Cefepime versus ceftazidime as empirical therapy for fever in neutropenic patients with haematological malignancies

An open randomized comparative study was conducted to evaluate the efficacy of Cefepime (2 gm iv. 8 hr.) vs. ceftazidime (2 gm iv. every 8 hr.) in empirical therapy of febrile neutropenic patients. A total of 40 eligible febrile episodes were randomized to be treated with study regimen. Twenty febrile episodes were treated with cefepime and 20 were treated with ceftazidime. The two groups were comparable in terms of age, sex, height, underlying neoplasm, number of pretherapy neutrophils, duration of neutropenia. The overall therapeutic success rate of cetepime group (60%) was comparable to that of ceftazidime group (55%). The results of this study suggest that cefepime is an effective and safe agent in empirical therapy of febrile episode in neutropenic patient and its efficacy is comparable with that of ceftazidime.     

Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients

 Infections remain the major cause of morbidity and mortality among neutropenic cancer patients. The current study addresses the question whether monotherapy with the new broad-spectrum carbapenem meropenem exhibits efficacy comparable to that of the standard combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Seventy-one patients with hematological malignancies (55%) or solid tumors (45%), neutropenia <500/μl, and fever <38.5  °C were randomly assigned to either meropenem (1 g every 8 h) or ceftazidime (2 g every 8 h) and amikacin (15 mg/kg/day) intravenously. Meropenem (n=34) and ceftazidime/amikacin (n=37) were equivalent with respect to the clinical response at 72 h (62% versus 68%) (p<0.05) and at the end of unmodified therapy (59% versus 62%). Gram-positive bacteremia responded poorly in the meropenem and ceftazidime/amikacin group (29% versus 25%), whereas all gram-negative bacteremias responded except for one in the meropenem group caused by Pseudomonas aeruginosa. All patients survived to 72 h. One patient in each group died of gram-positive sepsis resistant to study medication. No significant side effects occurred in any regimen. This study suggests that meropenem monotherapy might be as effective as combination therapy with ceftazidime and amikacin for the empirical treatment of febrile neutropenic patients. Received: 13 June 1997 / Accepted in revised form: 5 December 1997     

Vancomycin as part of initial empirical antibiotic therapy for febrile neutropenia in patients with cancer: pros and cons.

Gram-positive organisms predominate as the bacterial pathogens identified in episodes of febrile neutropenia. This has led to increased use of antibiotics with efficacy against gram-positive organisms (often vancomycin) as part of empirical antibiotic regimens for treating febrile neutropenia. Among 101 children randomized to receive amikacin, ticarcillin, and vancomycin or ticarcillin/clavulanate and amikacin along with vancomycin placebo, treatment success in those treated with vancomycin was higher (85% vs. 62%). In 1990, the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada Clinical Trials Group compared amikacin and ceftazidime with and without vancomycin and concluded that there was no need to include vancomycin in initial empirical antibiotic therapy. Results from another study and a retrospective review of a large clinical trial also support the previous conclusion. In 1999, most experts in the field recommend vancomycin not be part of the initial empirical therapy regimen for treating febrile neutropenia in patients with cancer.     

肿瘤患者粒细胞缺乏症并感染的经验性抗生素治疗回顾性分析

目的　总结肿瘤患者粒细胞缺乏症并感染的经验性抗生素治疗的临床经验。方法　回顾性分析 119例肿瘤患者 2 4 8例次的临床资料 ,观察头孢哌酮 (CFP)、氧哌嗪青霉素 (PPC)、头孢他定 (CTZ)、亚胺培南 (IMP)与丁胺卡那霉素 (AMK)分别组成BA、PA、CA、TA方案的疗效及副作用。结果　BA、PA、CA、TA方案分别治疗 10 3、87、35和 2 3例次 ,治疗的中位时间为 7～ 8d ,有效率分别为 6 3%、4 8%、6 8%和 74 % ,PA方案明显为低 (P <0 0 5 )。治疗无效者调整治疗 :改用CA或TA方案加减去甲万古霉素 (NVC)及抗真菌治疗 ;总有效率分别为 88%、83%、86 %和 91%。最常见副作用为胃肠功能紊乱 ,腹泻为 12 % ,皮疹和肝转氨酶轻度升高分别为 4 % ;2例NVC和AMK治疗者出现明显的听力下降和肾脏毒性。结论　BA、CA、TA方案具有相似的疗效 ,可作为一线经验性治疗方案。经验性治疗无效者 ,应改用具有更高抗菌活性的方案或尽早采用NCV和 (或 )抗霉菌治疗     

Meta-analysis: combination of meropenem vs ceftazidime and amikacin for empirical treatment of cancer patients with febrile neutropenia

