Kegg Pathway: Cephalosporins - parenteral agents

J Pediatr Hematol Oncol. 2009 Sep; 31(9): 635-41
Gupta A, Swaroop C, Agarwala S, Pandey RM, Bakhshi S

BACKGROUND: Outpatient oral therapy is infrequently used in pediatric low-risk febrile neutropenia (LRFN) as there is insufficient data regarding its equivalence as compared with parenteral therapy. METHODS: This is a single institutional, randomized control trial in pediatric LRFN aged 2 to 15 years, in which 123 episodes in 88 patients were randomized to outpatient oral ofloxacin 7.5 mg/kg 12 hourly and amoxycillin-clavulanate 12.5 mg/kg 8 hourly or outpatient intravenous (IV) ceftriaxone 75 mg/kg and amikacin 15 mg/kg once daily after blood cultures. RESULTS: Out of 119 evaluable episodes, one-third were leukemia patients in maintenance and rest were solid tumors. Success was achieved in 55/61 (90.16%) and 54/58 (93.1%) in oral and IV arms, respectively, (P=0.56). There were 3 hospitalizations but no mortality. Median days to resolution of fever, absolute neutrophil count >500/mm(3) and antibiotic use were 3, 5, and 6 days in both arms. There were 5 blood culture isolates (3 gram-positive and 2 gram-negative bacteria). Failure of outpatient therapy was associated with perianal infections, bacteremia, febrile neutropenia onset before day 9 of chemotherapy in solid tumors and Vincristine, actinomycin-D, and cyclophosphamide chemotherapy for rhabdomyosarcoma. All gram-positive isolates were successes, whereas both gram-negative isolates were failures. Diarrhea in IV arm and Vincristine, actinomycin-D, and cyclophosphamide chemotherapy in the oral arm predicted failure in subgroup analysis. CONCLUSIONS: Outpatient therapy is efficacious and safe in pediatric LRFN. There was no difference in outcome in oral versus IV outpatient therapy. Amoxycillin-clavulanate and ofloxacin may be the oral regimen of choice.

J Antimicrob Chemother. 2009 Sep; 64(3): 630-4
Hitchcock J, Jepson AP, Main J, Wickens HJ

BACKGROUND: Outpatient and home parenteral antimicrobial therapy (OHPAT) is becoming increasingly commonplace in the UK, enabling those patients who would previously have been obliged to remain in hospital for intravenous treatment to be managed as outpatients or in their own homes. The OHPAT service at St Mary's Hospital, London, was established in 2004. This paper describes the types of infection, antimicrobial management and outcomes of patients referred to the service in the 3.5 years since its inception. PATIENTS AND METHODS: All inpatients were eligible for OHPAT, provided that they had a serious infection requiring parenteral therapy, were well enough to leave hospital and fulfilled other criteria. We initially used an outpatient clinic model, but as the service developed, treatment was often delivered in patients' homes, with the OHPAT team providing training and assessment of primary care staff. RESULTS: Four hundred and sixty-seven patients were referred to the service between September 2004 and April 2008. Of these, 273 received 303 courses of OHPAT, 48 were discharged on oral therapy and 3 patients declined outpatient therapy; the remaining 143 patients were deemed unsuitable for inclusion, most commonly because the patient was too unwell for discharge (28.7%) or their social situation was inappropriate (14.7%). Causative organisms were identified in two-thirds of cases, with methicillin-resistant Staphylococcus aureus implicated in one-third of these. Mean treatment length was 24 days (range 1-165 days), with 7394 inpatient bed-days saved. Less than 5% of patients were readmitted within 28 days with infection- or drug-related problems. There were no cases of Clostridium difficile-associated diarrhoea during or after outpatient treatment, despite extensive use of Cephalosporins and other broad-spectrum agents. Patients found the service highly satisfactory and felt that it had improved their quality of life during the treatment period. CONCLUSIONS: The introduction of the OHPAT service at St Mary's Hospital has proved to be of benefit to patients and hospital efficiency alike.

