Assessment of pharmacokinetics-pharmacodynamics to support omadacycline dosing regimens for the treatment of patients with acute bacterial skin and skin structure infections.

Pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy were evaluated using data from omadacycline-treated patients with acute bacterial skin and skin structure infections (ABSSSI) enrolled in two phase 3 studies. Patients received omadacycline 100 mg intravenously (IV) every 12 hours for two doses, followed by 100 mg IV every 24 hours (q24h), with the option to switch to 300 mg oral (PO) q24h after 3 days or 450 mg PO q24h for two doses, followed by 300 mg PO q24h for a total duration of 7-14 days. Clinical response was evaluated at 48-72 hours [early clinical response (ECR)], end of treatment (EOT), and 7-14 days after EOT. Using a population pharmacokinetic (PK) model and PK data from patients with Staphylococcus aureus at baseline, omadacycline free-drug plasma area under the concentration-time curve (AUC) values were determined, and the relationships between free-drug plasma AUC:MIC ratio and dichotomous efficacy endpoints were evaluated. Using these relationships, the population PK model, simulation, and an omadacycline MIC distribution for S. aureus, mean percent probabilities of response were evaluated. Statistically significant PK--PD relationships were identified for ECR (P = 0.016 and 0.013 for optimized two- and three-group free-drug plasma AUC:MIC ratios, respectively). At an MIC value of 0.5 µg/mL, percent probabilities of model-predicted success for ECR based on the univariable PK-PD relationships using continuous and two-group free-drug plasma AUC:MIC ratio variables were 91.9 and 95.6%, respectively, for the IV-to-PO dosing regimen and 89.3 and 88.4%, respectively, for the PO-only dosing regimen. These data support for omadacycline IV-to-PO and PO-only dosing regimens for ABSSSI and an omadacycline susceptibility breakpoint of 0.5 µg/mL for S. aureus.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses Evaluating Omadacycline Dosing Regimens for the Treatment of Patients with Community-Acquired Bacterial Pneumonia Arising from Streptococcus pneumoniae and Haemophilus influenzae.

Omadacycline, a novel aminomethylcycline with in vitro activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and Haemophilus influenzae, is approved in the United States to treat patients with community-acquired bacterial pneumonia (CABP). Using nonclinical pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy and in vitro surveillance data for omadacycline against S. pneumoniae and H. influenzae, and a population pharmacokinetic model, PK-PD target attainment analyses were undertaken using total-drug epithelial lining fluid (ELF) and free-drug plasma exposures to evaluate omadacycline 100 mg intravenously (i.v.) every 12 h or 200 mg i.v. every 24 h (q24h) on day 1, followed by 100 mg i.v. q24h on day 2 and 300 mg orally q24h on days 3 to 5 for patients with CABP. Percent probabilities of PK-PD target attainment on days 1 and 2 by MIC were assessed using the following four approaches for selecting PK-PD targets: (i) median, (ii) second highest, (iii) highest, and (iv) randomly assigned total-drug ELF and free-drug plasma ratio of the area under the concentration-time curve to the MIC (AUC/MIC ratio) targets associated with a 1-log10 CFU reduction from baseline. Percent probabilities of PK-PD target attainment based on total-drug ELF AUC/MIC ratio targets on days 1 and 2 were ≥91.1% for S. pneumoniae for all approaches but the highest target and ≥99.2% for H. influenzae for all approaches at MIC90s (0.12 and 1 µg/mL for S. pneumoniae and H. influenzae, respectively). Lower percent probabilities of PK-PD target attainment based on free-drug plasma AUC/MIC ratio targets were observed for randomly assigned and the highest free-drug plasma targets for S. pneumoniae and for all targets for H. influenzae. These data provided support for approved omadacycline dosing regimens to treat patients with CABP and decisions for the interpretive criteria for the in vitro susceptibility testing of omadacycline against these pathogens.

Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model.

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data.

