Pharmacokinetics of First-Line Antituberculosis Drugs in HIV-Infected Children with Tuberculosis Treated with Intermittent Regimens in India

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C_max) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C_max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC_0–8]) of INH (C_max, 2.5 versus 5.1 μg/ml, respectively [P = 0.016]; AUC_0–8, 11.1 versus 22.0 μg/ml · h, respectively [P = 0.047[) and PZA (C_max, 34.1 versus 42.3 μg/ml, respectively [P = 0.055]; AUC_0–8, 177.9 versus 221.7 μg/ml · h, respectively [P = 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C_max of RMP (1.0 versus 2.8 μg/ml, respectively; P = 0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P = 0.045) were significantly lower. Among all factors studied, the PZA C_max influenced TB treatment outcome (P = 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C_max. The PZA C_max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.     

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/μl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (C_max) of 4.129 μg/ml (2.474 to 5.596 μg/ml), area under the curve from 0 to 24 h (AUC_0–∞) of 21.32 μg/ml · h (13.57 to 28.60 μg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, C_max of 3.97 μg/ml (2.979 to 4.544 μg/ml), AUC_0–24 of 22.5 (14.75 to 34.59 μg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, C_max of 34.21 μg/ml (30.00 to 41.60 μg/ml), AUC_0–24 of 386.6 μg/ml · h (320.0 to 463.7 μg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, C_max of 2.278 μg/ml (1.694 to 3.098 μg/ml), AUC_0–24 of 20.41 μg/ml · h (16.18 to 26.27 μg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the C_max and AUC_0–24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.     

Telaprevir and Ribavirin Interaction: Higher Ribavirin Levels Are Not Only Due to Renal Dysfunction during Triple Therapy

A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN-α), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin C_min) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-α plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV-coinfected patients were enrolled. The median ribavirin C_min for triple therapy (4.08 μg/ml; range, 2.14 to 5.56 μg/ml) was higher than that observed after telaprevir withdrawal (1.96 μg/ml; range, 0.41 to 3.45 μg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN-α plus ribavirin (1.65 μg/ml; range, 0.41 to 5.56 μg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r² = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC_0–12) (r² = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01818856","term_id":"NCT01818856"}}NCT01818856.)     

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (C_max) values were generally attained within 2 h postdose. The mean values of C_max and area under the concentration-time curve from 0 to 24 h (AUC_0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean C_max and AUC_0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These C_max and AUC_0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (V_ss/F), half-life (t_1/2), and renal clearance (CL_R) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, V_ss/F, t_1/2, and CL_R following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.     

Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia

While previous studies have examined the association between vancomycin (VAN) exposure and MIC with regard to outcomes in methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B), none have explored if a relationship exists with the VAN minimum bactericidal concentration (MBC). The objective of this study was to evaluate the VAN 24-h area under the curve (AUC₂₄)/MBC ratio as a pharmacodynamic predictor of mortality. This retrospective cohort study included patients treated with VAN for MRSA-B with the primary outcome of 30-day all-cause mortality. Data collected included patient demographics, comorbidities, antimicrobial treatment data, therapeutic drug levels, and laboratory and microbiological data. Vancomycin MICs and MBCs were determined by Etest (MIC only) and broth microdilution (BMD). The vancomycin AUC₂₄ was determined by pharmacokinetic maximum a posteriori probability Bayesian (MAP-Bayesian) analysis. The most significant breakpoint for 30-day mortality was determined by classification and regression tree (CART) analysis. The association between pharmacodynamic parameters (VAN AUC₂₄/MIC_BMD, VAN AUC₂₄/MIC_Etest, and AUC₂₄/MBC_BMD) and mortality were determined by χ² and multivariable Poisson regression. Overall mortality in this cohort (n = 53) was 20.8% (n = 11/53), and all corresponding MRSA blood isolates were VAN susceptible (MIC range, 0.5 to 2 μg/ml; MIC₅₀, 1 μg/ml; MIC₉₀, 1 μg/ml). The CART-derived breakpoints for mortality were 176 (VAN AUC₂₄/MBC) and 334 (VAN AUC₂₄/MIC_BMD). In multivariable analysis, the association between a VAN AUC₂₄/MBC of ≥176 and survival persisted, but VAN AUC₂₄/MIC_BMD values (≥334 or ≥400) were not associated with improved mortality. In conclusion, VAN AUC₂₄/MBC was a more important predictor of 30-day mortality than VAN AUC₂₄/MIC for MRSA-B.     

Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis

Ofloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC_0–24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (C_max), AUC_0–8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC_0–24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC_0–24 was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47; P = 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.     

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 ± 23.7 μg/ml. A CSF maximum (C_maxCSF) of 0.63 ± 0.50 μg/ml (mean ± standard deviation) was observed 4.1 ± 2.6 h after the end of the infusion. C_maxCSF and the area under the curve for CSF (AUC_CSF) depended on the AUC for serum (AUC_S), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at β phase [t_1/2β] of 7.36 ± 2.89 h in CSF versus t_1/2β of 1.69 ± 0.60 h in serum). The AUC_CSF/AUC_S ratio for meropenem, as a measure of overall CSF penetration, was 0.047 ± 0.022. The AUC_CSF/AUC_S ratio for meropenem was similar to that for other β-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C_max) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to C_max was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved C_max/MIC and AUC from time zero to 24 h (AUC_0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C_max/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC_0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.     

Ceftolozane-Tazobactam Pharmacokinetics in a Critically Ill Patient on Continuous Venovenous Hemofiltration

Extended-infusion ceftolozane-tazobactam treatment at 1.5 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa in a critically ill patient on continuous venovenous hemofiltration. Serum drug concentrations were measured at 1, 4, 5, 6, and 8 h after the start of infusion. Prefilter levels of ceftolozane produced a maximum concentration of drug (C_max) of 38.57 μg/ml, concentration at the end of the dosing interval (C_min) of 31.63 μg/ml, time to C_max (T_max) of 4 h, area under the concentration-time curve from 0 to 8 h (AUC_0–8) of 284.38 μg · h/ml, and a half-life (t_1/2) of 30.7 h. The concentrations were eight times the susceptibility breakpoint for the entire dosing interval.     

Potency and Spectrum of Activity of AN3365, a Novel Boron-Containing Protein Synthesis Inhibitor,Tested against Clinical Isolates of Enterobacteriaceae and Nonfermentative Gram-Negative Bacilli

AN3365 (MIC_50/90, 0.5/1 μg/ml) was active against Enterobacteriaceae, including a subset of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains (MIC_50/90, 1/2 μg/ml). AN3365 inhibited 98.0 and 92.2% of wild-type (MIC_50/90, 2/8 μg/ml) and carbapenem-resistant (MIC_50/90, 4/8 μg/ml) Pseudomonas aeruginosa strains, respectively, at ≤8 μg/ml. AN3365 also demonstrated activity against wild-type Acinetobacter baumannii (MIC_50/90, 2/8 μg/ml) and Stenotrophomonas maltophilia (MIC_50/90, 2/4 μg/ml), while it was less active against multidrug-resistant A. baumannii (MIC_50/90, 8/16 μg/ml) and Burkholderia cepacia (MIC_50/90, 8/32 μg/ml).     

In Vitro Activity of Biapenem plus RPX7009, a Carbapenem Combined with a Serine β-Lactamase Inhibitor,against Anaerobic Bacteria

Biapenem is a carbapenem being developed in combination with RPX7009, a new inhibitor of serine β-lactamases. Biapenem was tested alone and in combination with fixed concentrations of RPX7009 by agar dilution against 377 recent isolates of anaerobes. A separate panel of 27 isolates of Bacteroides spp. with decreased susceptibility or resistance to imipenem was also tested. Comparator drugs included meropenem, piperacillin-tazobactam, ampicillin-sulbactam, cefoxitin, ceftazidime, metronidazole, clindamycin, and tigecycline plus imipenem, doripenem, and ertapenem for the 27 selected strains. For recent consecutive strains of Bacteroides species, the MIC₉₀ for biapenem-RPX7009 was 1 μg/ml, with a MIC₉₀ of 4 μg/ml for meropenem. Other Bacteroides fragilis group species showed a MIC₉₀ of 0.5 μg/ml for both agents. The MIC₉₀s for biapenem-RPX7009 were 0.25 μg/ml for Prevotella spp., 0.125 μg/ml for Fusobacterium nucleatum and Fusobacterium necrophorum, 2 μg/ml for Fusobacterium mortiferum, 0.5 μg/ml for Fusobacterium varium, ≤0.5 μg/ml for Gram-positive cocci and rods, and 0.03 to 8 μg/ml for clostridia. Against 5 B. fragilis strains harboring a known metallo-beta-lactamase, biapenem-RPX7009 MICs were comparable to those of other carbapenems (≥32 μg/ml). Against Bacteroides strains with an imipenem MIC of 2 μg/ml, biapenem-RPX7009 had MICs of 0.5 to 2 μg/ml, with MICs of 0.5 to 32 μg/ml for meropenem, doripenem, and ertapenem. For strains with an imipenem MIC of 4 μg/ml, the MICs for biapenem-RPX7009 were 4 to 16 μg/ml, with MICs of 8 to >32 μg/ml for meropenem, doripenem, and ertapenem. The inhibitor RPX7009 had no antimicrobial activity when tested alone, and it showed little or no potentiation of biapenem versus anaerobes. Biapenem-RPX7009 showed activity comparable to that of imipenem and was superior to meropenem, doripenem, and ertapenem against imipenem-nonsusceptible Bacteroides spp.     

