Hepatotoxicity possibly caused by amphotericin B.

OBJECTIVE: To report a case of possible amphotericin B-induced hepatotoxicity in a patient with pulmonary blastomycosis. SUMMARY: A 26-year-old white man with life-threatening pulmonary blastomycosis developed elevation of his liver enzymes after the addition of amphotericin B to his initial itraconazole therapy. The hepatotoxicity resolved rapidly with discontinuation of the amphotericin B, and the blastomycosis was successfully treated with itraconazole alone. DISCUSSION: This case illustrates an unusual occurrence of hepatotoxicity associated with a short course of amphotericin B. Liver biopsy was compatible with drug-induced changes and showed no evidence of blastomycosis. Discontinuation of amphotericin B with no other therapeutic changes resulted in a rapid resolution of hepatotoxicity. A possible adverse drug interaction with itraconazole and amphotericin B is postulated based on the mechanism of action of each drug. CONCLUSIONS: Amphotericin B therapy can be associated with many adverse effects, but reports of hepatotoxicity are rare. Closer monitoring of liver enzymes in patients receiving amphotericin B, especially in combination with potentially hepatotoxic agents, including azole antifungal drugs, would be prudent.

Polymerase chain reaction-and RNA hybridization-based method for the investigation of deep-seated candidiasis.

OBJECTIVE: To determine the usefulness of a polymerase chain reaction (PCR) and RNA hybridization method for the diagnosis of invasive candidiasis and to compare its sensitivity with blood cultures. DESIGN: Blood cultures and a blood sample for PCR were taken from patients with suspected invasive candidiasis. A 105 base pair conserved segment within the rDNA of Candida species was amplified. The amplicon was detected by hybridization and gel electrophoresis. SETTING: Intensive care units of two tertiary care hospitals. PATIENTS: One hundred and eighteen patients 16 years of age or older with four more risk factors for invasive candidiasis were enrolled. Present or recent past treatment with broad spectrum antibiotics, cancer chemotherapy, immunosuppressive drugs, granulocytopenia or granulocytosis, intravascular catheterization, tracheal intubation, recent abdominal surgery and parenteral nutrition were considered risk factors. RESULTS: Forty-three patients had invasive candidiasis. PCR detected infections in 28 and 26 patients (sensitivity 65.1% and 60.4%) by hybridization and gel electrophoresis, respectively. The sensitivity of blood cultures was 58.1%. Of 25 patients with positive blood cultures, 17 were positive by PCR with the hybridization method. Eleven patients with invasive candidiasis had negative blood cultures but were positive by PCR. CONCLUSION: PCR, especially with a hybridization detection method, is more sensitive than blood culture for invasive candidiasis and may facilitate the diagnosis of nonfungemic disease.

Septic arthritis due to Mycobacterium marinum.

We describe a patient with septic arthritis and osteomyelitis of the ring finger due to Mycobacterium marinum. A review of the literature shows fewer than 40 reported cases of joint infection with this organism. Most of the patients reported had been previously in good health, and had been in contact with fish or otherwise involved in aquatic activities. The arthritis affects mainly the hands or wrists and is insidious in onset. Delay in diagnosis, and initial inappropriate treatment with intraarticular steroids are frequent. Therapy with antibiotics and/or surgical debridement is usually successful.

Menstrual toxic shock syndrome complicated by persistent bacteremia: case report and review.

An unusual case of menstrual toxic shock syndrome (TSS) is described in which the patient had persistent Staphylococcus aureus bacteremia despite therapy with iv cloxacillin. There was no demonstrable evidence of endocarditis or an abscess as a focus for persisting bacteremia. The strain of S. aureus isolated from the blood and vagina produced toxic shock syndrome toxin 1 (TSST-1) and enterotoxin A. Bacteremia occurs uncommonly in association with TSS; however, aggressive high-dose antistaphylococcal therapy should be instituted for treating this possible complication.

Clinical experience with multilamellar liposomal amphotericin B in patients with proven and suspected fungal infections.

Over a 3-year period, an unsonicated multilamellar vesicle preparation containing a low ratio of amphotericin B (5 mole %) was used as a routine alternative to amphotericin B-deoxycholate in treating 17 patients with a variety of systemic fungal infections representative of those commonly encountered on a tertiary care centre infectious disease service. Patient acceptability and convenience of administration were noteworthy. In 6/7 patients who had been given the liposomal drug after experiencing severe side effects (primarily hypokalemia and marked elevation of serum creatinine) on the non-liposomal form, the problems that had led to institution of the liposomal drug were reversed during treatment. However, multilamellar liposomal amphotericin B at conventional dosage was not without detectable toxicity in this patient population. Three transplant patients receiving cyclosporin at the same time as liposomal amphotericin B experienced a rise in serum creatinine, and 4 patients became hypokalemic during treatment: none of these effects was severe or required discontinuation of therapy. One or more liver enzymes rose measurably in 7 patients during treatment with liposomal amphotericin B, but remained unchanged or actually decreased in the remaining patients.