Background:Meropenem monotherapy vs ceftazidime plus amikacin have been approved for use against febrile neutropenia. To assess the effectiveness and safety of them for empirical treatment of cancer patients with febrile neutropenia, we conducted a meta-analysis of randomized controlled trial.Methods:Randomized controlled trials on ceftazidime plus amikacin, or/and monotherapy with meropenem for the treatment of cancer patients with febrile neutropenia were identified by searching Cochrane Library, PubMed, Science Direct, Wiley Online, Science Citation Index, Google (scholar), National Center for Biotechnology Information, and China National Knowledge Infrastructure. Data on interventions, participants’ characteristics and the outcomes of therapy, were extracted for statistical analysis. Seven trials fulfilled the inclusion criteria.Result:The treatment with ceftazidime plus amikacin was more effective than meropenem (OR = 1.17; 95% CI 0.93–1.46; 1270 participants). However, the treatment effects of the 2 therapy methods were almost parallel in adults (OR = 1.15; 95% CI 0.91–1.46; 1130 participants older than 16). Drug-related adverse effects afflicted more patients treated with ceftazidime plus amikacin (OR = 0.78; 95% CI 0.52–1.15; 1445 participants). The common responses were nausea, diarrhea, rash, and increased in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin.Conclusion:Ceftazidime plus amikacin should be the first choice for empirical treatment of cancer patients with febrile neutropenia, and meropenem may be chosen as a last defense against pathogenic bacteria.     

Piperacillin–Tazobactum Plus Amikacin Versus Ceftazidime Plus Amikacin as Empirical Therapy for Fever in Neutropenic Patients with Hematological Malignancies

Infections are one of the main cause of death in cancer patients particularly when granulocytopenia is present. A number of drugs have been used for the treatment of neutropenic patients with fever. Most published literature has shown piperacillin–tazobactum in combination with amikacin to be significantly more effective than ceftazidime plus amikacin in empirical treatment of febrile episodes in patients with neutropenia. In view of the reported literature we have tried this combination in our febrile neutropenic patients with haematological malignancies at PGIMS Rohtak. It was an open randomized trial. Patients were divided into two groups of 20 each. In the first group (group A) piperacillin–tazobactum (4 + 0.5 g 6 hourly) with single daily dose of amikacin 20 mg/kg was given. In the second group (group B) ceftazidime 40 mg/kg every 8 hourly with single daily dose of amikacin 20 mg/kg was given. The most common site of infection was blood followed by urinary tract, respiratory tract and oral cavity. 13 (65%) patients in group A and 12 (60%) patient in group B showed clinical success. In our study however in our patients a better response was seen in patients with piperacillin–tazobactum + amikacin (65% vs. 60%). So it is recommended that piperacillin–tazobactum + amikacin should be given in febrile neutropenic patients with haematological malignancies.     

A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients.

BACKGROUND--Neutropenic patients with cancer are traditionally treated with empiric antibiotic combinations when they become febrile. The availability of broad-spectrum antibiotics such as ceftazidime and imipenem has made it possible to initiate therapy with a single agent (monotherapy). The objectives of this trial were to compare ceftazidime and imipenem as single agents for the therapy of febrile episodes in neutropenic patients and to ascertain whether the addition of an aminoglycoside (amikacin) to either of these agents would provide an advantage. METHODS--A prospective clinical trial was conducted in which eligible neutropenic patients with cancer were randomized to one of four treatment arms: ceftazidime alone; imipenem alone; ceftazidime plus amikacin; and imipenem plus amikacin. Efficacy analysis was done for 750 assessable episodes. A multivariate logistic-regression analysis was also performed to examine the unique contribution of various prognostic factors. RESULTS--The overall response rates were 76% with imipenem plus amikacin, 72% with imipenem, 71% with ceftazidime plus amikacin, and 59% with ceftazidime alone. Single-organism gram-positive infections occurred in 101 of 750 episodes. Without a change in antibiotics, the response rates were 50% with imipenem, 40% with imipenem plus amikacin, 39% with ceftazidime plus amikacin, and 38% with ceftazidime. Most responded to vancomycin or other antibiotics, and the mortality associated with gram-positive infections was only 5%. Regardless of the antibiotic regimen, the majority of uncomplicated gram-negative infections responded to therapy and the majority of complicated gram-negative infections failed to respond. Multivariate logistic-regression analysis showed that recovery of the neutrophil count was the most favorable prognostic factor in a patient's response to infection, whereas the presence of gram-positive infection, acute leukemia, pulmonary or enteric infection, and therapy with ceftazidime were unfavorable factors. CONCLUSIONS--Single-agent therapy with imipenem is as effective as more conventional combination antibiotic therapy for the empirical treatment of febrile episodes in neutropenic patients with cancer.     

A RANDOMISED TRIAL OF EMPIRICAL ANTIBIOTIC THERAPY IN FEBRILE NEUTROPENIC PATIENTS WITH HEMATOLOGICAL DISORDERS: CEFTAZIDIME VERSUS AZLOCILLIN PLUS AMIKACIN

One hundred and two patients with neutropenia (<1 × 10⁹/L) secondary to primary hematological disorders or chemotherapy for hematological malignancies were prospectively randomised, upon the development of fever or other signs of infection, to receive empirical antibiotic treatment with either ceftazidime (± flucloxacillin) (n = 52) or azlocillin plus amikacin (± flucloxacillin) (A&A, n = 50). The two groups were equivalent with respect to clinical and laboratory parameters prior to antibiotic therapy and flucloxacillin was added to approximately 25% of the patients in each group on the clinical suspicion of Gram positive infection. When assessed at 96 hours, the complete response rates were 59.6% for the ceftazidime treated patients and 44% for A&A treated patients. Partial response rates were 17% and 20% respectively. This difference was not statistically significant. Eight patients died whilst on the trial, three of those initially randomised to ceftazidime and five initially randomised to A&A. Moderate to severe hypokalemia was encountered significantly less often in the ceftazidime treated group (p< 0.01), whilst other parameters of toxicity were equivalent. No primary or acquired resistance to ceftazidime was encountered. Separate analysis of those patients who did not receive flucloxacillin yielded identical results. We conclude that ceftazidime (±flucloxacillin) is as efficacious as azlocillin plus amikacin (±flucloxacillin) in the empirical antibiotic management of such patients and is associated with a lower incidence of moderate to severe hypokalemia.     

