Decreased ceftriaxone susceptibility in emerging (35B and 6C) and persisting (19A) Streptococcus pneumoniae serotypes in the United States, 2011-2012: ceftaroline remains active in vitro among ß-lactam agents.

Totals of 8.7% (103/1,190) and 21.0% (249/1,190) of the Streptococcus pneumoniae isolates recovered from specimens collected in the United States during the 2011-2012 AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) Surveillance Program were ceftriaxone nonsusceptible according to the CLSI (≤ 1 µg/ml for susceptible) and EUCAST (≤ 0.5 µg/ml for susceptible) criteria, respectively. Decreased susceptibility to ceftriaxone (MIC, 1 µg/ml) was frequently observed among serotypes 19 A (51.4%; 128/249) and 35 B (29.7%; 74/249), which were most often observed in the East South Central and South Atlantic U.S. Census regions. Ceftaroline (MIC50/90, 0.12/0.25 µg/ml) remained active (≥ 96.8% susceptible) when tested against these less susceptible isolates.

In vivo efficacy of ceftaroline fosamil in a methicillin-resistant panton-valentine leukocidin-producing Staphylococcus aureus rabbit pneumonia model.

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.

Efficacy of ceftaroline fosamil in a staphylococcal murine pneumonia model.

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 µg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log(10) kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log(10) CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log(10) kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.

Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.

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.

CANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections.

Scientific and regulatory interest in assessing clinical endpoints after 48 to 72 h of treatment for acute bacterial skin and skin structure infections (ABSSSI) has increased. Historical, pre-antibiotic-era data suggest that a treatment effect relative to untreated controls can be discerned in this time interval. Ceftaroline fosamil, a broad-spectrum bactericidal cephalosporin with activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative organisms was efficacious in two phase 3 trials of complicated skin infections (CANVAS 1 and 2) using clinical cure rates at the test-of-cure visit. To assess an early clinical response in the CANVAS trials, a retrospective analysis using a day 3 clinical endpoint was conducted. Adults with ABSSSI received intravenous ceftaroline fosamil at 600 mg every 12 h (q12h) or vancomycin at 1 g plus aztreonam at 1 g (V/A) q12h for 5 to 14 days. Clinical response at day 3, defined as cessation of infection spread and absence of fever, was analyzed in patients with a lesion size of ≥ 75 cm(2) and either deep and/or extensive cellulitis, major abscess, or an infected wound. Day 3 integrated CANVAS clinical response rates were 74.0% (296/400) for ceftaroline and 66.2% (263/397) for V/A (difference, 7.8%; 95% confidence interval [CI], 1.3% to 14.0%). In the individual studies, absolute treatment differences of 9.4% (CANVAS 1) and 5.9% (CANVAS 2) favoring ceftaroline were observed. For ABSSSI due to MRSA, response rates were 81.7% and 77.4% in the ceftaroline and V/A groups, respectively. In this retrospective analysis, ceftaroline fosamil monotherapy had a numerically higher clinical response than V/A at day 3 in the treatment of ABSSSI.

Characterization of methicillin-resistant Staphylococcus aureus displaying increased MICs of ceftaroline.

OBJECTIVES: To characterize the mechanisms responsible for elevated MICs of ceftaroline for methicillin-resistant Staphylococcus aureus (MRSA). METHODS: During the 2008 Assessing Worldwide Antimicrobial Resistance Evaluation ('AWARE') surveillance programme, four S. aureus collected from separate patients in Athens, Greece, demonstrated ceftaroline MICs of 4 mg/L. These isolates were clonally related and one strain (13101) was selected for further characterization. Two strains (4981 and 4977) displaying ceftaroline MICs of 1 and 2 mg/L, respectively, were included for comparison. All strains originated from the same hospital. Penicillin-binding protein (PBP) affinities for ceftaroline and comparators were determined. Strains were typed by single-locus typing (i.e. spa typing), multilocus sequence typing ('MLST') and by multiple-locus variable-number tandem repeat fingerprinting (MLVF). The presence of Pantone-Valentine leucocidin and the staphylococcal cassette chromosome mec types was assessed. We also performed nucleotide sequencing of the mecA (encoding PBP2a) promoter and ribosomal binding site (rbs) regions and mecR1. RESULTS: Ceftaroline demonstrated the highest PBP2a affinity with strain 4981 (ST5-MRSA-II) (IC(50) 0.06 mg/L; MIC 1 mg/L). Strains 4977 and 13101 (both ST239-MRSA-III) showed indistinguishable MLVF profiles. Ceftaroline PBP2a binding affinity in strains 4977 (IC(50) 0.25 mg/L; MIC 2 mg/L) and 13101 (IC(50) 1 mg/L; MIC 4 mg/L) was 4- and 16-fold lower than 4981, respectively. Strain 4981 contains a wild-type PBP2a, while strains 4977 and 13101 have N(146)K and E(150)K alterations in the non-penicillin-binding domain. Additionally, 13101 has one substitution (H(351)N) in the transpeptidase domain. Alterations in the mecR1, mecA promoter or rbs regions were not observed. CONCLUSIONS: Increased ceftaroline MICs were associated with decreased PBP2a binding affinity and reflected alterations in PBP2a.

