Community-acquired Bacterial Pneumonia Patients Research Articles

Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Omadacycline in the treatment of community-acquired bacterial pneumonia in patients with comorbidities: a post-hoc analysis of the phase 3 OPTIC trial.

The 2019 American Thoracic Society/Infectious Disease Society of America guidelines recommend respiratory fluoroquinolones to treat community-acquired bacterial pneumonia (CABP) in adults with comorbidities. Fluoroquinolones are effective against both typical and atypical pathogens. However, fluoroquinolone treatment has a risk of adverse effects, and the Food and Drug Administration has issued black box safety warnings for their use. Inpatient use of fluoroquinolones has reduced as a result; however, most antibiotic courses are completed as outpatients and discharge prescriptions account for the majority of fluoroquinolone use. As such, a new treatment option is needed to replace fluoroquinolones. Omadacycline is an aminomethylcycline antibiotic with a broad spectrum of activity and is available as a once-daily intravenous or bioequivalent oral formulation. This study assessed the safety and clinical efficacy of omadacycline compared with moxifloxacin for the treatment of adult CABP patients with Pneumonia Severity Index (PSI) risk class II/III and ≥1 comorbidity through a post-hoc analysis of the phase 3 OPTIC study (NCT02531438). In total, 239 omadacycline- and 222 moxifloxacin-treated patients were assessed. The median age was similar between groups (omadacycline: 57 years; moxifloxacin: 58 years), with 26.0% and 26.6%, respectively, ≥65 years of age. Early clinical response was 91.6% for patients with ≥1 comorbidity treated with omadacycline and 91.4% for those treated with moxifloxacin. Post-treatment evaluation results for overall response were 89.1% in the omadacycline group and 87.4% in the moxifloxacin group. Safety warnings have reduced inpatient use of fluoroquinolones; however, outpatient and discharge prescriptions account for the majority of fluoroquinolone use. Outpatients with comorbidities need an efficacious alternative to fluoroquinolones. Omadacycline maintains the similar efficacy and benefits of fluoroquinolones as a once-daily, monotherapy, bioequivalent oral option with potent in vitro activity against the most common CABP pathogens, including S. pneumoniae and atypical pathogens, but offers a materially different safety profile consistent with its tetracycline heritage. In conclusion, both omadacycline and moxifloxacin exhibited similar efficacy in patients with PSI risk class II/III and comorbidities. Omadacycline fulfills an unmet need as an oral monotherapy treatment option for adult patients with CABP, which will further reduce the use of fluoroquinolones. https://www.clinicaltrials.gov/study/NCT02531438, identifer: NCT02531438; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004071-13, identifier: EudraCT #2013-004071-13.

Potential Cost Savings Associated with Targeted Substitution of Current Guideline-Concordant Inpatient Agents with Omadacycline for the Treatment of Adult Hospitalized Patients with Community-Acquired Bacterial Pneumonia at High Risk for Clostridioides difficile Infections: Results of Healthcare-Decision Analytic Model from the United States Hospital Perspective

Introduction: Approximately 3% of hospitalized patients with community-acquired bacterial pneumonia (CABP) develop healthcare-associated Clostridioides difficile infection (HCA-CDI). The validated Davis risk score (DRS) indicates that patients with a DRS ≥ 6 are at an increased risk of 30-day HCA-CDI. In the phase 3 OPTIC CABP study, 14% of CABP patients with DRS ≥ 6 who received moxifloxacin developed CDI vs. 0% for omadacycline. This study assessed the potential economic impact of substituting current guideline-concordant CABP inpatient treatments with omadacycline in hospitalized CABP patients with a DRS ≥ 6 across US hospitals. Methods: A deterministic healthcare-decision analytic model was developed. The model population was hospitalized adult CABP patients with a DRS ≥ 6 across US hospitals (100,000 patients). In the guideline-concordant arm, 14% of CABP patients with DRS ≥ 6 were assumed to develop an HCA-CDI, each costing USD 20,100. In the omadacycline arm, 5 days of therapy was calculated for the entire model population. Results: The use of omadacycline in place of guideline-concordant CABP inpatient treatments for CABP patients with DRS ≥ 6 was estimated to result in cost savings of USD 55.4 million annually across US hospitals. Conclusion: The findings of this simulated model suggest that prioritizing the use of omadacycline over current CABP treatments in hospitalized CABP with a DRS ≥ 6 may potentially reduce attributable HCA-CDI costs. The findings are not unique to omadacycline and could be applied to any antibiotic that confers a lower risk of HCA-CDI relative to current CABP inpatient treatments.