Antimicrobial resistance among clinical isolates of Pseudomonas aeruginosa from patients in a teaching hospital, Riyadh, Saudi Arabia, 2001-2005

Antimicrobial resistance to nine anti-pseudomonal agents (azteronam, ceftazidime, cefepime, piperacillin/tazobactam, imipenem, meropenem, ciprofloxacin, amikacin and gentamicin), the magnitude of multidrug resistance, associated underlying conditions, and mortality among patients with Pseudomonas aeruginosa isolates from King Khalid University Hospital, Riyadh, Saudi Arabia from 2001 to 2005 were determined. The results showed that antimicrobial resistance among P. aeruginosa is gradually increasing for most anti-pseudomonal agents, particularly aztreonam, ceftazidime, piperacillin/tazobactam and imipenem. There were 19 (3%) and 12 (2%) multidrug-resistant (MDR) P. aeruginosa patients in 2004 and 2005, respectively, and MDR P. aeruginosa was more commonly found in non-intensive care unit (ICU) patients. Most MDR isolates were from surgical and diabetic patients. The mortality rate was higher among ICU patients.     

Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia.

Sixty-four consecutive febrile episodes in 50 consecutive patients with malignancy and neutropenia were empirically treated with a combination of ceftazidime and amikacin. Of 52 analysable episodes, the response rate was 59.6% overall and 26.3% of episodes with microbiologically documented infections with septicaemia. Infection-related death occurred in 10 patients (19.2% of episodes). The response rates were similar in patients with acute leukaemia or other malignancies. Poor response is attributed to increased frequency of infections with Gram-positive and fungal organisms. A modified empiric regimen including cover for Gram-positive and fungal organisms is suggested in similar patient populations.     

Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial

Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.     

Cefepime

Abstract

Cefepime (Maxipime®, Maxcef®, Cepimax®, Cepimex®, Axepim®¹), a parenteral fourth-generation cephalosporin, is active against many organisms causative in pneumonia. Cefepime has in vitro activity against Gram-positive organisms including Staphylococcus aureus and penicillin-sensitive, -intermediate and -resistant Streptococcus pneumoniae similar to that of cefotaxime and ceftriaxone. Cefepime also has good activity against Gram-negative organisms, including Pseudomonas aeruginosa, similar to that of ceftazidime. Importantly, cefepime is stable against many of the common plasmid- and chromosome-mediated β-lactamases and is a poor inducer of AmpC β-lactamases. As a result, it retains activity against Enterobacteriaceae that are resistant to third-generation cephalosporins, such as derepressed mutants of Enterobacter spp. Cefepime may be hydrolyzed by the extended-spectrum β-lactamases produced by some members of the Enterobacteriaceae, but to a lesser extent than the third-generation cephalosporins.Monotherapy with cefepime 1 or 2g, usually administered intravenously twice daily, was as effective for clinical and bacteriological response as ceftazidime, ceftriaxone or cefotaxime monotherapy (1 or 2g two or three times daily) in a number of randomized, clinical trials in hospitalized adult, or less commonly, pediatric, patients with generally moderate to severe community-acquired or nosocomial pneumonia. More limited data indicated that monotherapy with cefepime 2g three times daily was also as effective in treating patients with nosocomial pneumonia as imipenem/cilostatin 0.5g four times daily, and when combined with amikacin, cefepime was as effective as ceftazidime plus amikacin. Patients with pneumonia who failed to respond to previous antibacterial therapy with penicillins or other cephalosporins responded to treatment with cefepime.Cefepime is generally well tolerated, with a tolerability profile similar to those of other parenteral cephalosporins. In clinical trials, the majority of adverse events experienced by cefepime recipients were mild to moderate and reversible. The most common adverse events with a causal relationship to cefepime reported in clinical trials included rash and diarrhea. Other, less common, adverse events included pruritus, urticaria, nausea, vomiting oral candidiasis, colitis, headache, fever, erythema and vaginitis. Conclusion: Cefepime is an established and generally well tolerated parenteral drug with a broad spectrum of antibacterial activity which, when administered twice daily, provides coverage of most of the pathogens that may be causative in pneumonia. In randomized clinical trials in hospitalized patients with generally moderate to severe community-acquired or nosocomial pneumonia, cefepime monotherapy exhibited good clinical and bacteriological efficacy. Cefepime may become a preferred antibacterial agent for infections caused by Enterobacter spp. With prudent use in order to prevent the emergence of resistant organisms, cefepime will continue to be a suitable option for the empiric treatment of pneumonia.