Ceftaroline versus ceftriaxone in a highly penicillin-resistant pneumococcal pneumonia rabbit model using simulated human dosing.

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.

Activity of ceftaroline and epidemiologic trends in Staphylococcus aureus isolates collected from 43 medical centers in the United States in 2009.

A Staphylococcus aureus surveillance program was initiated in the United States to examine the in vitro activity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 from 43 medical centers. All isolates were screened for mecA by PCR and evaluated by pulsed-field gel electrophoresis. Methicillin-resistant S. aureus (MRSA) were analyzed for Panton-Valentine leukocidin (PVL) genes and the staphylococcal cassette chromosome mec (SCCmec) type. All isolates had ceftaroline MICs of ≤2 µg/ml with an MIC(50) of 0.5 and an MIC(90) of 1 µg/ml. The overall resistance rates, expressed as the percentages of isolates that were intermediate and resistant (or nonsusceptible), were as follows: ceftaroline, 1.0%; clindamycin, 30.2% (17.4% MIC ≥ 4 µg/ml; 12.8% inducible); daptomycin, 0.2%; erythromycin, 65.5%; levofloxacin, 39.9%; linezolid, 0.02%; oxacillin, 53.4%; tetracycline, 4.4%; tigecycline, 0%; trimethoprim-sulfamethoxazole, 1.6%; vancomycin, 0%; and high-level mupirocin, 2.2%. The mecA PCR was positive for 53.4% of the isolates. The ceftaroline MIC(90)s were 0.25 µg/ml for methicillin-susceptible S. aureus and 1 µg/ml for MRSA. Among the 2,247 MRSA isolates, 51% were USA300 (96.9% PVL positive, 99.7% SCCmec type IV) and 17% were USA100 (93.4% SCCmec type II). The resistance rates for the 1,137 USA300 MRSA isolates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6% (6.2% MIC ≥ 4 µg/ml; 1.4% inducible); tetracycline, 3.3%; trimethoprim-sulfamethoxazole, 0.8%; high-level mupirocin, 2.7%; daptomycin, 0.4%; and ceftaroline and linezolid, 0%. USA300 is the dominant clone causing MRSA infections in the United States. Ceftaroline demonstrated potent in vitro activity against recent S. aureus clinical isolates, including MRSA, daptomycin-nonsusceptible, and linezolid-resistant strains.

Review of ceftaroline fosamil microbiology: integrated FOCUS studies.

Ceftaroline fosamil, the prodrug form of ceftaroline, is a novel broad-spectrum parenteral cephalosporin that exhibits antibacterial activity against typical respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and common Gram-negative pathogens. In particular, ceftaroline has activity against resistant Gram-positive cocci, including penicillin- and multidrug-resistant S. pneumoniae, as well as methicillin-resistant S. aureus. The activity of ceftaroline against these phenotypes is attributed to its ability to bind to modified penicillin-binding proteins with high affinity when compared with other ß-lactams. The activity of ceftaroline is not compromised by the ability of H. influenzae to produce ß-lactamase. Ceftaroline fosamil was compared with ceftriaxone for safety and efficacy in two randomized, double-blinded, controlled Phase III clinical trials for the treatment of community-acquired pneumonia (CAP). Microbiological assessments at baseline included respiratory specimen cultures, blood cultures, urinary antigen testing and atypical pathogen serology testing. By-subject and by-pathogen microbiological outcomes were assessed in the microbiologically evaluable population at the test-of-cure visit. The favourable microbiological response rates by subject for ceftaroline were 87.0% compared with 81.0% for ceftriaxone. The by-pathogen microbiological response rates of ceftaroline and ceftriaxone were 87.3% and 72.9% for S. pneumoniae, 83.3% and 85.0% for H. influenzae and 76.0% and 70.4% for S. aureus, respectively. Key baseline pathogens such as S. pneumoniae, H. influenzae and methicillin-susceptible S. aureus were susceptible to ceftaroline, with MIC(90)s of 0.03, 0.03 and 0.25 mg/L, respectively, supporting its utility as a promising new agent for treatment of CAP.

Comparison of ceftaroline fosamil, daptomycin and tigecycline in an experimental rabbit endocarditis model caused by methicillin-susceptible, methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus.

