Michael L. Corrado* INC Research, 580 Union Square Drive, New Hope, PA 18938, USA

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1 J Antimicrob Chemother 2010; 65 Suppl 4: iv67 71 doi: /jac/dkq256 Integrated safety summary of CANVAS 1 and 2 trials: Phase III, randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections Michael L. Corrado* INC Research, 580 Union Square Drive, New Hope, PA 18938, USA *Tel: , ext. 6212; Fax: ; mlcorrado4444@yahoo.com Objectives: Treatment of complicated skin and skin structure infections (csssis) requires therapy that is effective against a range of Gram-positive and Gram-negative bacteria, including resistant pathogens such as methicillin-resistant Staphylococcus aureus. Equally important is the need to provide therapy that is safe and well tolerated. fosamil is a new-generation, parenteral cephalosporin that was developed for the treatment of moderate to severe bacterial infections, including csssis. This report provides an integrated safety summary of the CeftAroliNe Versus VAncomycin in Skin and Skin Structure Infections (CANVAS) 1 and 2 studies (registration numbers NCT and NCT ). Methods: Adult patients with csssis requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5 14 days (randomized 1:1). All patients were followed for treatment-emergent adverse events (TEAEs) occurring from the start of the initial study drug infusion up to the test-of-cure visit, 1 week following the last dose of study medication; serious adverse events (SAEs) that occurred within 30 days after the last dose were recorded. Results: A total of 1378 patients received any amount of study drug and were included in the safety analysis. The percentage of patients with an SAE was similar between the ceftaroline fosamil and the vancomycin plus aztreonam groups (4.3% versus 4.1%). The majority of patients (.75%) had either no or mild TEAEs and the distribution of TEAEs based on severity was comparable between the groups. The most commonly reported TEAEs in patients treated with ceftaroline fosamil included nausea (5.9%), headache (5.2%), diarrhoea (4.9%) and pruritus (3.5%). Conclusions: fosamil was well tolerated and did not result in any unexpected safety concerns. The data from the CANVAS trials suggest that ceftaroline fosamil has the expected safety and tolerability profile common to the cephalosporin class. Keywords: cephalosporins, tolerability, QTc intervals Introduction fosamil is a new-generation, parenteral cephalosporin that was developed for the treatment of moderate to severe bacterial infections, including complicated skin and skin structure infections (csssis). fosamil (subsequently referred to as ceftaroline ) is a prodrug that is rapidly converted by plasma phosphatases into active ceftaroline following intravenous (iv) administration. may be considered as both a classic and novel cephalosporin when its spectrum of antibacterial activity is considered. Against common Gramnegative bacteria, such as members of Enterobacteriaceae, non-extended-spectrum b-lactamase-producing Escherichia coli and Klebsiella pneumoniae, ceftaroline exhibits activity similar to third-generation cephalosporins. 1 3 However, bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae is what makes ceftaroline truly noteworthy 4 6 and interesting as a new treatment for csssis. Efficacy is only one part of the risk benefit evaluation. It is equally important to provide therapy that is both safe and well tolerated. The challenge for clinicians is in choosing the best therapeutic option while balancing the risk potential for adverse events (AEs). A number of currently available antimicrobial agents, such as vancomycin, linezolid and daptomycin, # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org iv67