J Chemother. 2009 Apr; 21(2): 193-8
Esposito S, Leone S, Noviello S, Ianniello F, Russo M, Foti G, Carpentieri MS, Cellesi C, Zanelli G, Cellini A, Girmenia C, De Lalla F, Maiello A, Maio P, Acone N, Marranconi F, Sabbatani S, Pantaleoni M, Ghinelli F, Soranzo ML, Viganò P, Re T, Viale P, Scudeller L,

Bacterial infections are the most frequent cause of hospitalization in elderly patients. In the early eighties, the advantages of Outpatient parenteral Antibiotic therapy (OPAT) were identified in the United States, and suitable therapeutic programs were established. In order to understand the different ways of managing OPAT, a National OPAT Registry was set up in 2003 in Italy. This study analyzes data concerning bacterial infections in 176 elderly patients including demographics, therapeutic management, clinical response, and side-effects. Bone and joint infections (48.9%) and skin and soft tissue infections (27.8%) were the most common infections treated with OPAT. Teicoplanin (28.9%) and ceftriaxone (22.1%) were the top two antibiotics chosen. OPAT was mainly performed at a hospital infusion center (52.8%). The clinical success rate was high and side-effects were low (12.6% of cases). Management of bacterial infections in the elderly with an outpatient program is effective and safe.

J Antimicrob Chemother. 2009 Jul; 64(1): 200-5
Coenen S, Muller A, Adriaenssens N, Vankerckhoven V, Hendrickx E, Goossens H,

OBJECTIVES: To assess the proportion of parenteral treatment of the total outpatient antibiotic use in Europe, and to identify the antibiotic groups and individual antibiotics most commonly administered in this way. METHODS: Within the European Surveillance of Antimicrobial Consumption (ESAC; www.esac.ua.ac.be), using the anatomic therapeutic chemical (ATC) and defined daily dose (DDD) classification, data on outpatient use of antibacterials for systemic use (ATC J01), aggregated at the level of the active substance and expressed in DDD per 1000 inhabitants per day (DID; WHO version 2007), were extracted for 2006 by route of administration and by country. parenteral use was expressed as a percentage of the total outpatient use in DID. RESULTS: In 20 European countries, the total outpatient antibiotic use ranged from 27.91 DID in France to 9.58 DID in Russia. The proportion of outpatient parenteral antibiotic treatment ranged from 6.75% in Russia to 0.001% in Iceland. The three most commonly used antibiotic groups for parenteral treatment in Europe were the Cephalosporins (J01D; 44.58%), the aminoglycosides (J01G; 25.27%) and the penicillins (J01C; 17.78%). Four antibiotics [gentamicin (J01GB03) 18.53%; ceftriaxone (J01DD04) 17.85%; cefazolin (J01DB04) 13.16%; and lincomycin (J01FF02) 5.47%] represented more than half of the use. CONCLUSIONS: In all 20 European countries studied together, 2.04% of outpatient antibiotics were used for parenteral treatment. However, as for the total outpatient antibiotic use and the use of different antibiotic groups and antibiotics, there is a striking variation in the proportions of parenteral antibiotic use in Europe. More in-depth data on outpatient antibiotic use are needed to explain this variation.

Clin Infect Dis. 2009 May 1; 48(9): 1201-10
Peltola H, Pääkkönen M, Kallio P, Kallio MJ,

BACKGROUND: The standard treatment for septic arthritis in children is antimicrobials for several weeks (initially administered intravenously) and arthrotomy (at least for the hip and shoulder joints). No sufficiently powered study has examined the true need for these treatments. METHODS: In a randomized, multicenter prospective trial in Finland, children aged 3 months to 15 years who had culture-positive septic arthritis were randomized to receive clindamycin or a first-generation cephalosporin for 10 days or 30 days (intravenously for the first 2-4 days). The number of surgical procedures was kept to a minimum. Illness was monitored with preset criteria. Antimicrobial therapy was discontinued when the clinical response was good and the C-reactive protein level decreased to 20 mg/L. The primary end point was full recovery without need for further administration of antimicrobial therapy because of an osteoarticular indication during the 12 months after therapy. RESULTS: Of the total 130 cases, 88% were caused by Staphylococcus aureus, Haemophilus influenzae, or Streptococcus pyogenes; 63 patients were in the short-term treatment group, and 67 were in the long-term treatment group. The median durations of antimicrobial treatment were 10 days and 30 days, respectively. Surgical procedures that were more extensive than percutaneous joint aspiration were performed for 12% of patients, with no preponderance to hip or shoulder arthritis. Two late-onset infections occurred in 1 child in the long-term treatment group; however, all patients recovered without sequelae. CONCLUSIONS: Large doses of well-absorbed antimicrobials for <2 weeks (initially administered intravenously) and only 1 joint aspiration are sufficient for treatment of most cases of childhood septic arthritis, regardless of the infecting pathogen or anatomical site, if the clinical response is good and the C-reactive protein level normalizes shortly after initiation of treatment.