In Vitro Activity of AZD0914, a Novel DNA Gyrase Inhibitor,against Chlamydia trachomatis and Chlamydia pneumoniae

The in vitro activities of AZD0914, levofloxacin, azithromycin, and doxycycline against 10 isolates each of Chlamydia trachomatis and Chlamydia pneumoniae were tested. For AZD0914, the MIC₉₀s for C. trachomatis and C. pneumoniae were 0.25 μg/ml (range, 0.06 to 0.5 μg/ml) and 1 μg/ml (range, 0.25 to 1 μg/ml), respectively, and the minimal bactericidal concentrations at which 90% of the isolates were killed (MBC₉₀s) were 0.5 μg/ml for C. trachomatis (range, 0.125 to 1 μg/ml) and 2 μg/ml for C. pneumoniae (range, 0.5 to 2 μg/ml).     

In Vitro Activity of Plazomicin against 5,015 Gram-Negative and Gram-Positive Clinical Isolates Obtained from Patients in Canadian Hospitals as Part of the CANWARD Study, 2011-2012

Plazomicin is a next-generation aminoglycoside that is not affected by most clinically relevant aminoglycoside-modifying enzymes. The in vitro activities of plazomicin and comparator antimicrobials were evaluated against a collection of 5,015 bacterial isolates obtained from patients in Canadian hospitals between January 2011 and October 2012. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with MICs interpreted according to CLSI breakpoints, when available. Plazomicin demonstrated potent in vitro activity against members of the family Enterobacteriaceae, with all species except Proteus mirabilis having an MIC₉₀ of ≤1 μg/ml. Plazomicin was active against aminoglycoside-nonsusceptible Escherichia coli, with MIC₅₀ and MIC₉₀ values identical to those for aminoglycoside-susceptible isolates. Furthermore, plazomicin demonstrated equivalent activities versus extended-spectrum β-lactamase (ESBL)-producing and non-ESBL-producing E. coli and Klebsiella pneumoniae, with 90% of the isolates inhibited by an MIC of ≤1 μg/ml. The MIC₅₀ and MIC₉₀ values for plazomicin against Pseudomonas aeruginosa were 4 μg/ml and 16 μg/ml, respectively, compared with 4 μg/ml and 8 μg/ml, respectively, for amikacin. Plazomicin had an MIC₅₀ of 8 μg/ml and an MIC₉₀ of 32 μg/ml versus 64 multidrug-resistant P. aeruginosa isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, with both having MIC₅₀ and MIC₉₀ values of 0.5 μg/ml and 1 μg/ml, respectively. In summary, plazomicin demonstrated potent in vitro activity against a diverse collection of Gram-negative bacilli and Gram-positive cocci obtained over a large geographic area. These data support further evaluation of plazomicin in the clinical setting.     

In Vitro Activities of Cefminox against Anaerobic Bacteria Compared with Those of Nine Other Compounds

