ppi-0903 and Pneumonia--Pneumococcal

Ceftaroline fosamil resulted in higher cure rates than ceftriaxone in patients with community-acquired bacterial pneumonia in 2 randomized trials (FOCUS 1 and FOCUS 2). The present analysis examines the subgroup of patients with Streptococcus pneumoniae infection to determine whether the apparent difference in cure rates persists after adjusting for potential covariates. We retrospectively pooled subjects with S. pneumoniae isolated at baseline in the original studies and employed logistic regression to evaluate the independent relationship between clinical cure and treatment with ceftaroline. Covariates evaluated included demographics, severity of illness, bacteremia, and pathogen characteristics. The final cohort included 139 subjects (69 ceftaroline, 70 ceftriaxone). Unadjusted cure rates were 85.5% and 68.6% (P = 0.009) in the ceftaroline and ceftriaxone groups, respectively. After logistic regression, ceftaroline remained associated with higher cure rates. Our findings indicate that ceftaroline may result in improved outcomes of S. pneumoniae pneumonia. Formal clinical trials are warranted to confirm this hypothesis.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Female; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Odds Ratio; Pneumonia, Pneumococcal; Retrospective Studies; Treatment Outcome

We evaluated trends in

Topics: Academic Medical Centers; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Epidemiological Monitoring; Humans; Levofloxacin; Linezolid; Microbial Sensitivity Tests; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Tigecycline; United States

Community-acquired pneumonia (CAP) is a common infection in developed countries and causes a large number of hospital admissions and deaths. In recent years, the incidence of this disease has increased, caused by progressive population aging. Following the introduction of the conjugate vaccine against Streptococcus pneumoniae, there have been significant epidemiological changes that require close monitoring because of the possible emergence of new patterns of resistance. This article aims to review the role of ceftaroline fosamil, a new parenteral cephalosporin with antibacterial activity against Gram-negative and Gram-positive pathogens, in the treatment of pneumonia. Several in vitro and in vivo studies have shown the efficacy of ceftaroline fosamil against penicillin-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Additionally, ceftaroline has shown similar efficacy and safety to ceftriaxone in the treatment of community-acquired pneumonia with severe prognosis (prognostic severity index III and IV) in two phase III clinical trials. Although a non-inferiority design was used for these clinical trials, some data suggest a superior efficacy of ceftaroline, with earlier clinical response and higher cure rate in infections caused by S. pneumoniae, making this drug particularly interesting for critically-ill patients admitted to the intensive care unit. Ceftaroline may also be considered for empirical and directed treatment of MRSA pneumonia.

Topics: Animals; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Pneumonia, Staphylococcal; Streptococcus pneumoniae

Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 μg/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 23 μg/ml, T(1/2) = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 10(7) CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥ 3 log(10) CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤ 0.008, 0.25, 0.25, and 0.5 μg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 μg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, -5.49 log(10) CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, -2.03 log(10) CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [-5.91 log(10) CFU/ml, P ≤ 0.002], SP 90 [-5.26 log(10) CFU/ml, P ≤ 0.008], and SP1466 [-5.14 log(10) CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Community-Acquired Infections; Culture Media; Half-Life; Humans; Microbial Sensitivity Tests; Models, Biological; Pneumonia, Pneumococcal; Streptococcus pneumoniae

To determine the activity of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil), a new cephalosporin recently approved in the USA for the treatment of community-acquired bacterial pneumonia, against serotyped Streptococcus pneumoniae causing community-acquired bacterial pneumonia from Europe and South Africa.. During 2007-08, 74 centres submitted 857 isolates of S. pneumoniae from patients with community-acquired bacterial pneumonia. These were re-identified and serotyped. MICs of ceftaroline and 12 comparators were determined by CLSI broth microdilution at a central laboratory.. Ceftaroline was very active against all 857 S. pneumoniae isolates (MIC(90) 0.12 mg/L). The MIC(50) for South African isolates was 0.06 mg/L compared with 0.004 or 0.008 mg/L for isolates from elsewhere. Antibiotic resistance was also higher in South Africa than other countries. Serotypes 3, 1, 7 and 11 were more susceptible to ceftaroline (MIC(90) = 0.008 mg/L) and the reference antibiotics than the population as a whole. Ceftaroline showed a biphasic MIC distribution (associated with cefuroxime susceptibility), the extent of which differed between isolate populations. Nevertheless, the highest ceftaroline MIC observed was only 0.5 mg/L (two isolates: one from the UK and one from South Africa).. These data from a large collection of S. pneumoniae isolates during 2007-08 from Europe and South Africa with varying serotype and antibiotic susceptibility, confirm the excellent in vitro activity of ceftaroline against S. pneumoniae causing community-acquired bacterial pneumonia in both adults and children.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Community-Acquired Infections; Europe; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Pneumococcal; Serotyping; South Africa; Streptococcus pneumoniae; Young Adult

Ceftaroline (CPT) is a new cephalosporin exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), as well as common Gram-negative pathogens. This study investigated the in vivo efficacy of a 48-hour simulated human dose regimen of CPT compared with ceftriaxone (CRO) against isolates of S. pneumoniae with different susceptibilities to penicillin in a rabbit pneumonia model. Three S. pneumoniae strains were used: CRO-susceptible penicillin-susceptible S. pneumoniae (CRO-S PSSP), CRO-susceptible penicillin-intermediate S. pneumoniae (CRO-S PISP), and CRO-resistant penicillin-resistant S. pneumoniae (CRO-R PRSP). Animals were randomized to the control group (no treatment) (n = 22) or to a group given intravenous (IV) CPT human equivalent (HE) dosage (600 mg/12 h; n = 19) or IV CRO HE dosage (1 g/24 h; n = 19). The total doses needed to achieve the HE dosage were 71 and 82 mg/kg of body weight/24 h for CRO and CPT, respectively. One group of rabbits infected with the CRO-R PRSP strain received intramuscular (IM) administration of CPT (5 or 20 mg/kg twice daily; n = 5 for each). Evaluation of efficacy was based on bacterial counts in the lungs and spleen. For IV CPT and IV CRO, the mean areas under the concentration-time curves from 0 to 24 h (AUC(0-24)s) were 155 and 938 mg · h/liter, respectively, the maximum concentrations in serum (C(max)s) were 20 and 158 mg/liter, respectively, and the minimum concentrations in serum (C(min)s) were 1.3 and 6 mg/liter, respectively. Both agents effectively treated pulmonary infections caused by CRO-S PSSP or CRO-S PISP with complete bacterial eradication in the lungs and spleen after 2 days of treatment. Against PRSP, CPT demonstrated excellent bactericidal activity, reducing bacterial counts in the lungs and spleen by approximately 8 and 4 log units, respectively (P < 0.001); CRO treatment resulted in a 2-log-unit reduction in the bacterial counts in lungs that did not reach statistical significance. Twice-daily IM CPT (5 mg/kg) reduced the bacterial burden by approximately 6 log units in the lungs and 3 log units in the spleen, and the 20-mg/kg dosage effectively eradicated PRSP infection. These findings further validate the in vivo bactericidal activity of CPT against pneumococci.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Humans; Male; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Pneumococcal; Rabbits; Streptococcus pneumoniae