Pediatrics. 2009 Apr; 123(4): e609-13
Bradley JS, Wassel RT, Lee L, Nambiar S

OBJECTIVES: Unsolicited reports regarding potentially serious adverse drug reactions in neonates and young infants were reported to the Food and Drug Administration, leading to changes in the package label for ceftriaxone. This report describes and summarizes the reported cases that led to safety concerns regarding the concurrent administration of intravenous ceftriaxone and calcium in this age group. METHODS: Nine reported cases were assessed. The Food and Drug Administration Adverse Event Reporting System database was searched for potential drug interactions in patients who were receiving concomitant ceftriaxone and calcium therapy. RESULTS: Eight of the reported 9 cases (7 were < or =2 months of age) represented possible or probable adverse drug events. There were 7 deaths. None of the cases were reported from the United States. The dosage of ceftriaxone that was administered to 4 of 6 infants for whom this information was available was between 150 and 200 mg/kg per day. The rate of occurrence of these serious adverse drug reactions cannot be accurately determined from available data. CONCLUSIONS: The concurrent use of intravenous ceftriaxone and calcium-containing solutions in the newborn and young infant may result in a life-threatening adverse drug reaction. Contributing factors for infants in this report may include the use of ceftriaxone at dosages higher than those approved by the Food and Drug Administration, intravenous "push" administration, and administration of the total daily dosage as a single infusion.

Acta Chir Belg. 2008 Nov-Dec; 108(6): 777-8
Ozen IO, Moralioğlu S, Karabulut R, Bagbanci B, Turkyilmaz Z, Demirogullari B, Sonmez K, Basaklar AC, Kale N

Cefoperazone is a parenteral third generation cephalosporin which is active against many Gram positive and Gram negative organisms. Cefaperazone, like other Cephalosporins which contain methyltiotetrazole side chain, can cause hypoprotrombinaemia and bleeding problems. Here we report a nine-year old child with Meckel's diverticulum who had cefoperazone induced massive gastrointestinal bleeding on the fifth day following the operation.

Drugs Today (Barc). 2008 Nov; 44(11): 801-25
Del Pozo JL, Patel R

Ceftobiprole is a novel parenteral cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin-binding protein (PBP) 2a, rendering it active against methicillin-resistant staphylococci. Its in vitro activity against staphylococci and multiresistant pneumococci, combined with its Gram-negative spectrum comparable to that of other extended-spectrum Cephalosporins, its stability against a wide range of beta-lactamases and its pharmacokinetic and safety profile make ceftobiprole an attractive new antimicrobial agent. Because of its low water solubility, ceftobiprole is administered intravenously as a prodrug, ceftobiprole medocaril. Ceftobiprole medocaril is generally well tolerated (with the exception of a caramel-like taste disturbance). Ceftobiprole medocaril has been evaluated in two phase III clinical trials for the treatment of complicated skin infections and skin structure infections. Its broad spectrum of activity may allow ceftobiprole to be used as monotherapy for some infections where combination therapy would otherwise be required, especially regimens requiring coverage of methicillin-resistant Staphylococcus aureus (MRSA).

