Pharmacokinetics of fluconazole in pediatric patients.

The pharmacokinetic properties of fluconazole were studied in more than 100 pediatric patients, including 12 premature neonates. The volume of distribution and the rate of elimination differed significantly from the values reported for adults. The volume of distribution varied with age, being greatest during the neonatal period (1.18 to 2.25 l/kg) and decreasing by young adulthood to a value similar to that reported for adults (0.7 l/kg). With the exception of neonates, fluconazole clearance was generally more rapid in children than in adults, with a mean plasma elimination half-life of just over 20 h for all pediatric age groups. In neonates, fluconazole was eliminated slowly, with a mean elimination half-life of 88.6 h at birth, 67.5 h approximately one week later and 55.2 approximately two weeks after birth. Fluconazole appeared to be well absorbed from the gastrointestinal tract. These pharmacokinetic results, taken in conjunction with the corresponding data for adults, provide a sound basis for establishing appropriate fluconazole dosage recommendations for pediatric patients.

Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group.

An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.

Pharmacokinetics and tissue penetration of fluconazole in humans.

The pharmacokinetics and tissue/fluid penetration of fluconazole have been studied in more than 400 healthy individuals and various subsets of patients. The pharmacokinetics of fluconazole are similar following intravenous and oral dosing. Oral bioavailability is greater than 90%, and concentrations peak approximately 2 hours after dosing. The apparent volume of distribution is 0.7 L/kg, and plasma protein binding is low (12%). The drug is metabolically stable, with renal excretion accounting for approximately 80% of the elimination as unchanged drug. Repeated once-daily dosing results in an increase in plasma levels of approximately 2.5-fold, with steady state achieved by day 7. Plasma levels are dose-proportional, and the elimination rate remains constant across the dosage range and over time. The plasma half-life of fluconazole is approximately 30 hours. The pharmacokinetics are similar in healthy young adults and in the elderly, but dose modification is required in patients with renal impairment. Fluconazole diffuses readily into the cerebrospinal fluid, sputum, and saliva and is concentrated in the urine and skin.

Management of fungal infection in neutropenic patients with fluconazole.

Fluconazole is a new orally absorbed antifungal azole which is effective in the treatment of mucosal and systemic infections caused by Candida, cryptococci and other fungi. In view of its favourable efficacy, safety and pharmacokinetic profile it was considered appropriate to evaluate its use prophylactically in patients undergoing a period of neutropenia. Two hundred and forty-eight patients receiving chemotherapy and/or bone marrow transplantation for the treatment of acute leukaemia, lymphoma or aplastic anaemia, and expected to be rendered temporarily neutropenic, have been entered into an ongoing multicentre comparative clinical study to compare the prophylactic efficacy of 50 mg daily oral fluconazole with that of widely used regimens of oral polyenes. The incidence of suspected fungal infection was less in the fluconazole group (27%) than in the polyene group (45%), the difference being statistically significant (P less than 0.05). Only one of the suspected infections in the fluconazole group was confirmed mycologically compared with 17 in the polyene group. Fluconazole prophylaxis was well tolerated and it therefore offers a promising new approach to the management of fungal infection in the neutropenic patient. Further studies are warranted to define the optimum dosage for use in this situation.

A comparison of fluconazole and ketoconazole in the oral treatment of vaginal candidiasis; report of a double-blind multicentre trial.

One hundred and eighty three patients with vaginal candidiasis were randomly allocated to treatment with either fluconazole in a single oral 150 mg dose, or ketoconazole, 200 mg twice daily for 5 days. Favourable clinical responses were obtained in 92% of the patients in the fluconazole group and in 89% of those in the ketoconazole group after 5-16 days. Long-term evaluation at 27-62 days showed favourable clinical responses in 86 and 88%, respectively. Candida was eradicated from the vagina in 77% of both treatment groups at the long-term evaluation. The relapse or reinfection rate was similar for both groups, ranging between 4-8%. One hundred and thirty two of the 160 patients who had rectal swabs cultured for yeast at baseline, gave positive results. Of the 27 patients in the fluconazole group whose rectal cultures remained negative at the long-term evaluation, 26 maintained mycological cure of their vaginal candidiasis. In contrast, patients with positive rectal cultures at this time were much less frequently associated with mycological cure. The results were similar for the patients in the ketoconazole group. Treatment-related side effects in both groups were few and minor. This double-blind multicentre study showed that a single oral 150 mg dose of fluconazole was as effective as 5 days of oral ketoconazole medication in the treatment of vaginal candidiasis.

Biliary pharmacokinetics of sulbactam plus ampicillin in humans.