Antibacterial Activity

Cefepime acts by binding to penicillin-binding proteins and inhibiting the synthesis of the bacterial cell wall. Due to its zwitterionic nature, cefepime can penetrate the porins of the outer membrane of Gram-negative bacteria faster than the third-generation cephalosporins.Cefepime has a broad spectrum of antibacterial activity in vitro. Data from large in vitro or surveillance studies collecting isolates since 1997 have shown that cefepime is active against Gram-positive and Gram-negative bacteria commonly implicated in pneumonia. Using the newly revised US National Committee for Clinical Laboratory Standards cefepime breakpoints for Streptococcus pneumoniae, cefepime is highly active against strains of penicillin-susceptible and -intermediate S. pneumoniae and has good activity against penicillin-resistant strains. Ceftazidime, cefotaxime, ceftriaxone and imipenem were also highly active against penicillin-susceptible strains of S. pneumoniae. Against penicillin-intermediate or -resistant strains, cefepime exhibited similar activity to cefotaxime, ceftriaxone and imipenem, but was more active than ceftazidime. Cefepime shows excellent activity against methicillin-susceptible Staphylococcus aureus, similar to that of cefotaxime, ceftriaxone and imipenem, and better than that of ceftazidime. However, like other β-lactam agents, cefepime is inactive against methicillin-resistant S. aureus.Cefepime has excellent in vitro activity against Escherichia coli, Klebsiella spp., Haemophilus influenzae and Moraxella catarrhalis similar to that of ceftazidime, ceftriaxone, cefotaxime and imipenem. Cefepime has good activity against Enterobacter spp. similar to that of imipenem and better than that of the third-generation cephalosporins. Additionally, cefepime has similar activity against Pseudomonas spp. as ceftazidime and imipenem. Cefepime showed little activity against Stenotrophomonas maltophilia and highly variable activity against Acinetobacter spp., similar to that of the third-generation cephalosporins. Additionally, like the third-generation cephalosporins, cefepime had highly variable activity against anaerobes, such as Bacteroides spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Prevotella spp. and Veilonella spp. that are commonly causative pathogens of aspiration pneumonia.Cefepime is stable against the common plasmid-mediated β-lactamases including TEM-1, TEM-2, SHV-1, OXA-2, OXA-3, PSE-1 to PSE-4 and ROB-1 and the chromosomal cephalosporinases K14, P99 and BRO-1. Unlike the third-generation cephalosporins, cefepime does not induce AmpC β-lactamase hyperproduction and has enhanced stability against the AmpC chromosomal β-lactamases produced by Enterobacter spp. and P. aeruginosa. Cefepime has moderate activity against Enterobacteriaceae producing plasmid-mediated AmpC β-lactamases. However, like most β-lactam agents, cefepime may be hydrolyzed by the extended-spectrum β-lactamases, but to a lesser extent than the third-generation cephalosporins.The administration of cefepime (1g twice daily for 5 or 8 days) to a total of 14 healthy men in two studies resulted in few changes to the fecal flora. The total mean counts of bacteria changed only slightly and returned to normal after the cessation of cefepime administration. Clostridium difficile was detected in the feces of one participant in each study; however, neither volunteer experienced diarrhea.Cefepime, like other β-lactam agents, exhibits time-dependent bactericidal activity. A number of studies using pharmacokinetic data from healthy volunteers combined with in vitro data for the inhibition of various bacterial isolates have shown that intermittent doses (1 or 2g twice daily) or continuous infusions (3 or 4g over a 24 hour period) of cefepime were associated with plasma concentrations above the minimum inhibitory concentration required to inhibit the growth of 90% of isolates for a sufficient proportion of the dosage interval for the majority of Enterobacteriaceae, streptococci and staphylococci tested.

Pharmacokinetic Properties

The absorption kinetics of cefepime are linear over the 0.25–2g dose range. After intravenous administration, maximum cefepime plasma or serum concentrations (C_max) were 16–133 mg/L over the 0.25–2g dose range, whereas the same doses of cefepime administered via intramuscular injection achieved C_max values of 8–58 mg/L in healthy volunteers. The absorption of intramuscular cefepime (0.25–2g) was rapid, as the time to C_max was reached after 1.00–1.58 hours. The bioavailability of intramuscular cefepime was approximately 100% in healthy volunteers. There was no accumulation of cefepime after multiple intravenous or intramuscular administration to individuals with normal renal function.The plasma protein binding of cefepime is relatively low (14–19% in healthy adult volunteers). Cefepime has been shown to penetrate bronchial mucosa and lung tissue. The volume of distribution at steady-state was not dependent on the dose and ranged from 16–19L in healthy adult volunteers.Cefepime undergoes minimal metabolism and is primarily eliminated as unchanged drug by the kidneys. The total clearance (CL_T) and renal clearance (CL_R) of cefepime are independent of the administered dose, but are directly proportional to the rate of creatinine clearance. After a single intravenous or intramuscular injection of cefepime (0.25–2g), CL_T and CL_R ranged from 7.32–9.12 L/h (122–152 mL/min) and 5.4–8.28 L/h (90–138 mL/min), respectively. The mean elimination half-life (t1/2) of cefepime is independent of the dose and after intravenous or intramuscular administration of cefepime (0.25–2g) in healthy adults was about 2–2.4 hours.The pharmacokinetics of cefepime were not significantly affected by acute respiratory illness. The elimination kinetics of cefepime in healthy elderly volunteers with normal renal function for their age differed from those of younger volunteers but this was not clinically significant. The pharmacokinetics of cefepime in children and adolescents were similar to those previously determined for healthy adults.As cefepime is eliminated by the kidneys, patients with renal impairment have slower elimination kinetics than healthy volunteers. In a study in patients with varying degrees of renal impairment, the CL_T and CL_R decreased and the t1/2 increased with decreasing renal function. Studies in patients with renal failure have shown that hemodialysis, hemofiltration and continuous renal replacement therapies effectively eliminate cefepime. The pharmacokinetics of cefepime in individuals with hepatic impairment are not appreciably different from those in healthy volunteers.