2 Corrado have been associated with troubling adverse effects, such as vancomycin nephrotoxicity necessitating the need for drug-level monitoring, 7,8 linezolid-associated myelosuppression 9,10 and daptomycin-related elevation of creatine phosphokinase. 11 In contrast, the cephalosporin class has traditionally maintained an excellent safety profile, 12 which is expected to continue as new agents are developed. This report provides an integrated safety summary of the CeftAroliNe Versus VAncomycin in Skin and Skin Structure Infections (CANVAS) 1 and 2 studies (registration numbers NCT and NCT ), which evaluated the efficacy and safety of 600 mg of ceftaroline administered iv every 12 h compared with vancomycin plus aztreonam in adult patients with csssis. Methods The CANVAS trials were designed as parallel, methodologically identical, multicentre, randomized, double-blind, comparative studies to evaluate the safety and efficacy of 600 mg of iv ceftaroline every 12 h versus 1 g of iv vancomycin plus 1 g of iv aztreonam every 12 h in patients with csssis. Details of the study design and integrated results for these two trials were described previously, 13 and efficacy results for the individual CANVAS 1 and CANVAS 2 trials are reported elsewhere in this Supplement. 14,15 This report provides an integrated safety summary of the CANVAS 1 and 2 studies. A total of 1378 patients received any amount of study drug and were included in the safety population for the two CANVAS trials; 692 in the ceftaroline arm and 686 in the vancomycin plus aztreonam arm. All patients who entered into the CANVAS trials met eligibility criteria, and provided informed consent after the risks and requirements of the trial were explained. At study entry (baseline), a history and physical examination, including a detailed evaluation of the infection site(s), were performed. Urine for baseline urinalysis and blood for a complete blood count (CBC), direct and indirect Coombs test, serum chemistry panel, and other laboratory measurements were obtained; 12-lead electrocardiograms were conducted at baseline. Patients were randomized in a blinded fashion to receive ceftaroline or vancomycin plus aztreonam for 5 14 days. All patients were followed for AEs occurring from the start of the initial study drug infusion up to the test-of-cure visit, 1 week following the last dose of study medication; all AEs were followed until resolution or stabilization. All AEs were recorded on case report forms, and assessed for degree of severity and causality by the investigator. Any AEs resulting in death, prolongation of existing hospitalization, a potentially life-threatening event, persistent or significant disability or incapacity, congenital anomaly or birth defect in the offspring of a subject who received study drug, or events that jeopardize the subject sufficiently that medical or surgical intervention may be required to prevent one of the above outcomes was considered a serious adverse event (SAE), regardless of whether or not the AE was judged to be drug related. Such SAEs were recorded if they occurred up to 30 days after the last dose of the study drug; all SAEs were followed until resolution. Urinalysis, CBCs and serum chemistries were repeated at the end of therapy and at the test-of-cure visit or, if felt necessary, at any time during the trial. Results The demographic and baseline characteristics of subjects in the ceftaroline and vancomycin plus aztreonam groups were well balanced in all regards, including race, age, co-morbid conditions and renal function. Thus, the comparative distribution of AEs between the ceftaroline regimen and the vancomycin plus aztreonam regimen was unlikely to be reflective of underlying demographic differences between arms. Treatment-emergent adverse events (TEAEs) were captured regardless of drug relationship and were defined as AEs with onset occurring or severity worsening on or after the first dose of study drug through the test-of-cure visit (for all TEAEs) or late follow-up visit (for SAEs only) (Table 1). The percentage of patients with an SAE (4.3% versus 4.1%) was similar between the ceftaroline and the vancomycin plus aztreonam groups, respectively. Discontinuation rates because of a TEAE were 3.0% for ceftaroline and 4.8% for vancomycin plus aztreonam subjects. Based on these parameters alone, ceftaroline appears as safe and tolerable as vancomycin plus aztreonam. The number of patients with at least one TEAE noted in the CANVAS trials is typical for clinical trials conducted in patients with csssis, as are the SAE and discontinuation rates. Table 1 lists TEAEs resulting in discontinuation of the study drug or withdrawal from the study. Interestingly, hypersensitivity reactions resulted in discontinuation in numerically more vancomycin plus aztreonam subjects than ceftaroline subjects (six versus three), as did rash (four versus two), allergic dermatitis (two versus one) and