Rev Bras Ginecol Obstet. 2008 Feb; 30(2): 93-100
Duarte G, Marcolin AC, Quintana SM, Cavalli RC

Several factors cause urinary tract infection (UTI) to be a relevant complication of the gestational period, aggravating both the maternal and perinatal prognosis. For many years, pregnancy has been considered to be a factor predisposing to all forms of UTI. Today, it is known that pregnancy, as an isolated event, is not responsible for a higher incidence of UTI, but that the anatomical and physiological changes imposed on the urinary tract by pregnancy predispose women with asymptomatic bacteriuria (AB) to become pregnant women with symptomatic UTI. AB affects 2 to 10% of all pregnant women and approximately 30% of these will develop pyelonephritis if not properly treated. However, a difficult-to-understand resistance against the identification of AB during this period is observed among prenatalists. The diagnosis of UTI is microbiological and it is based on two urine cultures presenting more than 10(5) colonies/mL urine of the same germ. Treatment is facilitated by the fact that it is based on an antibiogram, with no scientific foundation for the notion that a pre-established therapeutic scheme is an adequate measure. For the treatment of pyelonephritis, it is not possible to wait for the result of culture and previous knowledge of the resistance profile of the antibacterial agents available for the treatment of pregnant women would be the best measure. Another important variable is the use of an intravenous bactericidal antibiotic during the acute phase, with the possibility of oral administration at home after clinical improvement of the patient. At our hospital, the drug that best satisfies all of these requirements is cefuroxime, administered for 10-14 days. Third-generation Cephalosporins do not exist in the oral form, all of them involving the inconvenience of parenteral administration. In view of their side effects, aminoglycosides are considered to be inadequate for administration to pregnant women. The inconsistent insinuation of contraindication of monofluorinated quinolones, if there is an indication, norfloxacin is believed to be a good alternative to cefuroxime. In cases in which UTI prophylaxis is indicated, chemotherapeutic agents are preferred, among them nitrofurantoin, with care taken to avoid its use at the end of pregnancy due to the risk of kernicterus for the neonate.

Pediatr Infect Dis J. 2009 Jan; 28(1 Suppl): S37-42
Darmstadt GL, Batra M, Zaidi AK

BACKGROUND: A number of special issues must be considered when selecting simple, safe, inexpensive, and effective antimicrobial regimens for treatment of neonatal sepsis in developing country community settings. METHODS: We reviewed available data regarding pharmacologic profiles of parenteral antibiotics with specific attention to properties relevant to their use in the treatment of neonatal infections in developing country communities. RESULTS: For community-based management of neonatal infections, particularly attractive properties include efficacy and safety of extended-interval, intramuscular dosing regimens. The penicillins and Cephalosporins have relatively favorable efficacy and safety profiles. Although the aminoglycosides have narrow therapeutic indices, when used appropriately, they are safe and effective. Although inexpensive and effective, the potential for significant life-threatening toxicity among neonates associated with chloramphenicol makes it the least preferred of the parenteral agents for empiric therapy. CONCLUSIONS: The preferred parenteral regimens for community and first-level facility use are a combination of procaine penicillin G and gentamicin, or ceftriaxone given alone, which are safe and retain efficacy when dosed at extended intervals (> or =24 hours) by intramuscular administration.

Antimicrob agents Chemother. 2009 Mar; 53(3): 1278-80
Prakash V, Lewis JS, Herrera ML, Wickes BL, Jorgensen JH

Effective therapeutic options are needed for community-onset urinary tract infections due to Escherichia coli strains that produce CTX-M extended-spectrum beta-lactamases. We examined 46 urinary isolates producing CTX-M against several oral or long-acting parenteral antimicrobial agents. Approximately 90% were susceptible to fosfomycin and to a combination of cefdinir plus amoxicillin-clavulanate. All were susceptible to ertapenem.

Antimicrob agents Chemother. 2009 Mar; 53(3): 883-7
Zeller V, Durand F, Kitzis MD, Lhotellier L, Ziza JM, Mamoudy P, Desplaces N