1492. Targeted Substitution of Omadacycline in Place of Standard of Care for CABP Treatment is Associated with a Risk Reduction of Clostridioides difficile Infection and Financial Cost Savings in the Acute Care Setting

BackgroundReal-world evidence studies indicate that around 3% of hospitalized patients with community-acquired pneumonia (CAP) develop Clostridioides difficile infection (CDI; Chalmers et al, J Infect 2016;73:45–53). Factors associated with increased CDI risk include Davis risk score (DRS) ≥ 6, and treatment with high-risk antibiotics such as fluroquinolones (FQ) and ceftriaxone (CTX). Omadacycline (OMC) is indicated for the treatment of community-acquired bacterial pneumonia (CABP) and has demonstrated a low propensity to induce CDI in preclinical and clinical studies. In the phase 3 OPTIC study, 2% of CABP patients who received moxifloxacin (MOX) developed CDI vs 0% for OMC (Stets et al, N Engl J Med 2019;380:517–27); 14% of MOX patients with DRS ≥ 6 developed CDI vs 0% in the OMC group (Table 1; Figure 1). We assessed the economic impact of substituting current CABP treatment (FQ and CTX) with OMC for hospitalized CABP patients with DRS ≥ 6.Table 1 Figure 1 MethodsA deterministic healthcare-decision analytic model was performed. Only excess costs associated with each treatment were considered. Base-case model inputs were: yearly CAP admission in US, prevalence of CAP patients with DRS ≥ 6, CDI risk for CAP patients with DRS ≥ 6 with current CABP treatments, CDI costs (initial and recurrent), and OMC cost (Table 2). Efficacy and safety of treatments were assumed to be equal. CDI risk of 0% was assumed for OMC. Costs are reported as USD.Table 2 ResultsFor patients with CABP, total CDI costs were $738M, with first-episode costs of $489M plus recurrence costs of $249M. The cost of 5 days (mean hospital length of stay for CABP) of OMC was $207M. Use of OMC for the estimated 100,000 CABP patients with DRS ≥ 6 would result in a potential cost saving of up to $531M for this patient population, assuming CDI risk of 0% with OMC. As CDI is a risk from any antibiotic use, cost savings can be achieved when OMC is used in place of high-risk antibiotics patients when CDI risk rates exceed 3.9%.ConclusionOur findings suggest prioritizing use of omadacycline over current CABP treatments in hospitalized CABP with a DRS ≥ 6 may substantially reduce attributable CDI costs. These results can serve as a basis for stewardship interventions to reduce hospital CDI rates and associated costs.DisclosuresMauricio Rodriguez, PharmD, BCPS, BCCCP, BCIDP, Paratek Pharmaceuticals, Inc. (Employee) Surya Chitra, PhD, Paratek Pharmaceuticals, Inc. (Consultant) Kelly Wright, PharmD, Paratek Pharmaceuticals, Inc. (Employee, Shareholder) Thomas Lodise, PharmD, PhD, Paratek Pharmaceuticals, Inc. (Consultant)

722. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Hepatic Function

BackgroundPatients with chronic liver disease (CLD) have impaired immune function, are prone to community-acquired bacterial pneumonia (CABP), and experience greater morbidity/mortality and healthcare costs than CABP patients without CLD. LEF, a novel pleuromutilin antibiotic (IV/oral) with primary liver elimination, was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with hepatic impairment.MethodsIn this open-label study, subjects were allocated to 1 of 3 groups based on hepatic function level; Moderate (Child-Pugh score 7–9) or Severe subjects (Child-Pugh score ≥10) were matched (gender, age, and weight) to subjects in the Normal group (normal hepatic function, no liver cirrhosis). Subjects received a single 1-hour 150 mg LEF infusion. Blood and urine samples were collected predose and over a 48-hour period postdose for PK analysis; plasma and urine were assayed for LEF and BC-8041 using validated assays. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms.Results27 subjects enrolled in and completed the study (n = 11, Normal; n = 8, Moderate; n = 8, Severe). Mean LEF and BC-8041 plasma concentration profiles were comparable across all hepatic function groups through the first 12 hours following the start of infusion. Subjects with hepatic impairment had slightly slower rates of elimination in the later elimination phases. LEF and BC-8041 exposures were similar across all hepatic function groups (table), and the majority of LEF and BC-8041 were excreted nonrenally. TEAEs were reported in 2 (18.2%) subjects in the Normal group, 2 (25%) in the Moderate group, and 1 (12.5%) in the Severe group. None of the TEAEs were serious or led to study drug discontinuation. No subject met Hy’s law criteria. Within 4 hours postdose, the maximum mean change from baseline in the QTcF interval was 12.4, 19.2, and 14.1 msec in the Normal, Moderate, and Severe groups, respectively.ConclusionNo dosage adjustment for LEF appears to be required when treating subjects with hepatic impairment. LEF was generally well tolerated in all subjects regardless of hepatic functional status. Disclosures All authors: No reported disclosures

2230. Analysis of the Microbiological Data from the Delafloxacin (DLX) Phase 3 Community-acquired Bacterial Pneumonia (CABP) Trial

BackgroundDLX is a novel fluoroquinolone (FQ) antibiotic with Gram-positive/MRSA, Gram-negative and atypical activity. It offers IV and oral treatment with no QT restrictions. In a Phase 3 study in CABP patients, DLX was non-inferior to moxifloxacin (MOX) in the primary endpoint, early clinical response at 96 ± 24 hours (88.9 vs. 89.0; 95% CI: −4.4, 4.1) in the intent-to-treat (ITT) population. A detailed microbiological analysis was conducted.MethodsCABP pathogens were identified by culture/non-culture methods. Pathogens identified by non-culture methods included Streptococcus pneumoniae (Sp; culture, urinary antigen [UA], nasopharyngeal [NP] swab lytA PCR), Legionella pneumophila (Lp) (culture, UA, serology), Mycoplasma pneumoniae (Mp; culture, serology), and Chlamydia pneumoniae (Cp; serology). All other pathogens were identified using culture only. For Sp cultured from NP, a concomitant lytA PCR value of ≥ 1000 gene copies/mL was required. All isolates underwent susceptibility testing, and a subset of isolates underwent molecular or phenotypic characterization including whole-genome sequencing for FQ resistance mechanisms, PCR for PVL/mecA genes (S. aureus), β-lactamases (Haemophilus/Moraxella spp), and serotyping (Sp).ResultsIncluded in submitted image.ConclusionDLX demonstrated potent in vitro and clinical activity against CABP pathogens, including Sp [MRSP, MDRSP, PRSP], MRSA, Haemophilus species, Enterobacteriaceae, P. aeruginosa, and the atypical pathogens Cp, Mp, and Lp. Disclosures All authors: No reported disclosures.