urticaria (two versus one), respectively. Further, erythema and non-generalized pruritus resulted in discontinuation only for patients on the vancomycin plus aztreonam regimen (eight versus none). Table 2 describes TEAEs seen in either regimen with a frequency of 1% and in which a difference of 0.5% was observed between ceftaroline and vancomycin plus aztreonam. Pruritus, nausea, headache and diarrhoea were the most common of these TEAEs. Only two of the TEAEs demonstrated a difference of.1% between regimens. Diarrhoea occurred in 4.9% of ceftaroline subjects (1.1% more than the vancomycin plus aztreonam regimen) and pruritus occurred in 8.2% of vancomycin plus aztreonam subjects (4.7% more than the ceftaroline regimen). Regarding SAEs, no patterns or signals were demonstrable in either treatment group and virtually all were Table 1. Incidence of TEAEs leading to discontinuation (more than one per regimen) fosamil plus aztreonam (N¼686), n (%) Any TEAE 309 (44.7) 326 (47.5) SAEs 30 (4.3) 28 (4.1) Discontinuation secondary 21 (3.0) 33 (4.8) to TEAE hypersensitivity 3 (0.4) 6 (0.9) generalized pruritus 2 (0.3) 3 (0.4) rash 2 (0.3) 4 (0.6) generalized rash 2 (0.3) 1 (0.1) maculopapular rash 2 (0.3) 0 (0.0) allergic dermatitis 1 (0.1) 2 (0.3) urticaria 1 (0.1) 2 (0.3) erythema 0 (0.0) 5 (0.7) pruritus 0 (0.0) 3 (0.4) iv68

3 Integrated safety summary of CANVAS 1 and 2 JAC Table 2. Comparison of specific TEAEs occurring with a frequency of 1% (with D 0.5% between regimens) fosamil plus aztreonam (N¼686), n (%) Nausea 41 (5.9) 35 (5.1) Headache 36 (5.2) 31 (4.5) Diarrhoea 34 (4.9) 26 (3.8) Pruritus 24 (3.5) 56 (8.2) Rash 22 (3.2) 17 (2.5) Generalized pruritus 15 (2.2) 19 (2.8) Dizziness 14 (2.0) 8 (1.2) Hypokalaemia 10 (1.4) 15 (2.2) Anaemia 9 (1.3) 13 (1.9) Pain 9 (1.3) 4 (0.6) Pyrexia 9 (1.3) 16 (2.3) Chest pain 8 (1.2) 5 (0.7) ALT increase 8 (1.2) 12 (1.7) AST increase 7 (1.0) 13 (1.9) Infusion site erythema 7 (1.0) 2 (0.3) considered unrelated to the study drug; instead, they were related to a co-morbid condition or the underlying skin infection condition. Only one SAE occurred in more than one subject, in the ceftaroline arm, and this was a worsening of the cellulitis. All TEAEs (e.g. headache and nausea) were graded based on severity, as assessed by the investigator, as severe, moderate or mild. If a patient had more than one TEAE of the same term, severity was based on the worst severity rating observed. Generally, the distribution of TEAEs based on severity was comparable between regimens. The majority of patients had no (55.3% versus 52.5%) or mild (23.8% versus 25.7%) TEAEs in the ceftaroline and vancomycin plus aztreonam groups, respectively; 17.1% of ceftaroline-treated patients and 17.3% of vancomycin plus aztreonam-treated patients had moderate TEAEs. Severe TEAEs were reported in 3.8% of ceftaroline and 4.5% of vancomycin plus aztreonam subjects. The lower percentages in each category for ceftaroline were of no clinical relevance. In the renal analyses (Table 3), compared with vancomycin plus aztreonam, fewer ceftaroline subjects had serum creatinine levels rise to.1.5 mg/dl, where that rise also represented a.50% increase over baseline. This was also true for blood urea nitrogen (BUN) and decreases in creatinine clearance of.50%. In this regard, ceftaroline appears to have less of a renal effect than vancomycin plus aztreonam. When TEAEs of the kidney system were reviewed, rather than just chemistries, 1.3% of ceftaroline subjects had at least one such renal TEAE compared with 0.7% of vancomycin plus aztreonam subjects. When these TEAEs, whether related to the study drug or not, were examined further, acute renal failure, the most significant of the renal TEAEs, was more common in vancomycin plus aztreonam recipients (0.4% versus 0.1%). One additional patient in the ceftaroline group had renal failure listed as a TEAE, without defining whether the renal failure was acute or longstanding. Table 4 lists hepatic TEAEs in the CANVAS trials. Among these TEAEs, more vancomycin plus aztreonam-treated subjects had Table 3. Renal abnormalities Serum creatinine.1.5 mg/dl and.50% increase fosamil, plus aztreonam, 6/676 (0.9) 14/664 (2.1) BUN.1.5 ULN and.50% increase 2/676 (0.3) 8/664 (1.2) Creatinine clearance.50% decrease 3/676 (0.4) 7/663 (1.1) At least one renal TEAE 9/692 (1.3) 5/686 (0.7) Renal TEAE occurring in.1 subject per regimen renal impairment 2/692 (0.3) 0/686 (0.0) acute renal failure 1/692 (0.1) 3/686 (0.4) pollakiuria 2/692 (0.3) 1/686 (0.1) dysuria 2/692 (0.3) 2/686 (0.3) Table 4. Incidence of TEAEs indicating potential liver function abnormalities fosamil plus aztreonam (N¼686), n (%) At least one hepatic TEAE 19 (2.7) 29 (4.2) hepatobiliary disorders 2 (0.3) 2 (0.3) toxic hepatitis 1 (0.1) 0 (0.0) hepatomegaly 1 (0.1) 0 (0.0) cytolytic hepatitis 0 (0.0) 1 (0.1) hepatic failure 0 (0.0) 1 (0.1) investigations a 17 (2.5) 27 (3.9) ALT increased 8 (1.2) 12 (1.7) AST increased 7 (1.0) 13 (1.9) transaminases increased 2 (0.3) 0 (0.0) hepatic enzyme increased 1 (0.1) 6 (0.9) liver function tests abnormal 1 (0.1) 4 (0.6) a Incidence of subjects with at least one TEAE reflecting elevated liver enzymes. at least one TEAE referable to the hepatic system. Subjects who had a clinical TEAE, such as hepatic failure, plus a TEAE of abnormal liver function test are also represented in Table 4 under investigations (any TEAEs reflecting elevated liver enzymes); thus, they are described both as a clinical TEAE and investigation. This accounts for the difference in the percentage of subjects with at least one TEAE versus the summation of TEAEs described in Table 4. Table 5 looks specifically at liver function tests in a different way. Minor elevations in liver tests are difficult to evaluate and often of little meaning. However, by looking at significant increases or patterns of various tests together, a more meaningful evaluation and prediction of hepatocellular toxicity can be made. Table 5 describes increases in multiples of the upper limit of normal (ULN) for various tests. The vancomycin plus aztreonam regimen resulted more often in.3-fold iv69

4 Corrado Table 5. Liver function abnormalities or.5-fold increases above the ULN for both aspartate aminotransferase (AST) and, more significantly, alanine aminotransferase (ALT), because this measure is more specific for the liver. The most sensitive analysis of the potential to evoke hepatocellular damage is an analysis of subjects who have an increase in ALT or AST.3-fold above the ULN, less than a 2-fold increase in alkaline phosphatase plus a.2-fold increase in bilirubin above the ULN, in the same patient. This was not noted in any patient. Certain TEAEs of interest in the CANVAS trials were evaluated because of their known association with b-lactams or with other antibacterial classes. Diarrhoea was the most common of these TEAEs in both treatment groups, with 4.9% in the ceftaroline group compared with 3.8% in the vancomycin plus aztreonam group. During the CANVAS trials, three subjects had Clostridium difficile reported (two on ceftaroline and one on vancomycin plus aztreonam). No patients in either group experienced prolongation of the QT interval. Although a small percentage of patients receiving cephalosporins are known to test positive for direct Coombs, there is no clear association 12,20 23 with this finding and the risk of haemolytic anaemia. In the CANVAS trials, 11.6% of ceftaroline patients and 4.3% of vancomycin plus aztreonam patients tested positive in the direct Coombs test. Both treatment regimens, however, had,2% of the treated patients identified as having a TEAE suggestive of anaemia, none of which was haemolytic anaemia. Finally, only one patient had a seizure disorder, a ceftaroline patient. These data suggest that ceftaroline is safe and well tolerated, with a safety profile that is consistent with the cephalosporin class. Discussion fosamil, plus aztreonam, AST.3 ULN 6/510 (1.2) 13/488 (2.7) AST.5 ULN 1/510 (0.2) 5/488 (1.0) ALT.3 ULN 4/542 (0.7) 12/527 (2.3) ALT.5 ULN 3/542 (0.6) 5/527 (0.9) Total bilirubin.1.5 ULN 1/628 (0.2) 1/619 (0.2) ALT or AST.3 ULN, ALP,2 ULN 0/655 (0.0) 0/649 (0.0) and total bilirubin.1.5 ULN ALT or AST.3 ULN, ALP,2 ULN and total bilirubin.2 ULN 0/656 (0.0) 0/649 (0.0) ALP, alkaline phosphatase. On 8 June 1908, Paul Erhlich delivered a paper in which he described the objectives of modern chemotherapy of infectious diseases. 