The biliary pharmacokinetics of sulbactam and ampicillin was investigated in 19 patients with normal liver function who were undergoing surgery of the biliary tract. The combination of sulbactam (0.5 g) plus ampicillin (1 g) was given intravenously to five patients with T-tube drainage of the common bile duct. Mean peak concentrations of sulbactam (19.4 micrograms/ml) and ampicillin (471 micrograms/ml) in the bile occurred 0.5-1 hr after administration. Biliary excretion was estimated to account for approximately 0.24% of the sulbactam dose and 2.8% of the ampicillin dose. Fourteen other patients received the same dose of sulbactam/ampicillin immediately before elective cholecystectomy. Respective mean concentrations of sulbactam and ampicillin at the time of gallbladder removal were 4.3 micrograms/ml and 15.9 micrograms/ml in gallbladder bile and 6.3 micrograms/g and 7.7 micrograms/g in gallbladder wall tissue. These results, together with the antibacterial spectrum and potency of the combination, suggest that sulbactam/ampicillin is suitable for prophylactic use in biliary tract surgery.

Penetration of sulbactam into the cerebrospinal fluid of patients with bacterial meningitis receiving ampicillin therapy.

Concentrations of sulbactam in the CSF of 18 patients with bacterial meningitis who were undergoing treatment with intravenous (iv) ampicillin were determined. Six patients received single doses of sulbactam (1 g) and 12 patients received multiple doses (four times daily) by the iv route at various intervals before lumbar punctures were performed to monitor their condition. Concentrations of sulbactam up to 12 micrograms/ml were detected in the CSF between 1 and 4 hr after dosing, the higher levels being present in the CSF of patients with the most severe meningeal inflammation. There were no significant differences in the concentrations achieved after single or multiple doses of sulbactam, and the concentrations were generally similar to the concurrent concentrations of ampicillin. It is concluded that these results as well as the antibacterial properties of sulbactam plus ampicillin support the evaluation of this combination as an alternative in the treatment of bacterial meningitis.

Efficacy of UK-49,858 (fluconazole) against Candida albicans experimental infections in mice.

UK-49,858 (fluconazole), a new, orally absorbed bis-triazole derivative, has been evaluated against systemic infections with Candida albicans in normal and immunosuppressed mice and against an intestinal infection with C. albicans in immunosuppressed mice. Orally administered ketoconazole was used as a comparison agent throughout, and orally administered amphotericin B was included for comparative in the experimental intestinal infection. In a 10-day dosage regimen, UK-49,858 was far more active than ketoconazole against systemic infections with C. albicans in normal and immunosuppressed mice. In normal mice, extension of UK-49,858 dosing to 30 days resulted in prolongation of survival to over 90 days, and up to 60% of treated animals had no detectable C. albicans in their kidneys. In addition, over 90% of mice with intestinal candidiasis had culture-negative feces after a 3-day treatment with UK-49,858, but only 62 and 23% of mice gave this response after amphotericin B and ketoconazole therapy, respectively. These data suggest that UK-49,858 may be of value in the treatment of systemic and gastrointestinal infections due to C. albicans in humans.

Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes.

The therapeutic potential of UK-49,858, a difluorophenyl bis-triazole derivative, has been assessed by evaluating its activity against systemic infections with Candida albicans in normal mice and rats and in mice with impaired defence mechanisms, against vaginal infections with C. albicans in mice, and against dermal infections with Trichophyton mentagrophytes in guinea pigs. Orally administered ketoconazole was used as a comparative agent throughout, and parenterally administered amphotericin B was included in the study of C. albicans systemic infection in normal mice. The activity of UK-49,858 given orally to mice or rats infected systemically with C. albicans was far superior to that of ketoconazole. In addition, UK-49,858 showed activity comparable to that of amphotericin B when given parenterally, although the latter gave more prolonged protection. UK-49,858 was also effective orally in curing experimental candidal vaginitis in mice and trichophytosis in guinea pigs, against which it was approximately 10 times more active than ketoconazole. These data suggest that UK-49,858 may be of value in the treatment of both C. albicans and dermatophyte fungal infections in man.

The treatment of experimental schistosomiasis with a combination of oxamniquine and praziquantel.

The object of the study was to identify any potential therapeutic advantage in using the two antischistosomal drugs, oxamniquine and praziquantel, in combination rather than separately, in the treatment of schistosomiasis. The efficacy of the drugs was studied in albino mice with mature Schistosoma mansoni infections. It was found that the efficacy of combinations of the two drugs was markedly superior to that expected on the basis of a simple additive effect. The significance of this synergistic action is discussed in the context of schistosomiasis therapy in man.

Tioconazole, a new imidazole-antifungal agent for the treatment of dermatomycoses. Antifungal and pharmacologic properties.