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane, or Meropenem: the Pharmacological Basis for a Stand-Alone ß-Lactamase Inhibitor.

A major challenge in treating patients is the selection of the "right" antibiotic regimen. Given that the optimal ß-lactam/ß-lactamase inhibitor pair is dependent upon the spectrum of ß-lactamase enzymes produced and the frequency of resistance to the ß-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the "right" ß-lactam rather than only in a fixed combination. We describe herein a one-compartment in vitro infection model studies conducted to identify the magnitudes of the pharmacokinetic-pharmacodynamic (PK-PD) index for a ß-lactamase inhibitor, CB-618, that would restore the activity of four ß-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with various doses (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (n = 5), Escherichia coli (n = 2), and Enterobacter cloacae (n = 1) strains, which produced a wide variety of ß-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, and TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each ß-lactam partner. The magnitudes of the CB-618 ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (i.e., the AUC/MIC ratio) associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone ß-lactamase inhibitor.

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against ß-lactamase-producing Escherichia coli in a hollow-fibre infection model.

The proliferation of multidrug-resistant Gram-negative pathogens has been exacerbated by a lack of novel agents in current development by pharmaceutical companies. Ceftolozane/tazobactam was recently approved by the FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. In the present study, the activity of ceftolozane/tazobactam against four isogenic Escherichia coli strains was investigated in a hollow-fibre infection model simulating various clinical dosing regimens. The four investigational E. coli strains included #2805 (no ß-lactamase), #2890 (AmpC ß-lactamase), #2842 (CMY-10 ß-lactamase) and #2807 (CTX-M-15 ß-lactamase). Each strain was exposed to regimens simulating 1 g ceftolozane, 2 g ceftolozane, 1 g ceftolozane/0.5 g tazobactam, and 2 g ceftolozane/1 g tazobactam utilising a starting inoculum of ca. 106 CFU/mL. Whereas 1 g of ceftolozane eradicated strains #2805 and #2842 without subsequent regrowth, 1 g ceftolozane/0.5 g tazobactam was required to eradicate strain #2890. For strain #2890, ceftolozane monotherapy led to bacterial growth on plates impregnated with 20 mg/L ceftolozane by 24 h, whilst combination treatment with tazobactam completely suppressed the development of ceftolozane resistance. In contrast, none of the regimens, including 2 g ceftolozane/1 g tazobactam, were able to entirely suppress bacterial growth in strain #2807, with bacterial counts exceeding 108 CFU/mL by 48 h and ceftolozane-resistant populations being amplified after 24 h. Thus, the combination of ceftolozane and tazobactam achieved bactericidal activity followed by sustained killing over 10 days for three of four isogenic E. coli strains. Ceftolozane/tazobactam is a promising new agent to counter multidrug-resistant Gram-negative bacteria.

Pharmacokinetics-Pharmacodynamics of a Novel ß-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model.

The usefulness of ß-lactam antimicrobial agents is threatened as never before by ß-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum ß-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartment in vitro infection model to determine the exposure measure for CB-618, a novel ß-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel included Enterobacteriaceae clinical isolates, which collectively produced a wide range of ß-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challenge Klebsiella pneumoniae isolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10 CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0-24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0-24 (r(2) = 0.835) and Cmax (r(2) = 0.826). Using the CB-618 AUC0-24 indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10 CFU/ml at 24 h and CB-618 AUC0-24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0-24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined ß-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of ß-Lactam-ß-Lactamase Inhibitor Combinations.

Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains ofEscherichia colithat differed in the type of ß-lactamase they expressed. The four investigational strains included 2805 (no ß-lactamase), 2890 (AmpC ß-lactamase), 2842 (CMY-10 ß-lactamase), and 2807 (CTX-M-15 ß-lactamase), with MICs to ceftolozane of 0.25, 4, 8, and >128 mg/liter with no tazobactam, and MICs of 0.25, 1, 4, and 8 mg/liter with 4 mg/liter tazobactam, respectively. All four strains were exposed to a 6 by 5 array of ceftolozane (0, 1, 4, 16, 64, and 256 mg/liter) and tazobactam (0, 1, 4, 16, and 64 mg/liter) over 48 h using starting inocula of 10(6)and 10(8)CFU/ml. While ceftolozane-tazobactam achieved bactericidal activity against all 4 strains, the concentrations of ceftolozane and tazobactam required for a ≥3-log reduction varied between the two starting inocula and the 4 strains. At both inocula, the Hill plots (R(2)> 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC50s) at tazobactam concentrations of ≤4 mg/liter than those at concentrations of ≥16 mg/liter (P< 0.01). Moreover, the EC50s at 10(8)CFU/ml were 2.81 to 66.5 times greater than the EC50s at 10(6)CFU/ml (median, 10.7-fold increase;P= 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of ß-lactamase-producingE. colistrains.

Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model.

We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using anin vitroinfection model and the same isogenic CTX-M-15-producingEscherichia colitriplet set genetically engineered to transcribe different levels ofblaCTX-M-15, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different ß-lactam agent, or differentblaCTX-M-15transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 µg/ml for the low-, moderate-, and high-level CTX-M-15-producingE. colistrains, respectively. The MIC value for piperacillin in the presence of 4 µg/ml of tazobactam was 2 µg/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of ß-lactamase transcription (r(2)= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 µg/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2)= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log10-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a ß-lactam-ß-lactamase inhibitor combination is dependent on the amount of ß-lactamase produced. These data provide important information for the development of ß-lactam-ß-lactamase inhibitor combination agents.

Relationship between ceftolozane-tazobactam exposure and selection for Pseudomonas aeruginosa resistance in a hollow-fiber infection model.

It is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. Two Pseudomonas aeruginosa challenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.5 mg/liter) and a clinical isolate (ceftolozane-tazobactam MIC, 4 mg/liter). The experiment duration was 10 days, and the ceftolozane-tazobactam dose ratio (2:1) and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The studied ceftolozane-tazobactam dosing regimens ranged from 62.5/31.25 to 2,000/1,000 mg per dose in step fold dilutions. Negative-control arms included no treatment and tazobactam at 500 mg every 8 h. Positive-control arms included ceftolozane at 1 g every 8 h and piperacillin-tazobactam dosed at 4.5 g every 6 h. For the wild-type ATCC strain, resistance was not selected by any ceftolozane-tazobactam regimen evaluated. For the clinical isolate, an inverted-U-shaped function best described the relationship between the amplification of a drug-resistant subpopulation and drug exposure. The least (62.5/31.25 mg) and most (2,000/1,000 mg) intensive ceftolozane-tazobactam dosing regimens did not select for drug resistance. Drug resistance selection was observed with intermediately intensive dosing regimens (125/62.5 through 1,000/500 mg). For the intermediately intensive ceftolozane-tazobactam dosing regimens, the duration until the selection for drug resistance increased with dose regimen intensity. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance selection.

Pharmacological basis of ß-lactamase inhibitor therapeutics: tazobactam in combination with Ceftolozane.

We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single ß-lactamase enzyme and that clinical isolates typically produce multiple ß-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized ß-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r(2) values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r(2) value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized ß-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E. coli isolates performed well for the expanded data set (seven isolates in total; four E. coli and three K. pneumoniae), as evidenced by an r(2) value of 0.84. This simple translational relationship is especially useful as it is directly linked to in vitro susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.

Relationship between ceftolozane-tazobactam exposure and drug resistance amplification in a hollow-fiber infection model.

In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of blaCTX-M-15. This organism's blaCTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), ß-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.

Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model.

Despite ß-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla(CTX-M-15). These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 µg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different bla(CTX-M-15) transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and ß-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r(2) = 0.938). The threshold concentrations identified were 0.05 µg/ml for low and moderate and 0.25 µg/ml for the high-ß-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log10 CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.