Cefazolin has been used for many years to treat bone and joint infections. Because of its time-dependent antimicrobial activity, continuous infusion would potentially be beneficial. We report on the feasibility, safety, and efficacy of prolonged continuous intravenous cefazolin therapy in a cohort of 100 patients, their serum cefazolin levels, and the concomitant bone cefazolin concentrations in 8 of them. This retrospective cohort study included all the patients treated for bone or joint infection with a continuous cefazolin infusion administered over a 12-h period twice daily for >or=2 weeks. Drug monitoring was performed at least twice for all the patients. Serum and bone cefazolin concentrations were determined by standardized disk diffusion microbiological assays. The absence of clinical, biological, and radiological signs of infection after 2 years of follow-up and the same criteria after 1 year of follow-up defined cures and probable cures, respectively. The median treatment duration was 42 days, and the median daily cefazolin dose was 6 g. Half of the patients received parenteral antibiotic therapy on an outpatient basis. Two moderate-grade adverse events were observed. The median serum cefazolin concentrations were 63 microg/ml (range, 13 to 203 microg/ml) and 57 microg/ml (range, 29 to 128 microg/ml) on days 2 to 10 and days 11 to 21, respectively. The median bone cefazolin concentration reached 13.5 microg/g (range, 3.5 to 29 microg/g). The median bone concentration/serum concentration ratio was 0.25 (range, 0.06 to 0.41). Among 88 patients with a median follow-up of 25 months (range, 12 to 53 months), 52 were considered cured and 29 were considered probably cured. Thus, the treatment of bone and joint infections with a prolonged continuous intravenous cefazolin infusion was feasible, effective, well-tolerated, safe, and convenient, making it a strong candidate for home therapy.

Pediatr Int. 2008 Dec; 50(6): 797-800
Tseng MH, Lo WT, Lin WJ, Teng CS, Chu ML, Wang CC

BACKGROUND: There is growing concern regarding antimicrobial resistance worldwide, particularly of Escherichia coli, and the first choice of an antimicrobial agent for empiric treatment of pediatric urinary tract infection (UTI) is not well established. METHODS: The medical records from January 1991 to December 2005 for all children under 18 years of age admitted to Tri-Service General Hospital, Taipei for their first UTI were reviewed. Two study periods, early (1991-2000) and late (2001-2005), were chosen during the 15 year period for evaluating the trend of antimicrobial resistance. RESULTS: Of the 368 isolates, E. coli was the most common pathogen (81.0%), followed by Klebsiella pneumoniae (6.5%), Enterococcus spp. (6.0%), and Proteus mirabilis (3.5%). Of the 368 isolates, 77.4% were resistant to ampicillin, 44.6% to co-trimoxazole, 27.2% to cephalothin, 15.0% to gentamicin, and 8.4% to nitrofurantoin. In the early (1991-2000) and late (2001-2005) study periods, 199 isolates (54.1%) and 169 isolates (45.9%), respectively, were compared. The resistance to antimicrobial agents for overall pathogens in the early and late study periods, respectively, was as follows: 68.8% and 88.0% to ampicillin, 48.9% and 46.6% to co-trimoxazole, 26.8% and 28.9% to cephalothin, 16.2% and 19.8% to gentamicin, and 8.7% and 9.0% to nitrofurantoin. CONCLUSION: Among commonly used antimicrobial agents for the treatment of pediatric UTI, there is a trend towards increasing resistance to ampicillin and a persistently low resistance rate to gentamicin, cephalosporin, and nitrofurantoin. parenteral first-generation Cephalosporins, gentamicin, and oral nitrofurantoin should be considered for first-line agents, given the resistance patterns of this study.

Pediatr Rev. 2008 Dec; 29(12): 417-29; quiz 430
Mann K, Jackson MA

* Young infants who have meningitis may present with nonspecific clinical manifestations. * S. pneumoniae and N. meningitidis remain the most common causes of bacterial meningitis in the infant and child, and GBS continues to be the most common neonatal pathogen. * Empiric therapy for suspected bacterial meningitis in a non-neonate includes a combination of parenteral vancomycin and either cefotaxime or ceftriaxone. * Children whose GCS scores are less than 8, show signs of shock or respiratory compromise, and have focal neurologic findings or clinical signs of elevated intracranial pressure should be admitted to a pediatric intensive care unit. * Sensorineural hearing loss occurs in 30% of children who have pneumococcal and 10% of those who have meningococcal meningitis.

Antimicrob agents Chemother. 2009 Feb; 53(2): 552-6
McGee L, Biek D, Ge Y, Klugman M, du Plessis M, Smith AM, Beall B, Whitney CG, Klugman KP

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.