Therapeutic Efficacy

In randomized, generally nonblind trials, cefepime monotherapy was as effective as monotherapy with ceftazidime or ceftriaxone in adult patients with community-acquired (CAP). In clinically evaluable patients with CAP treated with cefepime (1 or 2g twice daily), clinical response rates (resolution or improvement) at the end of therapy ranged from 79–95% of patients and were generally similar to those achieved in the recipients of comparator drugs (1 or 2g two or three times daily; range 73–98% of patients). Bacteriological eradication rates (complete or presumed) in cefepime recipients (91–100% of patients or isolated pathogens) were similar to those achieved with ceftazidime and ceftriaxone (97–100% of patients or isolated pathogens).Similarly, in patients with CAP or nosocomial pneumonia (hospital-acquired pneumonia; HAP) or pneumonia of unspecified origin, cefepime monotherapy (1 or 2g twice daily) provided similar clinical efficacy to monotherapy with ceftazidime (1 or 2g two or three times daily) [58–90% vs 60–94% of patients] or cefotaxime (2g three times daily) [92% and 98% vs 86% and 93% of patients]. Cefepime recipients also achieved similar bacteriological eradication rates to those receiving ceftazidime (85–97% vs 73–97% of pathogens) or cefotaxime (100% vs 93% of patients with bacterial eradication and 95% of pathogens eradicated).Cefepime monotherapy (2g three times daily) produced a similar satisfactory response rate to (59% vs 57% of patients), and a slightly higher bacteriological eradication rate (52% vs 44%) than, imipenem/cilastatin 0.5g four times daily for patients with nosocomial pneumonia admitted to the ICU.In three randomized, comparative clinical trials in pediatric patients with CAP or HAP, monotherapy with cefepime (50 mg/kg/dose two to three times daily) was as effective as ceftazidime (50 mg/kg/dose three times daily) and appeared as effective as cefotaxime (30 mg/kg/dose four times daily) or cefuroxime (100 mg/kg/day in three divided doses), although the latter two comparisons involved ≤10 patients per treatment group. Additionally, in a randomized, double-blind trial in elderly patients with CAP, cefepime 2g twice daily produced a similar clinical (79% vs 75% of patients) and bacteriological response (94% vs 100% of patients) to ceftriaxone (1g twice daily).Cefepime monotherapy also proved clinically effective as a therapy for adult patients with pneumonia who had failed to respond to previous antibacterial therapy with penicillins or other cephalosporins (clinical response rate 70.1%). Cefepime achieved a satisfactory bacteriological response in 87.9% of patients with pneumonia who failed to respond to previous treatment with penicillins and in 78.6% in those previously treated with other cephalosporins.Cefepime was an effective treatment when used as part of a combination regimen with amikacin in ventilated patients with HAP. The cefepime (2g twice daily) plus amikacin (7.5 mg/kg twice daily) regimen was as effective as ceftazidime (2g three times daily) plus amikacin (7.5 mg/kg twice daily), with a clinical cure rate of approximately 68% of patients for the per-protocol analysis in both treatment groups and bacteriological eradication in 86.5% vs 89.3% of microbiologically evaluable patients.

Tolerability

In clinical trials, intravenous or intramuscular cefepime was generally well tolerated in hospitalized patients with pneumonia. The majority of adverse events were mild to moderate in intensity and reversible upon discontinuation of treatment.In a pooled analysis of patients with pneumonia, urinary tract infections and other serious infections, the most common adverse events that occurred during treatment with cefepime were rash and diarrhea. Other less common adverse events probably related to cefepime included pruritus, urticaria, nausea, vomiting, oral candidiasis, colitis, headache, fever, erythema and vaginitis.Comparative clinical trials in adults with pneumonia have indicated that cefepime 1 or 2g twice daily has a similar tolerability profile to that of ceftazidime, ceftriaxone and cefotaxime (1 or 2g twice or three times daily) with no significant difference in the incidence, type or severity of adverse events. The percentage of patients with HAP admitted to the ICU receiving cefepime 2g three times daily that experienced adverse events was also similar to the percentage of patients receiving imipenem 0.5g four times daily.Pediatric patients with pneumonia treated with cefepime 50 mg/kg/dose three times daily experienced a similar number, type and severity of adverse events as those receiving the same dose of ceftazidime three times daily. According to pooled tolerability data from pediatric patients, the most commonly reported adverse events in cefepime recipients were fever, diarrhea and rash.Cefepime has been associated with rare instances of neurotoxicity, including encephalopathy, myoclonus and seizures in postmarketing experience. Most episodes occurred in patients with renal impairment who received doses of cefepime greater than those recommended by the manufacturer.