Clinical outcomes of patients receiving daptomycin for the treatment of Staphylococcus aureus infections and assessment of clinical factors for daptomycin failure: a retrospective cohort study utilizing the Cubicin Outcomes Registry and Experience.

BACKGROUND: Daptomycin is most commonly used as a second-line treatment. Previous studies have not differentiated the effect of prior antibiotic therapy on daptomycin clinical outcomes. OBJECTIVES: The primary objective of this study was to compare clinical outcomes of patients treated with daptomycin as first-line therapy versus after prior antibiotic therapy (specifically, vancomycin). A secondary objective was to identify other factors associated with the clinical failure of daptomycin therapy. METHODS: This was a retrospective cohort study using data from a postlabeling registry database. The effects of relevant patient characteristics on the clinical outcome of individuals treated for Staphylococcus aureus infections with daptomycin were examined in an unblinded approach using univariate and multivariate analyses. Only patients with an evaluable clinical outcome (ie, cure, improvement, failure) and culture-confirmed S aureus infection were included in the analysis cohort. RESULTS: Of 1227 clinically evaluable patients, 250 (20%) received daptomycin as first-line therapy and 977 (80%) received daptomycin after other prior antibiotic therapy. Overall, 53% of patients were male; 64% were aged 31 to 65 years and 26% were aged >or=66 years. Race information was collected beginning in 2007; of the patients studied, 71% were white and 18% were black. The initial daptomycin dose (mean [SD]) overall was 5.1 (1.1) mg/kg and was highest for patients with endocarditis (5.9 [1.2] mg/kg) and lowest for those with uncomplicated skin and skin structure infections (4.4 [0.9] mg/kg). Clinical success, defined as an outcome of cured or improved at the end of daptomycin therapy, was reported for 1140 (93%) of the 1227 evaluable patients. The clinical success rates for first-line therapy with daptomycin and after prior antibiotics were both 93%. Using univariate analysis, 8 variables were associated with clinical failure (receipt of daptomycin in an intensive care unit setting, severe renal dysfunction [creatinine clearance <30 mL/min], dialysis, diabetes mellitus (DM), concomitant antibiotics, bacteremia, endocarditis, and failure of prior vancomycin therapy) and 3 with clinical success (outpatient daptomycin therapy and complicated and uncomplicated skin and skin structure infections). Using the stepwise multivariate regression analysis, only the presence of endocarditis (odds ratio [OR] = 2.56; 95% CI, 1.18-5.54; P = 0.017), bacteremia (OR = 1.77; 95% CI, 1.04-3.02; P = 0.037), severe renal dysfunction (OR = 1.78; 95% CI, 1.05-3.03; P = 0.034), and DM (OR = 1.79; 95% CI, 1.10-2.93; P = 0.02) were identified as factors independently associated with clinical failure of daptomycin therapy. Of the remaining patients, 9% were aged 18 to 30 years and 0.7% were aged 12 to 17 years. CONCLUSIONS: In this retrospective study, after controlling for clinical factors that are associated with suboptimal outcomes, clinical outcomes with daptomycin did not differ whether it was used as first-line therapy or after other antibiotics. Endocarditis, bacteremia, severe renal dysfunction, and DM were associated with higher rates of clinical failure of daptomycin treatment.

Evidence for daptomycin Etest lot-related MIC elevations for Staphylococcus aureus.