2234. Outcomes by Age and Gender from a Global Phase 3 Study of Delafloxacin (DLX) in Community-Acquired Bacterial Pneumonia (CABP)

BackgroundDelafloxacin (DLX) is a fluoroquinolone, approved in the United States for treatment of ABSSSI. DLX has no preclinical signals for QT prolongation and has no QT prolongation in a validated challenge study. Risk of QT prolongation is a consideration in antibiotic selection for elderly hospitalized CABP patients. A Phase 3 CABP trial with DLX was analyzed with a focus on age and gender.MethodsData on age and gender were reviewed from a multicenter, randomized, double-blind trial of adults with CABP. Patients were randomized 1:1 to DLX or moxifloxacin (MOX) treatment for 5–10 days. Patients received a minimum of 3 days of IV treatment, then were switched to oral at MD discretion. A key clinical endpoint was the investigator-assessment at Test of Cure (TOC) 5–10 days after the end of treatment. Clinical success was defined as complete or near resolution of signs and symptoms and no further antibiotics neededResultsIn the overall study, 859 patients were randomized with a mean age of 60 years (55.5% <65, 44.5% ≥65, 21.2% ≥75; range 18–93); 58.7% were male; 25.4% and 1.4% were PORT class IV and V; 28.6% multi-lobar pneumonia. Table shows the comparison of DLX and MOX clinical response at TOC in the Intent to Treat (ITT) population. Overall, DLX was well tolerated, with similar related adverse events (AE) between treatment groups regardless of age (< 65: 16.7% DLX, 13.3% MOX; ≥ 65: 13.4% DLX, 11.7% MOX) or gender (male: 16.0% DLX, 11.1% MOX; female 14.0% DLX, 14.9% MOX). The most common treatment-related AEs for DLX were diarrhea and transaminase elevations which were mild-to-moderate and did not routinely lead to discontinuation. There were no reports of potential QT prolongation on DLX.ConclusionBased on age and gender, DLX had comparable outcomes to MOX in clinical success at TOC. DLX was also well tolerated regardless of age or gender. DLX may offer a promising alternative in the treatment of CABP including elderly patients. Disclosures All authors: No reported disclosures.

DIAGNOSIS AND OUTCOMES IN PATIENTS WITH ATYPICAL PATHOGENS IN A PHASE-3 COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA TRIAL COMPARING DELAFLOXACIN TO MOXIFLOXACIN