The agar dilution MIC method was used to test the activity of cefminox, a β-lactamase-stable cephamycin, compared with those of cefoxitin, cefotetan, moxalactam, ceftizoxime, cefotiam, cefamandole, cefoperazone, clindamycin, and metronidazole against 357 anaerobes. Overall, cefminox was the most active β-lactam, with an MIC at which 50% of isolates are inhibited (MIC₅₀) of 1.0 μg/ml and an MIC₉₀ of 16.0 μg/ml. Other β-lactams were less active, with respective MIC₅₀s and MIC₉₀s of 2.0 and 64.0 μg/ml for cefoxitin, 2.0 and 128.0 μg/ml for cefotetan, 2.0 and 64.0 μg/ml for moxalactam, 4.0 and >128.0 μg/ml for ceftizoxime, 16.0 and >128.0 μg/ml for cefotiam, 8.0 and >128.0 μg/ml for cefamandole, and 4.0 and 128.0 μg/ml for cefoperazone. The clindamycin MIC₅₀ and MIC₉₀ were 0.5 and 8.0 μg/ml, respectively, and the metronidazole MIC₅₀ and MIC₉₀ were 1.0 and 4.0 μg/ml, respectively. Cefminox was especially active against Bacteroides fragilis (MIC₉₀, 2.0 μg/ml), Bacteroides thetaiotaomicron (MIC₉₀, 4.0 μg/ml), fusobacteria (MIC₉₀, 1.0 μg/ml), peptostreptococci (MIC₉₀, 2.0 μg/ml), and clostridia, including Clostridium difficile (MIC₉₀, 2.0 μg/ml). Time-kill studies performed with six representative anaerobic species revealed that at the MIC all compounds except ceftizoxime were bactericidal (99.9% killing) against all strains after 48 h. At 24 h, only cefminox and cefoxitin at 4× the MIC and cefoperazone at 8× the MIC were bactericidal against all strains. After 12 h, at the MIC all compounds except moxalactam, ceftizoxime, cefotiam, cefamandole, clindamycin, and metronidazole gave 90% killing of all strains. After 3 h, cefminox at 2× the MIC produced the most rapid effect, with 90% killing of all strains.     

Antimicrobial Activity of Ceftaroline Tested against Staphylococci with Reduced Susceptibility to Linezolid,Daptomycin, or Vancomycin from U.S. Hospitals, 2008 to 2011

Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, ≥8 μg/ml), 18 (0.09%) to daptomycin (MIC, ≥2 μg/ml), and 369 (1.9%) to vancomycin (MIC, ≥2 μg/ml; 368 isolates at 2 μg/ml and 1 at 4 μg/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, ≥8 μg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, ≥2 μg/ml). Ceftaroline was very active against S. aureus overall (MIC_50/90, 0.5/1 μg/ml; 98.5% susceptible), including MRSA (MIC_50/90, 0.5/1 μg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of ≥2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC_50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤1 μg/ml), including methicillin-resistant (MIC_50/90, 0.25/0.5 μg/ml), linezolid-resistant (MIC_50/90, 0.5/0.5 μg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 μg/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.     

Baseline Activity of Telavancin against Gram-Positive Clinical Isolates Responsible for Documented Infections in U.S. Hospitals (2011-2012) as Determined by the Revised Susceptibility Testing Method

Telavancin had MIC₅₀ and MIC₉₀ values of 0.03 and 0.06 μg/ml (100.0% susceptible), respectively, against methicillin-resistant and -susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.12/0.12 μg/ml; 100% susceptible) and Enterococcus faecium (MIC_50/90, 0.03/0.06 μg/ml), while higher MIC values were obtained against vancomycin-resistant E. faecium (MIC_50/90, 1/2 μg/ml) and E. faecalis (MIC_50/90, >2/>2 μg/ml). Streptococci showed telavancin modal MIC results of ≤0.015 μg/ml, except against Streptococcus agalactiae (i.e., 0.03 μg/ml). This study reestablishes the telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilution method.     

Ceftobiprole Activity against over 60,000 Clinical Bacterial Pathogens Isolated in Europe,Turkey, and Israel from 2005 to 2010

Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the in vitro antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible Staphylococcus aureus (MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and Streptococcus pneumoniae (99.3% susceptible), with MIC₉₀ values of 0.25, 0.12, ≤0.06, and 0.5 μg/ml, respectively. Ceftobiprole was active against methicillin-resistant S. aureus (MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC₉₀ of 2 μg/ml. Ceftobiprole was active against Enterococcus faecalis (MIC_50/90, 0.5/4 μg/ml) but not against most Enterococcus faecium isolates. Ceftobiprole was very potent against the majority of Enterobacteriaceae (87.3% susceptible), with >80% inhibited at ≤0.12 μg/ml. The potency of ceftobiprole against Pseudomonas aeruginosa (MIC_50/90, 2/>8 μg/ml; 64.6% at MIC values of ≤4 μg/ml) was similar to that of ceftazidime (MIC_50/90, 2/>16 μg/ml; 75.4% susceptible), but limited activity was observed against Acinetobacter spp. and Stenotrophomonas maltophilia. High activity was also observed against all Haemophilus influenzae (MIC₉₀, ≤0.06 μg/ml) and Moraxella catarrhalis (MIC_50/90, ≤0.06/0.25 μg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens.     