MIC testing was performed simultaneously by Etest and broth microdilution (BMD) on 587 Staphylococcus aureus isolates submitted by local laboratories to a reference laboratory for confirmatory testing (May 2005 to July 2008). Testing bias was assessed for Etest to BMD MIC ratios. Categoric and essential agreement, very major (BMD nonsusceptible, Etest susceptible), and major (BMD susceptible, Etest nonsusceptible) errors were evaluated. Agar and broth calcium concentrations were consistent with current Clinical and Laboratory Standards Institute and manufacturer recommendations. There was a consistent bias for higher Etest MIC values compared with BMD. Ratios ranged from 0.25 to 4 (average 1.3), with substantial variability noted among the 8 different Etest lots tested. Overall, 6% of all ratios were >2.0. Categoric agreement and essential agreement among the 8 Etest lots ranged from 73% to 96% and 74% to 100%, respectively; very major errors ranged from 3% to 9%, and major errors ranged from 6% to 35%. However, most of the discrepancies were limited to 3 Etest lots.

Daptomycin for the treatment of enterococcal bacteraemia: results from the Cubicin Outcomes Registry and Experience (CORE).

Enterococcal infections are a common cause of nosocomial bloodstream infections. Vancomycin resistance and the emergence of linezolid resistance necessitate alternative therapies. Studies in vitro as well as animal and case studies suggest that daptomycin may be effective in enterococcal infections. Patients with positive blood cultures for enterococci in the Cubicin((R)) Outcomes Registry and Experience (CORE) 2005-2006 were identified. Patients with endocarditis, intracardiac foreign body infections or non-speciated enterococci were excluded. Outcome was assessed using protocol-defined criteria. Of 159 patients included in the efficacy population, Enterococcus faecium and Enterococcus faecalis were isolated in 120 (75.5%) and 39 (24.5%) patients, respectively. Vancomycin resistance was detected in 91% and 23% of patients with E. faecium and E. faecalis infections, respectively. Prior to daptomycin, 94/159 (59.1%) and 35/159 (22.0%) patients had received vancomycin and linezolid, respectively. Daptomycin was first-line therapy in 27/159 cases (17%). Success was observed in 139/159 patients (87%) and in 104/120 (87%) and 35/39 (90%) patients with E. faecium and E. faecalis infections, respectively. Among the safety population (n=211), 20 (9.5%) experienced 28 adverse events possibly related to daptomycin, 8 of which were considered serious. Daptomycin may be a useful agent for treating enterococcal bacteraemia caused by E. faecium or E. faecalis. Further studies are warranted.

Clinical experience with daptomycin for the treatment of patients with documented gram-positive septic arthritis.

BACKGROUND: Septic arthritis is considered a rheumatologic emergency that can lead to joint destruction and long-term impairment of joint function. Daptomycin is bactericidal in vitro against Staphylococcus aureus, the primary pathogen associated with septic arthritis. OBJECTIVE: To describe the use of daptomycin in patients with septic arthritis. METHODS: Data were collected as part of the Cubicin Outcomes Registry and Experience (CORE) program, a retrospective, observational, multicenter study, to describe the clinical use of daptomycin. Efficacy at the end of daptomycin therapy was determined by each center's investigator(s) as cure, improved, failure, or nonevaluable. Patients who had a diagnosis of septic arthritis, excluding concomitant osteomyelitis, as well as a positive culture by needle aspirate or deep tissue biopsy, were selected from the combined 2005 and 2006 CORE database. RESULTS: Twenty-two patients were included in this analysis. S. aureus was the most common pathogen isolated, with the majority resistant to methicillin. All patients received an antibiotic prior to daptomycin; in 7 patients, at least one of the prior antibiotics was continued with daptomycin. Almost two-thirds of patients received an antibiotic with daptomycin; rifampin was the most common. The median final dose and duration of daptomycin therapy were 5 mg/kg (range 3-6.3) and 22 days (range 3-52), respectively. Eighty-two percent of patients received daptomycin while admitted to a hospital; however, 68% received at least part of their daptomycin therapy as an outpatient. The outcomes of cure or improved were reported in 41% and 50% of the patients, respectively. Two adverse events were reported; neither was considered to be related to daptomycin. CONCLUSIONS: Daptomycin appeared to be effective when used as part of a treatment regimen for septic arthritis. These results require verification via a prospective clinical trial.