SESSION TITLE: Monday Electronic Posters 1 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM PURPOSE: An etiological agent is often not identified at the time of diagnosis of community-acquired bacterial pneumonia (CABP) and as such, the Infectious Diseases Society of America/American Thoracic Society Guidelines recommend that empirical treatment cover atypical pathogens. Fluoroquinolones (FQ) have a spectrum of activity that covers gram-positive, gram-negative and atypical pathogens common in CABP. Delafloxacin (DLX) is a new FQ with activity against many Gram-positive FQ-resistant strains. A Phase 3 global, randomized, double-blind, active-controlled study was recently completed to evaluate IV-to-oral DLX compared with moxifloxacin (MOX) in the treatment of CABP. We report the clinical outcomes among patients with atypical pathogens. METHODS: CABP patients were randomized to receive 5-10 days of either DLX or MOX and could switch from IV to oral dosing after Day 3. Serologic diagnosis of Legionella pneumophila (Lp), Mycoplasma pneumoniae (Mp), and Chlamydophila pneumoniae (Cp) was made using paired acute and convalescent sera showing at least a 4-fold increase in titer. Additionally, Lp could be diagnosed by sputum culture or urinary antigen and Mp could be diagnosed by culture of oropharyngeal swabs. Susceptibility testing was performed on Lp and Mp isolates. Efficacy assessments were performed at 96 (±24) hours for Early Clinical Response (ECR) and at the Test of Cure (TOC) visit 5-10 days after the end of treatment. RESULTS: 859 patients were enrolled from sites in 18 countries, and a microbiological diagnosis (all pathogens) was established in 60.5% of patients. In the patients with baseline pathogens, Lp, Mp and Cp were detected in 11.9, 12.5 and 7.9% of these patients, respectively. Overall, 13.1% of microbial diagnoses were monomicrobial infections with atypical pathogens. DLX had potent activity against Mp and Lp. The DLX MIC90 was 0.5 μg/mL for Mp and the MICs ranged from 0.00025-0.001 μg/mL (n=4) for Lp. Overall DLX was non-inferior to MOX for the treatment of CABP in the primary outcome of ECR and by-pathogen success rates were high. In the evaluable population, ECR (DLX vs. MOX) was 93.1% vs. 87.5% for Lp, 85.7% vs. 96.7% for Mp, and 96.0% vs 87.5% for Cp. At the TOC visit, clinical success was 93.1% vs. 100% for Lp, 96.7% vs. 100% for Mp, and 100% vs 100% for Cp. CONCLUSIONS: Atypical pathogens were frequently identified in this Phase 3 study in CABP, including as monomicrobial infections. DLX, which is approved for treatment of acute bacterial skin and skin structure infections in the US, was confirmed as efficacious in monotherapy for CABP and provided comparable outcomes to MOX for the treatment of patients with atypical pathogens. CLINICAL IMPLICATIONS: DLX may be a useful treatment option for monotherapy in CABP on either an inpatient or outpatient basis when empirical coverage of atypical pathogens is desired. DISCLOSURES: Employee relationship with Melinta Please note: >$100000 Added 03/03/2019 by Sue Cammarata, source=Web Response, value=Salary Employee relationship with Melinta Therapeutics, Inc. Please note: >$100000 Added 03/04/2019 by Kara Keedy, source=Web Response, value=Salary Stock holder relationship with Melinta Therapeutics, Inc. Please note: $1001 - $5000 Added 03/12/2019 by Kara Keedy, source=Web Response, value=stock Employee relationship with Melinta Therapeutics Please note: >$100000 Added 03/12/2019 by Laura LAWRENCE, source=Web Response, value=Salary No relevant relationships by Yang Li, source=Web Response Employee $100000 Added 03/12/2019 by Sandra McCurdy, source=Web Response, value=Salary<br former employee relationship with Melinta Therapeutics Please note: >$100000 Added 03/12/2019 by Ashley Nenninger, source=Web Response, value=salary and stock Employee relationship with Melinta Therapeutics, Inc. Please note: >$100000 Added 03/12/2019 by Megan Quintas, source=Web Response, value=Salary Employee relationship with Melinta Therapeutics Inc Please note: >$100000 Added 03/12/2019 by Amanda Sheets, source=Web Response, value=Salary Stock holder relationship with Melinta Therapeutics Inc Please note: $1-$1000 Added 03/12/2019 by Amanda Sheets, source=Web Response, value=Consulting fee Removed 03/12/2019 by Amanda Sheets, source=Web Response Stock holder relationship with Melinta Therapeutics Inc Please note: $1001 - $5000 Added 03/12/2019 by Amanda Sheets, source=Web Response, value=Stock

1462. Hospital Admission Patterns in Adult Patients with Community-Acquired Bacterial Pneumonia Who Received Ceftriaxone and a Macrolide by Pneumonia Severity Index Score