Tioconazole is a new imidazole antifungal agent with broad-spectrum activity. Its in vitro activity against common dermal pathogens is generally better than miconazole by a factor of 2-8. This activity is paralleled by good topical efficacy in a guinea pig dermatomycosis model. Pharmacokinetic studies in animals have demonstrated minimal systemic exposure following dermal application. Acute general pharmacology studies have shown that the compound is well tolerated in animals and unlikely to produce side-effects in man.

6 beta-Iodopenicillanic acid (UI-38,006), a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactam compounds: initial bacteriological characterization.

UK-38,006, 6 beta-iodopenicillanic acid, was shown to be a potent inhibitor of beta-lactamase enzymes. It potentiated the antibacterial action of ampicillin in vitro against beta-lactamase-producing strains of Staphylococcus aureus, Haemophilus influenzae, Bacteroides fragilis. Neisseria gonorrhoeae, and many Enterobacteriaceae. This ability to synergize with ampicillin was also demonstrated in vivo after oral administration of UK-38,006 to experimentally infected mice. UK-38,006 was also shown to synergize in vitro with other penicillins and cephalosporins against beta-lactamase-producing strains of Escherichia coli, Proteus mirabilis, and Klebsiella species.

Synthesis and antibacterial activity of 1-N-(1,3-dihydroxy-2-propyl)kanamycin B (UK-31,214).

1-N-(1,3-Dihydroxy-2-propyl)kanamycin B was prepared and its in vitro activity against aminoglycoside-sensitive and aminoglycoside-resistant organisms was compared with that of kanamycin B and gentamicin. This kanamycin B derivative (code No. UK-31,214) demonstrated potent activity in all of these tests and gave good protection in experimental infections in mice.

Inhibition of transpeptidase activity in Escherichia coli by thienamycin.

Thienamycin was shown to be a more potent inhibitor than ampicillin of the enzyme peptidoglycan transpeptidase from Escherichia coli.

Peptidoglycan transpeptidase inhibition in Pseudomonas aeruginosa and Escherichia coli by Penicillins and Cephalosporins.

Peptidoglycan transpeptidase activity has been studied in cells of Escherichia coli 146 and Pseudomonas aeruginosa 56 made permeable to exogenous, nucleotide-sugar peptidoglycan precursors by ether treatment. Transpeptidase activity was inhibited, in both organisms, by a range of penicillins and cephalosporins, the Pseudomonas enzyme being more sensitive to inhibition in each case. Conversely, growth of E. coli 146 was more susceptible to these antibiotics than growth of P. aeruginosa 56. Furthermore, similar transpeptidase inhibition values were ob-obtained for the four penicillins examined against the Pseudomonas enzyme, although only two of these (carbenicillin and pirbenicillin) inhibited the growth of this organism. We therefore conclude that the high resistance of P. aeruginosa 56 to growth inhibition by most beta-lactam antibiotics cannot be due to an insensitive peptidoglycan transpeptidase.

Antifungal activity of tioconazole (UK-20,349), a new imidazole derivative.

Tioconazole (UK-20,349), a new antifungal imidazole derivative, was compared with miconazole for activity in vitro against Candida spp., Torulopsis glabrata, Cryptococcus neoformans, Aspergillus spp., and dermatophyte fungi (Trichophyton spp. and Microsporum spp.). Tioconazole was more active than miconazole against all the fungal species examined except Aspergillus, against which both agents showed similar activity. Both tioconazole and miconazole inhibited the growth of all fungi examined at concentrations well below their quoted minimum inhibitory concentrations. Their activity against fungi in vivo was investigated in mice infected systemically with Candida albicans. Both agents significantly reduced the numbers of viable Candida cells recoverable from the kidneys of infected animals, with tioconazole producing a generally more marked reduction. After administration of a single oral dose (25 mg/kg) to beagle dogs or white mice, higher and more sustained circulating levels of bioactive drug were detectable of tioconazole than of miconazole. These observations suggest that tioconazole may have potential in the treatment of both superficial and systemic mycoses in humans.

UK-18,892: resistance to modification by aminoglycoside-inactivating enzymes.

UK-18,892, a new semisynthetic aminoglycoside, was active against bacteria possessing aminoglycoside-inactivating enzymes, with the exception of some known to possess AAC(6') or AAD(4') enzymes. This activity has been rationalized by using cell-free extracts of bacteria containing known inactivating enzymes, where it was shown that UK-18,892 was not a substrate for the APH(3'), AAD(2''), AAC(3), and AAC(2') enzymes. It was also demonstrated that UK-18,892 protected mice against lethal infections caused by organisms possessing aminoglycoside-inactivating enzymes.