Daptomycin in the treatment of bacteremia.

The aim of this study was to describe the clinical experience with daptomycin in the treatment of bacteremia. Patients with a diagnosis of catheter-related or non-catheter-related bacteremia and no other concurrent infection were identified from the Cubicin Outcomes Registry and Experience (CORE) 2004. Treatment success was determined by investigators using protocol criteria and defined as cure or improvement. Of 168 patients with bacteremia, 126 were clinically evaluable. Of those, 52 (41%) patients were aged > or =66 years, 54 (43%) received daptomycin in an intensive care unit, and 25 (20%) had chronic renal failure. The most common pathogens isolated were methicillin-resistant Staphylococcus aureus (33%), vancomycin-resistant enterococci (30%), and coagulase-negative staphylococci (30%). Of 126 patients, 86% received daptomycin after previous antibiotic therapy and most (69%) received concomitant antibiotics with daptomycin. Daptomycin therapy was started at a median dose of 4.0 mg/kg (range, 2.5 to 9.2 mg/kg). Daptomycin therapy had an overall clinical success rate of 89%. Clinical success was independent of baseline renal function, daptomycin dose, pathogen, first-line use, or concomitant antibiotic therapy. These results support the findings of a recent study in which daptomycin was demonstrated to be an effective option in the treatment of S aureus bacteremia. Data in the current study provide insight into the clinical experience using daptomycin to treat bacteremia caused by other gram-positive pathogens. Given the limitations of retrospective studies and lack of follow-up data, additional studies are needed to make definitive evaluations with these pathogens.

Clinical experience with daptomycin for the treatment of patients with osteomyelitis.

Data from a registry were analyzed to describe the clinical experience with daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) for the treatment of patients with osteomyelitis. The Cubicin Outcomes Registry and Experience (CORE) 2004 database was used to identify patients treated for osteomyelitis. Posttherapy follow-up outcome assessments were collected for a subset of these patients. A total of 67 patients with osteomyelitis were clinically evaluable for outcome at the end of daptomycin therapy and had outcome assessed at a posttherapy visit. The median follow-up interval after the last dose of daptomycin was 76 days (range, 1 to 547 days). The median initial dose was 5.6 mg/kg (range, 3.2 to 7.5 mg/kg), and the median duration of therapy was 35 days (range, 3 to 546 days). Daptomycin was given concurrently with other antibiotics in 48% of cases. Methicillin-resistant Staphylococcus aureus was the most common pathogen (45%). Clinical outcomes at follow-up were cure, 42 (63%); improved, 13 (19%); failure, 7 (10%); and nonevaluable, 5 (7%). A total of 82% of patients with an orthopedic device (n = 17) were successfully treated, as were 88% of patients with concurrent bacteremia (n = 16). Failures were more likely if surgical debridement was not performed (24% vs. 5%; P = 0.045). The clinical success rate for patients treated with an initial daptomycin dose >4 mg/kg was significantly higher than for patients treated with an initial dose < or =4 mg/kg (88% vs. 65%; P = 0.013, chi2 test). Daptomycin had a 94% success rate when used alone with no follow-up antibiotics. The results indicate that daptomycin is being used in clinical practice to treat patients with osteomyelitis caused by gram-positive pathogens including MRSA. Prospective, controlled clinical trials of daptomycin are warranted that include rigorous data collection and long-term follow-up analysis.

Cubicin Outcomes Registry and Experience (CORE) methodology.

The Cubicin Outcomes Registry and Experience (CORE), was designed to retrospectively collect the real-world postmarking experience of patients who received daptomycin. A standardized case report form was used by trained investigators from 45 institutions across the United States. Data on 1,160 patients from November 2003 until December 2004 were collected on demographics, infections, treatments and outcomes at the end of daptomycin therapy. The data from CORE 2004 provide insight into the early clinical use of daptomycin.