Dermatol Clin. 2009 Jan; 27(1): 49-61
Rosen T, Vandergriff T, Harting M

Sexually transmissible diseases (STDs) remain a major health issue worldwide, with approximately 300 million new cases annually. STDs caused by bacteria can be treated with antibiotics, although the susceptibility pattern of many etiologic microbes has changed over the past few decades. Syphilis remains best managed with single-dose benzathine penicillin G. Other single-dose antibiotic regimens for lues are either associated with clinical failure or of uncertain dosage. However, single-dose azithromycin and ceftriaxone are suitable for chancroid. Lymphogranuloma venereum, reemergent as a cause of proctitis, is treated with prolonged courses of doxycycline or minocycline. Trimethoprim-sulfamethoxazole has replaced tetracycline derivatives as preferred treatment for donovanosis in many regions. parenteral Cephalosporins, such as ceftriaxone, cefotaxime, and ceftizoxime, are initial interventions for disseminated gonococcemia. Pending culture results, genital bite wounds (often consisting of deep, painful ulcerations) should be treated with high-dose amoxicillin-clavulanic acid.

Int J Antimicrob agents. 2009 Feb; 33(2): 163-7
Arguedas A, Cespedes J, Botet FA, Blumer J, Yogev R, Gesser R, Wang J, West J, Snyder T, Wimmer W,

The carbapenem antibiotic ertapenem has been shown to be safe, well tolerated and effective in treating adults with complicated urinary tract infection, skin and soft-tissue infection and community-acquired pneumonia. In this study, we evaluated ertapenem for treating these infections in children in a randomised, double-blind, active-controlled clinical trial. The primary outcome was the incidence of clinical and laboratory drug-related serious adverse events (AEs). Children were randomised in a 3:1 ratio (ertapenem:ceftriaxone) stratified by index infection and age to receive ertapenem or ceftriaxone; 303 children received ertapenem and 100 children received ceftriaxone. The median duration of parenteral therapy was 4 days for both treatments. The most commonly reported drug-related clinical AEs during parenteral therapy were diarrhoea (5.9% ertapenem, 10% ceftriaxone), infusion site erythema (3% ertapenem, 2% ceftriaxone) and infusion site pain (5% ertapenem, 1% ceftriaxone). One child in each group reported a serious drug-related clinical AE. No serious drug-related laboratory AEs were reported. In children aged 3 months to 17 years, ertapenem was well tolerated and had a comparable safety profile to that of ceftriaxone.

Recenti Prog Med. 2008 Jul-Aug; 99(7-8): 343-6
Montini G

Urinary tract infection (UTI) is one of the most common bacterial infections in infancy, its prevalence being 5% in febrile infants (2 to 24 months of age). 10 to 20% of febrile UTIs may result in permanent renal damage (scar), whose long-term significance (hypertension or proteinuria) in previously normal kidneys remains unclear. A wide variety of antibiotic agents have been used, generally administered aggressively by intravenous route and for long periods (up to three weeks), to possibly prevent scar formation and/or sepsis complications. Recent studies suggest that children with febrile UTIs can be effectively treated with oral antibiotics such as cefixime or amoxycillin/clavulanic acid for 10 to 14 days.

Perit Dial Int. 2008 Sep-Oct; 28(5): 540-2
Lam MF, Tang BS, Tse KC, Chan TM, Lai KN

Bioorg Med Chem Lett. 2008 Sep 1; 18(17): 4849-52
Toda A, Ohki H, Yamanaka T, Murano K, Okuda S, Kawabata K, Hatano K, Matsuda K, Misumi K, Itoh K, Satoh K, Inoue S

We describe herein the synthesis and biological evaluation of a series of novel Cephalosporins with potent activity against Pseudomonas aeruginosa. Introduction of various amino groups to the 4-position of a 3-amino-2-methylpyrazole cephalosporin 3-side chain resulted in enhanced MIC values against multiple Pseudomonas aeruginosa strains and ultimately led to the discovery of FR264205 (15) with excellent anti-bacterial activity and weak convulsion effect by direct intracerebroventricular injection assay.