Pharmacoeconomic Considerations

Two cost analyses in patients with HAP or various bacterial infections, using similar acquisition costs for cefepime and ceftazidime, found that the institutional costs associated with cefepime therapy appear less than those of ceftazidime although no statistics were given in one model. When other factors (such as the cost of concomitant antibacterial agents, agents used to treat clinical failures, the preparation costs, and any medications used to treat adverse events) were considered, costs associated with cefepime therapy were significantly lower than those associated with ceftazidime treatment in one model, but not in the other.

Dosage and Administration

In countries other than the US, cefepime is indicated for the treatment of mild to very severe pneumonia in adults and children (aged ≥1 month). The recommended dosage of cefepime for adult or pediatric patients more than 40kg with mild to moderate pneumonia is 1g twice daily administered by intramuscular injection or intravenous infusion (dependent on the severity of infection) for 7–10 days. For adult or pediatric patients more than 40kg with severe to very severe pneumonia the recommended dosage of cefepime is 2g twice or three times daily via intravenous infusion (again, dependent on the severity of infection) for 7–10 days. For pediatric patients (aged >2 months and up to 40kg in bodyweight), with bacterial pneumonia, the recommended dosage is 50 mg/kg/dose twice daily for 10 days; however, for more severe infections, a dosage interval of 8 hours can be used. Experience of the efficacy and tolerability of cefepime is limited in pediatric patients aged <2 months; however, pharmacokinetic modelling suggests that a dose of 30 mg/kg/dose twice daily or three times daily may be considered in these patients.In the US, cefepime is approved for the treatment of moderate to severe pneumonia caused by S. pneumoniae, P. aeruginosa, K. pneumoniae or Enterobacter spp. in adults or children (aged >2 months). The recommended dosage of cefepime for adult patients with moderate to severe pneumonia in the US is 1 or 2g administered intravenously for 10 days. For children (≤40kg in bodyweight), the recommended dosage is 50mg/kg/dose twice daily administered by intravenous infusion for 10 days.No dosage modifications are recommended for the elderly or patients with hepatic dysfunction; however, the dose or frequency of administration of cefepime should be adjusted for patients with renal impairment or those receiving renal dialysis.Cefepime should not be directly mixed with other antibacterial agents. If other antibacterial agents are to be used in a combination regimen they should be administered separately.

     

头孢他啶及头孢吡肟对产超广谱β内酰胺酶肺炎克雷伯菌大鼠肺炎的治疗作用

目的评价头孢他啶及头孢吡肟对产超广谱β内酰胺酶(ESBL)肺炎克雷伯菌大鼠肺炎的治疗效果。方法选取产ESBL肺炎克雷伯菌3种菌株,建立3组大鼠肺炎模型(kpn1、kpn2、kpn3组)。3种菌体外试验对头孢噻肟耐药,对哌拉西林/他唑巴坦敏感,对头孢他啶、头孢吡肟为:1组均敏感;2组头孢他啶敏感,头孢吡肟耐药;3组头孢吡肟敏感,头孢他啶耐药。每组分5个治疗亚组(头孢他啶、头孢吡肟、哌拉西林/他唑巴坦、头孢噻肟、生理盐水对照亚组),治疗96h后进行评价。结果kpn1组:哌拉西林/他唑巴坦、头孢他啶、头孢吡肟亚组生存率(75.0%、76.9%、80.0%)明显高于头孢噻肟、生理盐水对照亚组(36.0%、32.0%),前3组肺组织匀浆活菌计数[(10.8±2.8)、(11.1±3.2)、(11.0±3.7)lgCFU/g]明显低于头孢噻肟、生理盐水对照亚组[(15.7±5.6)、(16.0±5.5)lgCFU/g]。kpn2组:哌拉西林/他唑巴坦、头孢他啶亚组生存率(79.2%、73.1%)明显高于头孢噻肟、生理盐水对照亚组(42.3%、33.3%),前2组肺组织匀浆活菌计数[(10.7±2.3)、(11.0±2.7)lgCFU/g]明显低于头孢噻肟、生理盐水对照亚组[(15.5±5.4)、(15.8±4.6)lgCFU/g]。kpn3组:哌拉西林/他唑巴坦、头孢吡肟亚组生存率(80.8%、75.0%)明显高于头孢噻肟、生理盐水对照亚组(37.5%、34.6%)。结论体外敏感的头孢他啶、头孢吡肟治疗产ESBL肺炎克雷伯菌大鼠肺炎,可提高生存率,降低肺组织lgCFU/g,与哌拉西林/他唑巴坦作用相当。     

Pharmacokinetics of ceftazidime in febrile neutropenic patients

Eight patients with fever and neutropenia were given 2 g of ceftazidime i.v. as a bolus injection over the course of 3 min. The pharmacokinetic variables for ceftazidime were similar to those found previously in febrile, acutely ill, non-neutropenic patients. The area under the plasma-concentration-time curve was significantly smaller, and the terminal half-life (t1/2lambda(z)) significantly shorter, compared with elderly, healthy subjects (p < 0.005). Three patients survived long enough to be assayed after normalization of temperature and neutrophil counts. Glomerular filtration rates and clearances tended to be higher and the area under the curve and half-life lower on the day of fever and neutropenia. When considering our data in relation to known MIC values for common pathogens, ceftazidime administered intermittently every 6 h seems an appropriate regimen in patients with febrile neutropenia. Larger studies are needed to confirm this.     

