterial effect was measured over 24 h by the area under the bacterial kill curve (AUBKC) and the log change in viable count at 24 h (Δ24). A high 108CFU/ml and low 106CFU/ml initial inocula were used. Employing the Δ24 effect measure, the time above MIC (T>MIC) 50% maximum effect (EC50) for S. pneumoniaewas in the range 21 to 28% with an 80% maximal response of 41 to 51%, for the AUBKC measure, the value was 26 to 39%, irrespective of inoculum. For H. influenzae, the T>MIC EC50was 28 to 37%, and the 80% maximum response was 32 to 48% for the Δ24 measure and 20 to 48% for AUBKC. The maximum response occurred at a T>MIC of 50 to 60% for both species and inocula. The S. pneumoniaedata were analyzed by analysis of variance to assess the effect of inoculum, formulation, and MIC on antibacterial effect. Standard and enhanced formulations had different effects depending on MIC, with the standard formulation less effective at higher amoxicillin-clavulanate MICs. This is explained by the greater T>MICs of the enhanced formulation. Although resistant to amoxicillin-clavulanate by conventional breakpoints, S. pneumoniaeand H. influenzaestrains for which MICs are 2 or 4 mg/liter may well respond to therapy with pharmacokinetically enhanced formulation amoxicillin-clavulanate.

ABSTRACTA strain of Escherichia colicontaining TEM-1 and CTX-M-1 was tested in an in vitro pharmacokinetic model against ceftazidime with and without AM-112, a serine β-lactamase inhibitor. Ceftazidime alone was less effective than ceftazidime plus AM-112, and a single dose was more effective than three fractionated doses.

ABSTRACTThe susceptibilities of clinical vancomycin-intermediate Staphylococcus aureus(VISA), heterogenous VISA, and laboratory-generated linezolid-resistant S. aureusstrains to the new oxazolidinone AZD2563 were assessed by agar dilution MIC determination. All clinical strains were susceptible to linezolid, and the linezolid MICs for them were equal to or twofold higher than those of AZD2563. Cross-resistance with linezolid was seen in laboratory-generated mutants, and for these strains the MIC of AZD2563 was twofold higher than that of linezolid.