OBJECTIVES: The aim of this study was to compare the in vivo activities of the new antistaphylococcal drugs ceftaroline fosamil, daptomycin and tigecycline at projected human therapeutic doses against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains in a rabbit model of endocarditis. METHODS: The efficacy of therapeutic regimens in our model was evaluated following 4 days of treatment by determining colony counts of infected vegetations. Emergence of resistant variants during therapy was assessed. RESULTS: Using this model of infective endocarditis, ceftaroline fosamil and daptomycin demonstrated high bactericidal in vivo activity (reduction of >5 log(10) cfu/g of vegetation) after a 4 day treatment against MSSA, MRSA and GISA strains. Both drugs were more efficacious than tigecycline, which showed moderate activity but failed to exhibit a bactericidal effect. Ceftaroline was superior to daptomycin in terms of sterilization of the vegetations. Emergence of resistant variants during daptomycin therapy was observed in two animals (one in the MSSA group and one in the MRSA group) but was not observed in ceftaroline- or tigecycline-treated animals. CONCLUSIONS: The novel ß-lactam agent ceftaroline fosamil was the most active bactericidal drug in this model and is a promising therapeutic option for the treatment of severe S. aureus infections, including those caused by MRSA and GISA strains.

In vitro and in vivo activity of GT-1, a novel siderophore cephalosporin, and GT-055, a broad-spectrum ß-lactamase inhibitor, against biothreat and ESKAPE pathogens.

Antimicrobial-resistance (AMR) has become an increasingly difficult issue to overcome for bacteria associated with both community- and hospital-acquired infections as well as potential biodefense threats. The need to identify new therapeutics of novel classes and/or with unique mechanisms is critical to combatting AMR in the coming years. GT-1 (LCB10-0200), a siderophore-linked cephalosporin, is one such novel option and is formulated to be used either alone or in combination with a novel broad-spectrum ß-lactamase inhibitor, GT-055 (LCB18-055). This study assessed the in vitro and in vivo efficacy of GT-1 and GT-055 against a broad array of multi-drug resistant and biothreat pathogens. Here, we demonstrated sub-4 µg ml-1 efficacy against a number of pathogens in vitro. We further determined that in mice infected via aerosol route with Yersinia pestis, efficacy of GT-1/GT-055 treatment is at least equivalent to the comparator antibiotic, ciprofloxacin.

Activity of ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States.

The in vitro activity of ceftaroline against 891 pneumococci collected in 2008 from 22 centers in the United States was investigated. Ceftaroline was the most potent agent tested, with the MICs being <0.008 to 0.5 microg/ml and the MIC(90)s being <0.008 to 0.25 microg/ml against 11 prevailing serotypes. The overall rates of susceptibility were as follows: penicillin G, 86.2%; ceftriaxone, 90.7%; cefuroxime, 70.1%; erythromycin, 61.6%; clindamycin, 79.2%; levofloxacin, 99.4%; and vancomycin, 100%. Serotype 19A isolates were the least susceptible. These results support the use of ceftaroline for the treatment of pneumococcal infections, including those caused by pneumococci resistant to other agents.

Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity.

Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available ß-lactams. The activity of ceftaroline against MRSA and the ß-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T  >  MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T  >  MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T  >  MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤ 2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.

Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis.

OBJECTIVES: To evaluate the activity of a new cephalosporin, ceftaroline, in comparison with other antistaphylococcal drugs (linezolid and vancomycin) at projected human therapeutic doses against methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains. METHODS: Using a rabbit experimental model of acute osteomyelitis, efficacy was assessed following 4 days of treatment by colony counts of infected bone tissues (joint fluid, femoral bone marrow and bone). RESULTS: Although vancomycin remains the standard treatment for MRSA osteomyelitis, it was ineffective against the MRSA strain and poorly active against GISA infections in this model. Ceftaroline and linezolid demonstrated significant activity in bone marrow and bone, and were significantly better than vancomycin treatment. However, ceftaroline was the only drug to exhibit significant activity against MRSA in infected joint fluid. CONCLUSIONS: The present study supports ceftaroline as a promising therapeutic option for the treatment of severe MRSA infections, including osteomyelitis.

In vivo activity of a novel anti-methicillin-resistant Staphylococcus aureus cephalosporin, ceftaroline, against vancomycin-susceptible and -resistant Enterococcus faecalis strains in a rabbit endocarditis model: a comparative study with linezolid and vancomycin.

We assessed the in vitro and in vivo efficacy of the novel parenteral broad-spectrum cephalosporin ceftaroline against Enterococcus faecalis in time-kill experiments and in a rabbit endocarditis model with simulated human dosing. Ceftaroline was more active than either vancomycin or linezolid against vancomycin-sensitive and -resistant isolates of E. faecalis.

In vitro evaluation of the antimicrobial activity of ceftaroline against cephalosporin-resistant isolates of Streptococcus pneumoniae.