Prevalence and antibiotic susceptibility of Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae in Estonian intensive care units in comparison with European data

This prospective cohort study was performed from April to December 2003 for the purpose of collecting a maximum of 50 non-duplicate isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae from each of 4 ICUs to determine minimum inhibitory concentrations. The most prevalent species were Enterobacteriaceae (13%), K. pneumoniae and A. baumannii (both 12%). 60% of A. baumannii strains were susceptible to ampicillin/sulbactam and cefepime, 95% to meropenem and imipenem, and 75% to amikacin. 79% of P. aeruginosa strains were piperacillin/tazobactam, 58% ceftazidime, 81% meropenem, 72% imipenem, 69% ciprofloxacin and 97% amikacin susceptible. The susceptibility of K. pneumoniae to meropenem and imipenem was 99%, to ciprofloxacin was 91% and to amikacin was 98%. Gram-negative bacteria (especially K. pneumoniae and A. baumannii) were prevalent in our ICUs compared to other European studies. Carbapenem susceptibility of Estonian strains was higher, but P. aeruginosa sensitivity to ceftazidime was lower, compared to other EU countries.     

Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th-generation cephalosporin + aminoglycosides: comparative study

1998, a consensus meeting was held in Miyazaki, Japan, to develop an approach to management of febrile neutropenia (FN). The K-HOT study group decided to examine whether this proposal was applicable to clinical practice in a multicenter study. Patients who developed fever with neutrophil counts <1,000/microL were randomized to receive either a single antibiotic, cefepime or one of the carbapenems, or a combination of cefepime and an aminoglycoside. Patients who became afebrile within the first 3 days were continued on the same treatment. Patients who remained febrile were switched to a combination regimen if they were randomized to receive a single agent, and patients on combination medication were changed from cefepime to another cephalosporin. A total of 165 patients were entered into the trial. One hundred fifty-three patients were evaluable for response. The average age was 52 years, and 70% of the patients had acute leukemia. Severe neutropenia, defined as <100/microL at the time of FN, was seen in 62% of the patients on entry and during the course of treatment 71% of patients experienced neutrophil counts of <100/microL. Microbiologically documented infection was seen in 6.5% for monotherapy, and 10.5% for a combination treatment, and fever of unknown origin occurred in 75.3% and 59.2% of the patients in each regimen, respectively. Excellent to good response was seen in two-thirds of the patients in all treatment groups. Adverse events were minimal, and three early deaths were observed at days 9, 16, and 16 among patients treated with a single antibiotic and three in the combination regimen group at days 14, 15, and 20. These results indicate that cefepime or a carbapenem alone is as effective as a combination of cefepime and an aminoglycoside for treating FN.     

Salvage chemotherapy with IAPVP-16 for advanced refractory or relapsed follicular lymphomas.

BACKGROUND AND OBJECTIVE: Patients with follicular lymphoma (FL) who do not respond to first-line chemotherapy or those who relapse after obtaining a remission have a poor outcome with standard treatment. In an effort to obtain a high rate of responses we designed an intensive brief duration salvage chemotherapy regimen. DESIGN AND METHODS: Forty-four consecutive patients with advanced follicular lymphoma were treated. Nine had primary refractory disease, 13 had achieved a partial remission, 16 were in untreated relapse or progression and six were in chemosensitive relapse. The IAPVP-16 regimen consists in ifosfamide 5 g/m(2) iv on day 1, etoposide 100 mg/m(2) iv on days 1-3, Ara-C 1.2 g/m(2)/12 hours iv on days 1-2 and methylprednisolone, 80 mg/m(2) iv on days 1-5. Granulocyte colony-stimulating factor was used from day 6 in 68 of 114 courses. RESULTS: Eighteen patients (41%) achieved a complete remission and 17 (39%) a partial remission, for an overall response rate of 80%. There were no treatment-related deaths. All treatment courses were followed by severe neutropenia, and 66% also by severe thrombocytopenia, but there were no serious hemorrhagic events. Neutropenic fever occurred in 56% of the courses with only four severe infections. Non-hematologic toxicity was modest. Twenty-eight patients proceeded to a stem cell transplantation. After a median follow-up of 25 months (range 4-95), the median progression-free survival and overall survival are 32 and 58 months, respectively. The median PFS was 33 months for responders and 11 months for non-responders (p=0.05), while the median OS has not been reached in responders and is 23 months in non-responders (p=0.0005). INTERPRETATION AND CONCLUSIONS:. The IAPVP-16 regimen is an effective and well tolerated treatment for advanced FL, allowing most eligible patients to proceed with significant tumor reduction to high-dose therapy and SCT.     