Granulomatous hepatitis and fever of unknown origin. An 11-year experience of 23 cases with three years' follow-up.

Granulomatous hepatitis is a common cause of fever of unknown origin in up to 13% of patients with prolonged fever. Attempts to define an exact etiology of the granulomatous hepatitis frequently does not yield a precise diagnosis, so that the physician must consider empiric treatment. In this paper we retrospectively review 23 patients in whom granulomatous hepatitis was found as part of the initial assessment of fever of unknown origin, and we report on their outcomes after an overall prospective follow-up of 37 months. In 26% a precise diagnosis was established at the time of assessment: Q-fever in three, mycobacterial disease in two, and histoplasmosis in one. In the remaining 74% no etiology was established after 44 months follow-up. Forty-one percent of the idiopathic group resolved spontaneously without therapy, and 18% received short-term prednisone or indomethacin with a favourable outcome. The remaining 41% required long-term prednisone therapy for a mean of 33.1 months, but all have remained afebrile and otherwise healthy after 59.6 months follow-up. We conclude that patients with fever of unknown origin who are diagnosed as having idiopathic granulomatous hepatitis have an excellent prognosis, even the minority who require long-term corticosteroids.

Liposomal amphotericin B: an effective, nontoxic preparation for the treatment of urinary tract infections caused by Candida albicans.

Liposomal amphotericin B without prior administration of Fungizone was found to be an effective treatment in 4 patients with urinary tract infections caused by Candida albicans. Urine typically became culture negative after 1-4 days of dosing at 50 mg/day, demonstrating that therapeutic levels of amphotericin B were reached in the urine at conventional doses given in liposomal form. The low incidence of toxicity with this preparation was particularly useful in patients with impaired renal function, including renal transplant patients on cyclosporine immunosuppression.

Comparative in vitro effects of liposomal amphotericin B, amphotericin B-deoxycholate, and free amphotericin B against fungal strains determined by using MIC and minimal lethal concentration susceptibility studies and time-kill curves.

Multilamellar liposomal amphotericin B (L-AmB) was generally less active in vitro against yeast strains than was amphotericin B-deoxycholate or free amphotericin B, although continual agitation of the broth disproportionately increased the activity of L-AmB. Time-kill studies also demonstrated a slower onset of action of L-AmB and supported the hypothesis that liposomes may act as reservoirs for free amphotericin B, which is the active moiety.

Enterobacter meningitis--treatment complicated by emergence of mutants resistant to cefotaxime.

A case of Enterobacter cloacae meningitis in a postoperative patient is reported. A slow response to cefotaxime necessitated the use of gentamicin and trimethoprim-sulfamethoxazole for cure. Two types of resistance in the strain of E. cloacae isolated to cefotaxime were demonstrated: an inducible beta-lactamase that likely was the cause of the poor response to cefotaxime and a constitutive beta-lactamase in a mutant strain detected by a disc susceptibility test.

Successful antimicrobial therapy of hepatic, intra-abdominal and intrapelvic abscesses.

Antimicrobial therapy without surgical drainage or therapeutic aspiration was effective in the management of four patients with deep abscesses ranging in diameter from 1.3 to 10.0 cm. Two of the patients had multiple hepatic abscesses, one had hepatic, intra-abdominal and intrapelvic abscesses, and one had an intrapelvic abscess alone. Anaerobic bacteria were isolated from the blood or abscesses in all four patients, and an aerobic-anaerobic infection was present in one patient. The patients were treated with metronidazole, alone or in combination with other antibiotics, for 3 to 6 weeks. Therefore, in selected patients with deep abscesses, a therapeutic trial of antimicrobial agents instead of surgery may be justified.

Susceptibility of Trichomonas vaginalis strains to metronidazole: response to treatment.

The effect of the susceptibility of Trichomonas vaginalis strains to metronidazole on response to treatment was determined from minimal inhibitory concentrations (MICs) for organisms isolated during a clinical trial in which single 1- and 2-g doses of metronidazole were compared. Fifty-seven strains were isolated from patients receiving 1 g of metronidazole, and 75 from those receiving 2 g. The mean MIC for all strains was 1.50 microgram/ml (range, 0.5-4.5 microgram/ml) and was similar in both groups. The mean MICs for isolates from patients who were cured were significantly less than the mean MICs of isolates from those who were treatment failures. The cure rates, compared to the MICs for the strains isolated, varied from 84% (MIC, 0.5 microgram/ml) to 16% (MIC, greater than or equal to 3.0 microgram/ml) for the group given the single 1-g dose and from 94% (MIC, 0.5 microgram/ml) to 43% (MIC, greater than or equal to 3.0 micrograms/ml) for those given the 2-g dose. The data demonstrate a direct relationship between susceptibility of T. vaginalis isolates and response to treatment with single-dose regimens of metronidazole.

Comparative antimicrobial activity of metronidazole and the hydroxy metabolite against Gardnerella vaginalis.

