Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies.

Consistent with expectations based on human in vitro microsomal experiments, administration of fluconazole (400 mg/day) for 6 days to six human volunteers significantly reduced the cytochrome P450 (P450)-dependent metabolic clearance of the warfarin enantiomers. In particular, P4502C9 catalyzed 6- and 7-hydroxylation of (S)-warfarin, the pathway primarily responsible for termination of warfarin's anticoagulant effect, was inhibited by approximately 70%. The change in (S)-warfarin pharmacokinetics caused by fluconazole dramatically increased the magnitude and duration of warfarin's hypoprothrombinemic effect. These observations indicate that co-administration of fluconazole and warfarin will result in a clinically significant metabolically based interaction The major P450-dependent, in vivo pathways of (R)-warfarin clearance were also strongly inhibited by fluconazole. 10-Hydroxylation, a metabolic pathway catalyzed exclusively by P4503A4, was inhibited by 45% whereas 6-, 7-, and 8-hydroxylations were inhibited by 61, 73, and 88%, respectively. The potent inhibition of the phenolic metabolites suggests that enzymes other than P4501A2 (weakly inhibited by fluconazole in vitro) are primarily responsible for the formation of these metabolites in vivo as predicted from in vitro kinetic studies. These data suggest that fluconazole can be expected to interact with any drug whose clearance is dominated by P450s 2C9, 3A4, and other as yet undefined isoforms. Overall, the results strongly support the hypothesis that metabolically based in vivo drug interactions may be predicted from human in vitro microsomal data.

Infection with Chlamydia trachomatis lymphogranuloma venereum serovar L1 in homosexual men with proctitis: molecular analysis of an unusual case cluster.

Among 767 rectal isolates of Chlamydia trachomatis obtained from men over the period 1981-1991, 7 were found to be a rare lymphogranuloma venereum serovar, L1. These isolates were from rectal specimens taken from five male patients in 1982-1983. Six of the seven isolates were available for DNA sequencing studies. All six of these isolates shared the same DNA sequence in the major outer membrane protein (MOMP) gene variable domains and had different MOMP sequences than did the prototype L1, L2, and L3 strains, suggesting a point source outbreak. All five patients infected with serovar L-1 were homosexual men who had symptomatic proctitis characterized by rectal pain, discharge, tenesmus, abnormalities seen on anoscopy, and leukocytes seen on gram stains of rectal specimens. We conclude that an unrecognized point source outbreak of the rare chlamydial L1 serovar occurred among homosexual men in Seattle in 1982-1983, and that the clinical manifestations of L1 infection may be less severe than those of L2 infections.

Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center, 1984-1992.

The etiology of brain abscess in patients undergoing marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle was assessed in a retrospective review. Fifty-eight patients with histology- or culture-proven brain abscess diagnosed between January 1984 and March 1992 were identified. A fungus was isolated in 92% of cases. Aspergillus species were the most prevalent fungi (58% of cases), and Candida species were second in frequency (33%); sporadic cases were caused by Rhizopus, Absidia, Scopulariopsis, and Pseudallescheria species. Bacteria were involved in fewer than 10% of cases. There was no appreciable variation from year to year in the incidence of brain abscess over this period. Aspergillus brain abscess was associated with concomitant pulmonary disease (87% of cases), whereas candida brain abscess often occurred in association with fungemia (63% of cases) or neutropenia (63%). Mortality was high (97%); the risk of death was unrelated to etiology or therapeutic regimen. Since the etiology of brain abscess in patients undergoing marrow transplantation is primarily fungal, the development of better antifungal therapeutic and/or prophylactic modalities is warranted.

Diagnosis of Chlamydia trachomatis urethritis in men by polymerase chain reaction assay of first-catch urine.

To determine the accuracy of a recently developed polymerase chain reaction (PCR) urine assay to detect Chlamydia trachomatis urethral infection in men, we obtained urethral swabs and first-catch urine from 365 men attending a sexually transmitted diseases clinic. Thirty-three (9%) of the 365 men were infected with C. trachomatis as defined by urethral culture. Thirty-two of the 33 men with culture-positive urethral swabs also had PCR-positive urine assays. Of 332 patients with culture-negative urethral swabs, 325 had PCR-negative urine. Compared with chlamydia culture of urethral specimens, PCR assay of urine samples thus had a sensitivity of 97% and a specificity of 98%. The positive predictive value of the urine PCR assay was 82%, and the negative predictive value was 99%. Analysis of discrepant results indicated that six of seven PCR-positive, urethral culture-negative patients probably had chlamydial urethritis. All six patients had symptoms of urethritis and had either a positive urethral swab PCR or a positive urine PCR with a different amplification target. After resolution of discrepant results, (defining true positives as the 33 culture-positive patients and the 6 PCR-positive, culture-negative patients just described), the sensitivity and specificity of culture were 85% (33 of 39) and 100% (326 of 326), respectively. The revised sensitivity and specificity of PCR were 97% (38 of 39) and 99.7% (325 of 326), respectively. We conclude that this urine PCR assay provides a highly sensitive, noninvasive alternative method for the detection of C. trachomatis urethral infection in high-risk men attending a sexually transmitted diseases clinic. This assay could greatly facilitate the testing of larger numbers of male patients for chlamydial infection and should be studied in other settings.