Efficacy and safety of cefepime in late-onset ventilator-associated pneumonia in infants: a pilot randomized and controlled study

Multidrug-resistant organisms cause late-onset ventilator-associated pneumonia (VAP). In a pilot, randomized and controlled study, the efficacy and safety of cefepime, in late-onset VAP in infants, have now been evaluated in Malaysia. Thirty children aged <1 year with late-onset VAP (i.e. VAP occurring 5 or more days after intubation) were randomized to receive cefepime or, as a control, ceftazidime. The clinical responses and the microbiological clearance of tracheal aspirates were evaluated in each arm. Adverse events, if any, were monitored clinically and by blood tests. Ten of the 15 children given cefepime and five of the 15 given ceftazidime showed a satisfactory clinical response (P<0.1). Cefepime appeared significantly better at clearing polymicrobial infections from tracheal aspirates. There were no fatalities in the cefepime arm but three in ceftazidime (P<0.1). The mean (S.E.) durations of antibiotic use were 9.4 (1.5) days for cefepime and 7.6 (1.0) days for ceftazidime (P>0.05). No serious adverse effects were observed in either arm. In conclusion, in late-onset VAP in infants, cefepime monotherapy appears to be at least as effective and safe as ceftazidime monotherapy, with better microbiological clearance.     

Using teicoplanin for empiric therapy of febrile neutropenic patients with haematological malignancies

S ummary The cumulative experience with teicoplanin in treating febrile neutropenic patients included in three different comparative clinical trials conducted at a single institution during a 3-year period, is presented. 1 52 febrile episodes in 129 neutropenic patients were treated with iv. teicoplanin (6 mg/kg/d) combined with amikacin (15 mg/kg/d) plus ceftazidime (90 mg/kg/d). The study population comprised 75 patients with acute leukaemia and 77 marrow recipients: 53(% (81/152) had a central venous catheter in place and 68%) (103/152) had severe neutropenia (< 100/mm³) at the beginning of the febrile episode.
The overall response rate of the evaluiable febrile episodes was excellent: 88% (107/122) improved. Bacteraemias due to Gram-positive cocci accounted for 75% of the total (42/56) and pathogens in the blood isolates were mostly staphylo-cocci (coagulase-negative 14, coagulase-positive 13) and streptococci (131. The response rate of Gram-positive bacteraemias was good: 88% (37/42) improved and 75% (9/12) of Gram-positive bacteraemias having teicoplanin as the only antibiotic with in vitro activity against the infective strains were cured. Death due to infection accounted for 7% of total febrile episodes (11/152). Side effects were documented in 14(%, of the episodes. In a setting of high prevalence of Grampositive infections caused by strains with a high rate of resistance to aminoglycoside and betalactam antibiotics, there may be an advantage in including teicoplanin in the initial empiric antibiotic regimen for febrile neutropenic cancer patients.     

Cefepime: a review of its use in the management of hospitalized patients with pneumonia

Cefepime (Maxipime), Maxcef, Cepimax, Cepimex, Axepim, a parenteral fourth-generation cephalosporin, is active against many organisms causative in pneumonia. Cefepime has in vitro activity against Gram-positive organisms including Staphylococcus aureus and penicillin-sensitive, -intermediate and -resistant Streptococcus pneumoniae similar to that of cefotaxime and ceftriaxone. Cefepime also has good activity against Gram-negative organisms, including Pseudomonas aeruginosa, similar to that of ceftazidime. Importantly, cefepime is stable against many of the common plasmid- and chromosome-mediated beta-lactamases and is a poor inducer of AmpC beta-lactamases. As a result, it retains activity against Enterobacteriaceae that are resistant to third-generation cephalosporins, such as derepressed mutants of Enterobacter spp. Cefepime may be hydrolyzed by the extended-spectrum beta-lactamases produced by some members of the Enterobacteriaceae, but to a lesser extent than the third-generation cephalosporins. Monotherapy with cefepime 1 or 2g, usually administered intravenously twice daily, was as effective for clinical and bacteriological response as ceftazidime, ceftriaxone or cefotaxime monotherapy (1 or 2g two or three times daily) in a number of randomized, clinical trials in hospitalized adult, or less commonly, pediatric, patients with generally moderate to severe community-acquired or nosocomial pneumonia. More limited data indicated that monotherapy with cefepime 2g three times daily was also as effective in treating patients with nosocomial pneumonia as imipenem/cilostatin 0.5g four times daily, and when combined with amikacin, cefepime was as effective as ceftazidime plus amikacin. Patients with pneumonia who failed to respond to previous antibacterial therapy with penicillins or other cephalosporins responded to treatment with cefepime. Cefepime is generally well tolerated, with a tolerability profile similar to those of other parenteral cephalosporins. In clinical trials, the majority of adverse events experienced by cefepime recipients were mild to moderate and reversible. The most common adverse events with a causal relationship to cefepime reported in clinical trials included rash and diarrhea. Other, less common, adverse events included pruritus, urticaria, nausea, vomiting oral candidiasis, colitis, headache, fever, erythema and vaginitis. CONCLUSION: Cefepime is an established and generally well tolerated parenteral drug with a broad spectrum of antibacterial activity which, when administered twice daily, provides coverage of most of the pathogens that may be causative in pneumonia. In randomized clinical trials in hospitalized patients with generally moderate to severe community-acquired or nosocomial pneumonia, cefepime monotherapy exhibited good clinical and bacteriological efficacy. Cefepime may become a preferred antibacterial agent for infections caused by Enterobacter spp. With prudent use in order to prevent the emergence of resistant organisms, cefepime will continue to be a suitable option for the empiric treatment of pneumonia.