24 Ehrlich described his search for structural modifications in arsenicals that were less toxic for the host and yet effective in eradicating an infection. From that time forward pharmaceutical scientists have examined this balancing act, looking for new drugs or novel modifications to older classes of drugs to treat resistant infections while maintaining the lowest toxic potential for patients. The discovery of penicillin, the first b-lactam, by Alexander Fleming, 25 and the subsequent identification of the structurally related cephalosporins 26 seemed to represent the discovery of ideal drugs. Although cefaloridine, unlike cefalotin, could be comfortably given intramuscularly, it was found to have nephrotoxic potential. 22 Subsequently, numerous cephalosporins have been developed, each with marginal or significant expansion in the spectrum of activity and safety profile. Although the occasional cephalosporin exhibits a unique toxicity (e.g. moxalactam-associated bleeding), overall, the cephalosporins as a class have maintained an excellent record of safety and tolerability, 12 and are among the most frequently prescribed classes of antimicrobials. In this analysis of the CANVAS studies, no new safety concerns for ceftaroline were noted in.1300 patients evaluated. Both ceftaroline and vancomycin plus aztreonam were well tolerated in the integrated safety analysis, and the incidence of TEAEs was similar between groups. The TEAEs shown in Table 2 are generally those that are common in any study population, and have previously been described in association with cephalosporin and/or vancomycin use. 12 The most commonly reported TEAEs in patients treated with ceftaroline included nausea, headache, diarrhoea and pruritus. It is generally accepted that 5% of the population develop allergic reactions to cephalosporins, 22 and the results from the CANVAS trials suggest a similar rate for ceftaroline. Notably, hypersensitivity reactions resulted in more discontinuations in vancomycin plus aztreonam patients than in ceftaroline subjects. In this study, the majority of patients (.75%) had either no or mild TEAEs and the distribution of TEAEs based on severity was comparable between groups. There was no indication of potential to evoke renal or hepatocellular damage. The fact that no prolongation in the QT interval was seen is consistent with previous data that showed no clinically meaningful QT interval prolongation with ceftaroline 27 and is in keeping with the belief that this is not an event associated with b-lactam antibiotics. The data from the CANVAS trials, which should be confirmed in other clinical studies, suggest that ceftaroline, as a novel cephalosporin, has the traditional safety and tolerability profile that is expected and prized of this class of agents. At this time there appear to be no unusual risks associated with ceftaroline compared with other cephalosporins. It is only the passage of time and the cumulative experience with ceftaroline use that will fully elucidate the complete safety profile of this agent. Based on the safety and tolerability profile of ceftaroline, as well as the efficacy (described separately in this Supplement) demonstrated in the CANVAS trials, it would appear, and is likely to be the case, that ceftaroline fulfils the Ehrlich directive for modern chemotherapy of infectious diseases of a safe and effective antimicrobial agent. offers clinicians a safe and simple monotherapy option, without the need for extensive laboratory monitoring, for the management of csssis when empirical coverage for Gram-positive and Gram-negative pathogens is warranted. Funding Funding for editorial assistance was provided by Forest Laboratories, Inc. iv70

5 Integrated safety summary of CANVAS 1 and 2 JAC Transparency declarations This article was developed from a scientific panel of CANVAS investigators and experts in skin and skin structure infections, held on August 2009 in New York, NY, USA. This article is part of a Supplement sponsored by Forest Laboratories, Inc. M. L. C. has received no funding or pecuniary compensation of any kind other than an honorarium for participation time. Grace Johnson and Monica Dodge of Scientific Therapeutics Information, Inc. (Springfield, NJ, USA) provided editorial assistance on this manuscript. References 1 Mushtaq S, Warner M, Ge Y et al. In vitro activity of ceftaroline (PPI- 0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes. J Antimicrob Chemother 2007; 60: Talbot GH, Thye D, Das A et al. Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. 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