Metronidazole (M) (1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole) undergoes oxidative metabolism with the formation of several metabolites, the most important quantitatively in serum and urine being the "hydroxy" metabolite (HM) (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole). The antimicrobial activity of HM was compared with M against strains of G. vaginalis using minimal inhibitory (MIC) and bactericidal (MBC) concentration determinations and time-kill curve studies. At an inoculum of 10(6) colony forming units per ml (cfu/ml), and anaerobic incubation for 48 hours, the median MIC and MBC of HM were 1 and 2 micrograms/ml, respectively, compared to 4 and 16 micrograms/ml for M. HM also demonstrated a more rapid bactericidal effect than M in time-kill curves against exponential (10(6) cfu/ml) and stationary phase (10(10-13) cfu/ml) organisms. However, the cidal effect of HM against G. vaginalis was slower than that previously shown for M against obligate anaerobes such as B. fragilis. The degree of inactivation of both HM and M, determined by high pressure liquid chromatography, was similar during the time-kill studies and averaged less than 10% with exponential phase organisms and approximately 40% against stationary phase organisms after 48 hours' incubation. Pharmacokinetic studies have shown that on usual dosage regimens of M used for non-specific vaginitis the serum levels of HM would likely exceed the MIC/MBC for most strains of G. vaginalis. Therefore, HM likely contributes a significant antimicrobial effect against this organism.

Metronidazole in a single dose for the treatment of trichomoniasis. Failure of a 1-g single dose.

To determine the minimum effective dose of metronidazole in the treatment of vaginal trichomoniasis, a randomised clinical trial comparing single 1-g and 2-g doses was carried out on 163 patients attending sexually transmitted diseases and family planning clinics. Seventy-two of 86 (84%) patients receiving a single 2-g dose of metronidazole were cured compared with only 42 of 77 (55%) receiving a 1-g dose. The body weight of the patient was a significant variable affecting treatment outcome only in the latter group; 69% of patients weighing more than 57 kg or less when cured compared with only 43% of those weighing more. Patients who failed after either dose regimen were retreated with a single 2-g dose. Eighteen of 21 (86%) and seven of 10 (70%) failures with the initial 1-g and 2-g doses respectively were cured. A single 1-g dose of metronidazole is not recommended as routine treatment for vaginal trichomoniasis.

Relative susceptibilities of Gardnerella vaginalis (Haemophilus vaginalis), Neisseria gonorrhoeae, and Bacteroides fragilis to Metronidazole and its two major metabolites.

The susceptibilities of strains of Gardnerella vaginalis (Haemophilus vaginalis), Neisseria gonorrhoeae, and Bacteroides fragilis to metronidazole and its principal oxidative metabolites (1-[2-hydroxyethyl]-2-hydroxymethyl-5-nitroimidazole) ("hydroxy" metabolite) and 1-acetic acid-2-methyl-5-nitroimidazole ("acid" metabolite), were compared by determinations of the minimal inhibitory concentrations (MICs) of these compounds. Against ten strains of G. vaginalis, the hydroxy metabolite was the most active (median MIC, 2 microgram/ml); the median MICs of metronidazole and of the acid metabolite were 8 and 64 microgram/ml, respectively. The hydroxy metabolite was also the most active against 15 strains of N. gonorrhoeae (median MIC, 32 microgram/ml). In contrast, metronidazole was the most active against ten strains of B. fragilis (median MIC, 1 microgram/ml); the hydroxy and acid metabolites had median MICs of 2 and 64 micrograms/ml, respectively. These results indicate that in the treatment of G. vaginalis-associated vaginitis with metronidazole, the hydroxy metabolite may contribute a significant antimicrobial effect, in view of its excellent activity in vitro.

Metronidazole in treatment against Haemophilus vaginalis (Corynebacterium vaginale).

The rate of bactericidal activity and inactivation of metronidazole was studied in time-kill curves with Haemophilus vaginalis (Corynebacterium vaginale). The minimum inhibitory concentrations of metronidazole for the eight strains tested ranged from 4 to 16 micrograms/ml. At a concentration of 20 micrograms/ml, metronidazole demonstrated a slow cidal effect against exponential-phase organisms, requiring 24 to 48 h for completion. Inactivation of metronidazole during the time-kill curve was quite variable and averaged 28% of the starting concentration after 48 h. Against stationary-phase organisms (inoculum, 10(10) to 10(11) colony-forming units per ml), a slow cidal effect was also seen, with an average inactivation of metronidazole of 38% after 48 h. At a subinhibitory concentration of 5 micrograms/ml, metronidazole was inactivated to the greatest degree (57% after 48 h). Therefore, in contrast to earlier studies in which metronidazole was rapidly and consistently cidal within 4 h against obligate anaerobes and was almost completely inactivated by 8 h, the bactericidal effect of metronidazole againsts H. vaginalis in this study was much slower and was associated with a variable and slower rate of inactivation.