Effects of renal dysfunction on the pharmacokinetics of loracarbef.

Loracarbef, the first carbacephem antibiotic to undergo clinical development, is excreted primarily unchanged in the urine (> 90%). Data analyzed from subjects with various degrees of renal dysfunction who were given single oral doses of loracarbef indicated a linear relationship between creatinine clearance (CLCR) and plasma clearance [CLP (L/hr) = 0.106.CLCR (ml/min/1.73 m2)]. The mean area under the plasma concentration-time curve in normal subjects and in patients with severe renal insufficiency (no dialysis/receiving dialysis) was 32 micrograms.hr/ml and 1085 micrograms.hr/ml/103 micrograms.hr/ml, respectively. Therefore, for individuals with moderate renal insufficiency (CLCR, 10 to 49 ml/min/1.73 m2), the dose should be halved or the dosing interval doubled; patients with severe renal insufficiency who are not receiving dialysis should be treated with the normal dose given once every 3 to 5 days. Loracarbef is readily cleared from plasma by hemodialysis; dosing should be repeated after a hemodialysis treatment.

The safety profile of loracarbef: clinical trials in respiratory, skin, and urinary tract infections.

The efficacy and safety of the antibiotic loracarbef have been demonstrated in a series of 22 clinical trials involving over 9,000 patients. The data compiled from these trials indicate that loracarbef is well tolerated by the majority of patients, including children and elderly patients. Most adverse events in patients receiving loracarbef were mild and transient in nature; only 1.5% of patients discontinued therapy because of drug-related adverse events. The frequency of adverse events associated with this agent compares favorably with that reported for the other antibiotics in these trials. The most commonly reported adverse reaction in the loracarbef study group was diarrhea, but this condition occurred less frequently in patients who received loracarbef than in those treated with the comparative agents. Other gastrointestinal events, such as nausea and vomiting, were reported infrequently. Headache was the second most common adverse event reported and occurred at a slightly higher frequency in the loracarbef-treated group than in patients receiving comparative antibiotics. No clinically significant alterations in laboratory parameters or gastrointestinal flora were observed following loracarbef administration. The compiled data indicate that loracarbef is a safe therapeutic option for the treatment of a wide spectrum of bacterial infections.

Loracarbef (LY 163892) vs amoxicillin/clavulanate in bacterial maxillary sinusitis.

Loracarbef (LY 163892), a beta-lactam antibiotic (carbacephem), was compared with amoxicillin/clavulanate potassium in a 10-day, single-blind, randomized parallel trial in the treatment of acute bacterial maxillary sinusitis. Based on posttherapy aspirate and culture, there was a 95.2% bacteriologic cure rate in patients receiving loracarbef (400 mg twice daily) and an 86.7% cure rate in patients receiving amoxicillin/clavulanate (500/125 mg three times daily) (p = 0.359). Loracarbef was comparable in efficacy to amoxicillin/clavulanate with a more desirable safety profile.

Loracarbef (LY163892) versus amoxicillin/clavulanate in the treatment of acute purulent bacterial bronchitis.

In this single-blind study, 488 patients with acute bronchitis were randomly assigned to receive 400 mg of loracarbef twice daily or 500/125 mg of amoxicillin/clavulanate three times daily for seven days. Treatment efficacy was evaluated in 98 patients treated with loracarbef and in 99 treated with amoxicillin-clavulanate in whom pretreatment positive cultures of pathogens susceptible to both study drugs were found. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Klebsiella pneumoniae were isolated in pure or mixed cultures in 64% of the evaluable patients; S pneumoniae was found in 26%. Among the evaluable patients, the rate of favorable clinical responses (cure and improvement) in the loracarbef group (96 of 98 patients; 98.0%) was similar to that in the amoxicillin/clavulanate group (96 of 99 patients; 97.0%); the favorable bacteriologic response rates were also similar (93.7% vs 92.9%, respectively). Eight patients in the loracarbef group and nine in the amoxicillin/clavulanate group discontinued treatment because of adverse events. The events were presumed to be drug related in five of the loracarbef group and in seven of the amoxicillin/clavulanate group. During therapy, diarrhea was the most frequently reported event in both groups. However, it occurred in only 8.2% of the loracarbef-treated patients compared with 22.5% of the amoxicillin/clavulanate patients (P less than 0.001). It is concluded that both loracarbef and amoxicillin/clavulanate are safe and effective in the treatment of acute purulent bacterial bronchitis.