BackgroundGiven the disparity in cost between inpatient and outpatient care, the IDSA/ATS community-acquired pneumonia (CAP) guidelines recommend use of site-of-care severity of illness indicators to identify CAP patients who may be candidates for outpatient treatment. Despite this level 1 recommendation, there are limited data on US hospital community-acquired bacterial pneumonia (CABP) admissions patterns stratified by Pneumonia Severity Index (PSI) score and presence of comorbidities. This study described hospitalization and length of stay (LOS) patterns among adult patients with CABP who received ceftriaxone (CTX) and a macrolide (M) at admission in the MedAssets database. The primary objective was to quantify the proportion of admissions and associated hospital LOS among “low-risk” patients (PSI score ≤ 90) where outpatient or short admission is advocated.MethodsA retrospective study of patients hospitalized for CABP and in the MedAssets database during 2012–2015 was performed. Inclusion criteria: (1) age ≥ 18 years, (2) a primary diagnosis for CABP, (3) received CTX and a M on hospitalization Day 1 or 2, and (3) ≥1-year enrollment before the index date. For patients with multiple hospitalizations for CABP during the study period, only the first episode was considered. Distribution of hospital admissions was stratified by PSI categories and Charlson Comorbidity Index (CCI). Both PSI and CCI were derived from diagnosis codes. Hospital LOS and mortality rates were tabulated across resulting PSI-CCI categories.ResultsDuring the study period, 68,254 patients met inclusion criteria. Among hospitalized CABP patients, 35% had a PSI score ≤ 70 and 33% had a PSI score between 71–90. The mean LOS for patients with a PSI score ≤70 and 71–90 ranged between 5.2 and 6.6 days, depending on CCI score. Mortality was less than 0.5% for patients with PSI score ≤70 and 1.4% for patients with a 71–90 PSI score.ConclusionMore than two-thirds of hospitalized CABP patients who received CTX and an M had a PSI score ≤ 90. On average, hospital LOS was 5–6 days for CABP patients with PSI ≤ 90. These findings reflect the critical need to identify outpatient treatments that can effectively reduce hospital admissions.Disclosures T. Lodise, Paratek Pharmaceuticals: Consultant and Scientific Advisor, Consulting fee. K. LaPensee, Paratek Pharmaceuticals: Employee, Salary.

Ceftaroline fosamil as first-line versus second-line treatment for acute bacterial skin and skin structure infections (ABSSSI) or community-acquired bacterial pneumonia (CABP)

The Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment.

Ceftaroline fosamil for treating skin and skin structure infections or community-acquired pneumonia in patients with renal insufficiency

The Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) is a multicenter retrospective study, conducted in the USA, describing the contemporary use of ceftaroline fosamil. Ceftaroline is primarily excreted by the kidneys and the dose should be reduced in patients with moderate to severe renal insufficiency. This article describes the clinical effectiveness of ceftaroline fosamil in the treatment of acute bacterial skin and skin structure infection (ABSSSI) or community-acquired bacterial pneumonia (CABP) patients with renal insufficiency. There were 985 ABSSSI patients and 344 CABP patients, of which 22 and 31%, respectively, had renal insufficiency. Ceftaroline fosamil was mostly administered to patients as second-line therapy. Overall clinical success was 78–91% among ABSSSI or CABP patients with renal insufficiency and, overall, >50% of patients were discharged to home. Ceftaroline fosamil is an effective treatment option for ABSSSI or CABP patients with renal insufficiency.

Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community‐acquired bacterial pneumonia

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2) = 0.93) and individual post-hoc (r(2) = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

A Prospective, Randomized, Multicenter Comparative Study of Clinafloxacin Versus a Ceftriaxone-based Regimen in the Treatment of Hospitalized Patients with Community-acquired Pneumonia

In an open-label, phase 3, randomized, multicenter study, clinafloxacin (200 mg/d) was compared to ceftriaxone (2 g/d; with or without erythromycin) in 527 patients with acute community-acquired bacterial pneumonia (CAP). Primary efficacy parameters were clinical cure rate and microbiologic eradication rates (by pathogen and by patient) determined 5-9 d post-therapy (test of cure; TOC). Clinical cure rates at TOC for the 2 treatment groups were equivalent in the intention-to-treat (clinafloxacin 79.3, ceftriaxone 78.6%), clinically evaluable (clinafloxacin 88.1, ceftriaxone 85.0%), modified intention-to-treat (clinafloxacin 82.6, ceftriaxone 86.9%) and microbiologically evaluable populations (clinafloxacin 86.2, ceftriaxone 86.2%). Microbiologic eradication rates were similar in the 2 treatment groups. Both drugs were tolerated. Treatment of hospitalized CAP patients with clinafloxacin is a reasonable choice, especially when a resistant pathogen is anticipated.