Diagnosis of Chlamydia trachomatis endocervical infections by a commercial polymerase chain reaction assay.

We evaluated a prototype polymerase chain reaction (PCR)-based assay for Chlamydia trachomatis developed by Roche Molecular Systems to detect endocervical infection in women. Of 587 endocervical samples obtained from women attending the Harborview Medical Center sexually transmitted diseases clinic, 58 (10%) were positive for C. trachomatis by cell culture. Compared with culture, the PCR method had a sensitivity of 88% (51 of 58) and a specificity of 99.2% (525 of 529). The positive and negative predictive values were 92.7% (51 of 55) and 98.7% (525 of 532), respectively. After resolution of discrepant results whereby true positives were considered to be either culture-positive patients (58 patients) or culture-negative patients positive upon PCR analysis using both plasmid- and major outer membrane protein-based primers (4 patients), the resolved sensitivities of the PCR and culture were 89 and 93%, respectively. We subsequently performed a second analysis of 362 women, comparing the proposed commercial PCR assay from Roche Molecular Systems with chlamydia cultures. Thirty (8%) women were infected with C. trachomatis. Compared with culture, the assay had a sensitivity of 60% (18 of 30) and a specificity of 99% (328 of 332). Repeat PCR assay done 2 to 5 days later subsequently yielded positive results for 7 of 11 PCR-negative samples from culture-positive women. We conclude that the Roche Molecular Systems PCR assay provides highly specific results compared with culture in a high-risk population of women. Further study is needed, however, to more clearly define the sensitivity of the PCR assay in detecting endocervical C. trachomatis infection in women and to identify factors that may compromise sensitivity.

Invasive Haemophilus influenzae infections in older children and adults in Seattle.

We recently saw two unusual manifestations of Haemophilus influenzae infection in adults in the Seattle area: fulminant sepsis in an otherwise-healthy man and three episodes of bacteremia in a woman with chronic liver disease. We retrospectively identified 79 bacteremic and 40 non-bacteremic cases of invasive H. influenzae infection developing in patients > or = 9 years of age between 1 January 1980 and 31 December 1990. The most common clinical presentations among patients with bacteremia included pneumonia (52%), septicemia (27%), meningitis (8%), gynecologic infection (5%), and epiglottitis (5%). Underlying illnesses were common in these patients, and overall mortality was 35.5%. Factors associated with mortality included underlying neurological disease, polymicrobial bacteremia, and advanced age. The clinical presentations of the 40 patients without bacteremia included soft-tissue abscesses (45%), lung abscesses (18%), peritonitis (13%), meningitis (8%), gynecologic infection (8%), epididymitis (5%), mastoiditis (3%), and osteomyelitis (3%). Thus H. influenzae disease has a variety of presentations and is associated with significant mortality in older children and adults. Further study is required to determine whether widespread administration of H. influenzae type b conjugate vaccine to infants will alter the development of subsequent disease in later life.

Cytomegalovirus-induced hemorrhagic cystitis following bone marrow transplantation.

Cytomegalovirus (CMV) is a common cause of morbidity and mortality following bone marrow transplantation but has not been demonstrated to cause hemorrhagic cystitis in this setting. We describe a patient who developed gross hematuria and lower abdominal pain 47 days after bone marrow transplantation was performed. Subsequently, CMV was detected in bladder endothelial cells with use of monoclonal antibody staining that was specific for the virus. No other cause for the patient's hemorrhagic cystitis was discovered. The gross hematuria and pain persisted until the patient received intravenous ganciclovir. This case demonstrates that CMV-induced hemorrhagic cystitis can occur following bone marrow transplantation and may respond to antiviral therapy.

Bordetella bronchiseptica pneumonia and bacteremia following bone marrow transplantation.

Bordetella bronchiseptica is a frequent cause of respiratory infections in animals but rarely causes disease in humans. We describe a patient with B. bronchiseptica pneumonia and bacteremia that developed following bone marrow transplantation. B. bronchiseptica infection persisted despite antimicrobial therapy and may have progressed because of the combined effects of the patient's underlying immunosuppression and the antimicrobial antagonism between doxycycline and ciprofloxacin.