Increasing pneumococcal resistance to extended-spectrum cephalosporins warrants the search for novel agents with activity against such resistant strains. Ceftaroline, a parenteral cephalosporin currently in phase 3 clinical development, has demonstrated potent in vitro activity against resistant gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae. In this study, the activity of ceftaroline was evaluated against highly cefotaxime-resistant isolates of pneumococci from the Active Bacterial Core surveillance program of the Centers for Disease Control and Prevention and against laboratory-derived cephalosporin-resistant mutants of S. pneumoniae. The MICs of ceftaroline and comparators were determined by broth microdilution. In total, 120 U.S. isolates of cefotaxime-resistant (MIC > or = 4 microg/ml) S. pneumoniae were tested along with 18 laboratory-derived R6 strains with known penicillin-binding protein (PBP) mutations. Clinical isolates were characterized by multilocus sequence typing, and the DNAs of selected isolates were sequenced to identify mutations affecting pbp genes. Ceftaroline (MIC(90) = 0.5 microg/ml) had greater in vitro activity than penicillin, cefotaxime, or ceftriaxone (MIC(90) = 8 microg/ml for all comparators) against the set of highly cephalosporin-resistant clinical isolates of S. pneumoniae. Ceftaroline was also more active against the defined R6 PBP mutant strains, which suggests that ceftaroline can overcome common mechanisms of PBP-mediated cephalosporin resistance. These data indicate that ceftaroline has significant potency against S. pneumoniae strains resistant to existing parenteral cephalosporins and support its continued development for the treatment of infections caused by resistant S. pneumoniae strains.

In vitro profiling of ceftaroline against a collection of recent bacterial clinical isolates from across the United States.

This study evaluated the in vitro activity of ceftaroline, a novel cephalosporin with broad-spectrum activity against gram-negative and -positive pathogens, against 4,151 recent clinical isolates collected in the United States. Ceftaroline was very potent against bacteria found in community- and hospital-acquired infections, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and common Enterobacteriaceae spp.

Fosfomycin and Comparator Activity Against Select Enterobacteriaceae, Pseudomonas, and Enterococcus Urinary Tract Infection Isolates from the United States in 2012.

INTRODUCTION: Fosfomycin is a broad-spectrum cell wall active agent that inhibits the MurA enzyme involved in peptidoglycan synthesis and is FDA-approved for treatment of uncomplicated urinary tract infections (UTIs) caused by Escherichia coli and Enterococcus faecalis in women. Data regarding the susceptibility of recent UTI isolates to fosfomycin are limited. METHODS: This study compared the fosfomycin susceptibility of 658 US UTI isolates with susceptibility to ciprofloxacin, levofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole (SXT). Isolates included E. coli (n = 257), Klebsiella spp. (n = 156), Enterobacter spp. (n = 79), Pseudomonas aeruginosa (n = 60), E. faecalis (n = 54), and Proteus spp. (n = 52). Extended-spectrum ß-lactamase (ESBL)-producing E. coli, Klebsiella spp., and Proteus mirabilis, ceftazidime-nonsusceptible P. aeruginosa and Enterobacter spp., and vancomycin-nonsusceptible E. faecalis were included. RESULTS: Overall, the minimum concentration inhibiting 50% of isolates (MIC50) and 90% of isolates (MIC90) for fosfomycin were 4 and 64 µg/mL, respectively. Of the 257 E. coli isolates, 99.6% were susceptible to fosfomycin. Ciprofloxacin, levofloxacin, SXT, and nitrofurantoin susceptibility rates were 65.4%, 65.8%, 59.9%, and 90.3%, respectively. The fosfomycin-susceptibility rate for E. faecalis (94.4%) was comparable with the nitrofurantoin-susceptibility rate (98.1%). Among the 144 ESBL-producing isolates, the fosfomycin MIC50 and MIC90 values were 2 and 32 µg/mL, respectively. Fosfomycin MIC50 and MIC90 values were 16 and 128 µg/mL for the 38 ceftazidime-nonsusceptible Enterobacter isolates and 64 and 128 µg/mL for the 15 ceftazidime-nonsusceptible P. aeruginosa isolates, respectively. CONCLUSION: These results demonstrate that fosfomycin has in vitro activity against many US UTI isolates, including drug-resistant isolates, and may provide another therapeutic option for treatment of UTIs caused by antibiotic-resistant pathogens.

Evolution of Ceftaroline-Resistant Mrsa in a Child with Cystic Fibrosis Following Repeated Antibiotic Exposure.

Ceftaroline is the first ß-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). We describe a ceftaroline-resistant MRSA strain, isolated from a girl with cystic fibrosis after 22 ceftaroline treatment courses. MRSA genome sequencing documented a Tyr446Asn alteration in penicillin binding protein 2 that appeared responsible for resistance. Noncompartmental ceftaroline pharmacokinetic evaluation in our patient documented increased clearance and volume of distribution compared with adults.