Antimicrobial activity of DC-159a, a new fluoroquinolone, against 1,149 recently collected clinical isolates

The activity of DC-159a, a novel orally administered fluorinated quinolone, was evaluated by reference broth microdilution or agar dilution methods against 1,149 recently collected clinical isolates from five continents. Against pathogens associated with community-acquired respiratory tract infections (CA-RTIs), the MIC₉₀s were 0.12 μg/ml for Streptococcus pneumoniae, 0.015 to 0.03 μg/ml for Haemophilus influenzae, 0.03 μg/ml for Moraxella catarrhalis, and 0.12 μg/ml for beta-hemolytic streptococci. Similarly, DC-159a was potent against various types of staphylococci (MIC₉₀ range, 0.03 to 2 μg/ml), Enterococcus faecalis (MIC₉₀, 4 μg/ml), wild-type isolates of the family Enterobacteriaceae (MIC₉₀ range, 0.06 to 2 μg/ml), wild-type Pseudomonas aeruginosa (MIC₉₀, 2 μg/ml), and Acinetobacter spp. (MIC₉₀, 0.12 μg/ml). Fluoroquinolone-nonsusceptible organism subsets usually had elevated DC-159a MICs, but the MICs were often two- to fourfold lower than those of levofloxacin and moxifloxacin. In conclusion, DC-159a appears to possess a balanced broad spectrum of activity that exceeds the activities of the currently marketed fluoroquinolones, especially against pathogens that cause CA-RTIs.     

Safety,Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (C_max) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC_{0–72 h}) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t_1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC_{0–72 h} and AUC_0–∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01944774","term_id":"NCT01944774"}}NCT01944774.)     

Ceftazidime-Avibactam Activity Tested against Enterobacteriaceae Isolates from U.S. Hospitals (2011 to 2013) and Characterization of β-Lactamase-Producing Strains

Ceftazidime-avibactam (MIC_50/90, 0.12/0.25 μg/ml) inhibited 99.9% (20,698/20,709) of Enterobacteriaceae isolates at ≤8 μg/ml. This compound was active against resistant subsets, including ceftazidime-nonsusceptible Enterobacter cloacae (MIC_50/90, 0.25/0.5 μg/ml) and extended-spectrum β-lactamase (ESBL) phenotype isolates. An ESBL phenotype was noted among 12.4% (1,696/13,692 isolates from targeted species) of the isolates, including 776 Escherichia coli (12.0% for this species; MIC_50/90, 0.12/0.25 μg/ml), 721 Klebsiella pneumoniae (16.3%; MIC_50/90, 0.12/0.25 μg/ml), 119 Klebsiella oxytoca (10.3%; MIC_50/90, 0.06/0.25 μg/ml), and 80 Proteus mirabilis (4.9%; MIC_50/90, 0.06/0.12 μg/ml) isolates. The most common enzymes detected among ESBL phenotype isolates from 2013 (n = 743) screened using a microarray-based assay were CTX-M-15-like (n = 307), KPC (n = 120), SHV ESBLs (n = 118), and CTX-M-14-like (n = 110). KPC producers were highly resistant to comparators, and ceftazidime-avibactam (MIC_50/90, 0.5/2 μg/ml) and tigecycline (MIC_50/90, 0.5/1 μg/ml; 98.3% susceptible) were the most active agents against these strains. Meropenem (MIC_50/90, ≤0.06/≤0.06 μg/ml) and ceftazidime-avibactam (MIC_50/90, 0.12/0.25 μg/ml) were active against CTX-M-producing isolates. Other enzymes were also observed, and ceftazidime-avibactam displayed good activity against the isolates producing less common enzymes. Among 11 isolates displaying ceftazidime-avibactam MIC values of >8 μg/ml, three were K. pneumoniae strains producing metallo-β-lactamases (all ceftazidime-avibactam MICs, >32 μg/ml), with two NDM-1 producers and one K. pneumoniae strain carrying the bla_KPC-2 and bla_VIM-4 genes. Therapeutic options for isolates producing β-lactamases may be limited, and ceftazidime-avibactam, which displayed good activity against strains, including those producing KPC enzymes, merits further study in infections where such organisms occur.