Loracarbef (LY163892) versus amoxicillin/clavulanate in the treatment of acute bacterial exacerbations of chronic bronchitis.

In this single-blind study, 579 patients with chronic bronchitis were randomly assigned to receive 400 mg of loracarbef twice daily or 500/125 mg of amoxicillin/clavulanate thrice daily for seven days. Treatment efficacy was evaluated in 129 of the loracarbef-treated patients and 120 amoxicillin/clavulanate-treated patients in whom pretreatment positive cultures of pathogens susceptible to both antibiotics were isolated. Three organisms predominated in either pure or mixed cultures in 57.0% of the evaluable patients: Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella (Branhamella) catarrhalis; H influenzae was isolated in 25.0% of the patients with single pathogens. Among the evaluable patients, favorable clinical responses (cure or improvement) were noted in 93.8% of the loracarbef-treated patients and in 95.0% of the amoxicillin/clavulanate-treated patients. A favorable bacteriologic response (pathogen eliminated or presumed eliminated) was found in 82.2% of loracarbef-treated patients and 90.0% of amoxicillin/clavulanate-treated patients. Six patients in the loracarbef group and 14 in the amoxicillin/clavulanate group discontinued treatment because of adverse events. The events were judged to be drug related in four loracarbef-treated patients and in 11 amoxicillin/clavulanate-treated patients. The incidence of diarrhea and other gastrointestinal symptoms was significantly more frequent in the amoxicillin/clavulanate group (13.5% and 5.6%) than in the loracarbef group (4.5% and 1.7%), while the incidence of severe headaches was significantly more frequent in the loracarbef than the amoxicillin/clavulanate group (7.2% vs 3.1%). It is concluded that loracarbef and amoxicillin/clavulanate are safe and effective in the treatment of acute bacterial exacerbations of chronic bronchitis.

Comprehensive safety profile of cefaclor AF in respiratory, urinary tract and skin infections.

The safety of cefaclor advanced formulation (cefaclor AF) was evaluated in 3,272 patients participating in 11 controlled clinical trials in comparison with cefaclor (2,210 patients) for a variety of infectious illnesses. Daily doses of cefaclor AF ranged from 500 to 1500 mg, with a mean duration of treatment of 8.1 days (range 1-18 days). There were no significant differences between the cefaclor AF- and cefaclor-treated groups in the frequency of adverse events by body system for all events reported. The majority of adverse events related to therapy were mild and transient. Severe adverse events occurred in 2.1% of the cefaclor AF group and 2.7% of the cefaclor group. The most frequently reported adverse events for cefaclor AF were diarrhoea (3.4%), headache (3.2%), nausea (2.5%) and vaginal moniliasis (2.5% of females). Drug-related adverse events led to early discontinuations in 1.7% of cefaclor AF-treated patients and 1.6% of cefaclor-treated patients. Overall, there were few significant differences in the frequency of adverse reactions between older and younger patients. Notably, elderly patients reported significantly less diarrhoea and fewer hypersensitivity-type reactions. There were, however, more therapy discontinuations due to adverse effects in patients aged 65 years or older than in those less than 65 years of age. Many of the discontinuations were thought to be unrelated to therapy. Alterations in laboratory values in patients treated with cefaclor AF were similar to those seen with other beta-lactam antibiotics. The comprehensive data indicate that cefaclor AF is a safe therapeutic option for a variety of common bacterial infections.

Loracarbef versus penicillin VK in the treatment of streptococcal pharyngitis and tonsillitis in adults.

Loracarbef, a member of a unique class of beta-lactam compounds (carbacephems), has excellent chemical and beta-lactamase stability, as well as documented clinical effectiveness against a broad spectrum of bacteria. Ten-day treatment regimens of loracarbef (200-mg capsule BID or 15 mg/kg/day suspension) and penicillin VK (250-mg capsule QID or 20 mg/kg/day suspension) were compared in the treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis and tonsillitis. Adults (greater than or equal to 12 years of age) were administered loracarbef (n = 58) or penicillin (n = 58) in a double-blind, randomized, parallel study of clinical and bacteriologic response to treatment. Favorable clinical responses among qualified (evaluable) patients in the loracarbef-treated group (46/47; 97.9%) were similar to those for evaluable patients in the penicillin-treated group (43/43; 100%). Forty-one of 47 (87.2%) of the evaluable loracarbef-treated patients and 100% (43/43) of the evaluable penicillin-treated patients had negative posttherapy throat cultures for GABHS. Thirty-nine evaluable patients in each treatment group were assessed 28 to 35 days after completion of therapy: 2.6% of patients in each group experienced relapse of symptoms; and 7.7% of loracarbef-treated patients had positive cultures, compared to 12.8% of penicillin-treated patients. Two (1.9%) loracarbef-treated patients with rashes and one (0.9%) penicillin-treated patient with diarrhea withdrew from the study due to these adverse events. Diarrhea, the most frequently occurring adverse event during therapy in the loracarbef group, was reported by 8.6% of the loracarbef group and by 5.2% of the penicillin group. These data support the conclusion that loracarbef is comparable in safety and efficacy to penicillin VK for the treatment of streptococcal pharyngitis and tonsillitis in adults.

Loracarbef (LY163892) versus cefaclor in the treatment of acute bacterial bronchitis.

In this double-blind study, 319 patients (133 men, 186 women) with acute bronchitis were randomly assigned to receive 200 mg of loracarbef twice daily (n = 160; mean age, 42 years) or 250 mg of cefaclor thrice daily (n = 159; mean age, 43 years) for seven days. Clinical and bacteriologic responses were assessed in 63 loracarbef-treated and 56 cefaclor-treated patients in whom pretreatment positive cultures of pathogens susceptible to loracarbef and cefaclor were found. Among these evaluable patients, a clinical cure was found in 68.3% of the loracarbef-treated patients and in 66.1% of the cefaclor-treated patients and improvement in 27.0% and 28.6%, respectively; the pathogen was eliminated in 7.9% and 10.7% and presumed eliminated in 82.5% and 82.1%, respectively. Three in the loracarbef group discontinued treatment because of adverse events, two of which (nausea, nausea/diarrhea/vomiting) were presumably related to the drug. Headache was reported by 9.4% of the 160 patients in the loracarbef group and 6.9% of the 159 patients in the cefaclor group; diarrhea by 5.6% and 6.9%, respectively; and dyspepsia/abdominal pain/gastrointestinal disorders by 5.6% and 4.4%, respectively. It is concluded that both loracarbef and cefaclor are safe and effective in the treatment of acute bacterial bronchitis.

The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection.

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.

The epidemiology of pseudallescheriasis complicating transplantation: Nosocomial and community-acquired infection.

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.

Compliance with a restricted antimicrobial agent policy in a university hospital.

Compliance with a policy for use of antimicrobial agents that requires both oral approval from the infectious diseases service and completion of a restricted antimicrobial agent use form was evaluated in a 950-bed teaching hospital. The charts of patients for whom a restricted antimicrobial agent was ordered during four one-week periods between January 1987 and April 1987 were audited to determine whether completed use forms had accompanied orders for restricted antimicrobial agents. The validity of the information on completed forms was determined by comparing the information on the form with notes in patients' charts and through discussions with infectious diseases physicians. Two infectious diseases physician reviewers evaluated the appropriateness of prescribing of piperacillin and ceftazidime by analyzing data collected by pharmacists. Forms were submitted with 132 of 154 orders written for restricted agents; incomplete forms were received and accepted by pharmacists for 39 courses of therapy. The infectious disease service had not been contacted to approve use of a restricted agent in 25 cases. Eight of the 48 courses of piperacillin or ceftazidime therapy were deemed inappropriate despite initial infectious diseases approval. Compliance with a formal antimicrobial agent restriction policy at this institution has been good, but periodic re-education and follow-up monitoring appear to be necessary to ensure optimal use of restricted agents.