Evaluation of new anti-infective drugs for the treatment of diarrhea caused by Giardia lamblia. Infectious Diseases Society of America and the Food and Drug Administration.

Giardia lamblia is a flagellate protozoan that produces symptoms by infecting the small bowel and biliary tract in the trophozoite form. Diagnosis is currently established by microscopic visualization of the organism in appropriate intestinal contents (stool, small-bowel contents, or biopsy specimen). Adult patients with diarrhea and one or more enteric symptoms may be enrolled in clinical trials of new drugs for the treatment of giardial disease. A randomized, double-blind, active-concurrent-control design is recommended. Post hoc stratification by age, immune status, chronicity of disease, and ease of establishing diagnosis (organism load) may be performed. Microbiological assessment 48 hours to 7 days after the completion of therapy is paramount for determining final outcome.

Evaluation of new anti-infective drugs for the treatment of diarrhea caused by Entamoeba histolytica. Infectious Diseases Society of America and the Food and Drug Administration.

Entamoeba histolytica causes colonic infection that ranges from asymptomatic carriage to invasive disease with infection of extraintestinal organs, particularly the liver. The disease occurs in both sporadic and epidemic forms. Diagnosis requires visualization of trophozoites or cysts by microscopic examination of stool, colonic scrapings, or biopsy specimens. Patients with either asymptomatic or symptomatic disease may be eligible for clinical trials. A prospective, randomized, double-blind, placebo-controlled study design is recommended for asymptomatic carriers and an active-concurrent-control study design for symptomatic patients. Final outcome should be assessed 48 hours to 7 days after completion of therapy. Assessment of microbiological outcome is paramount.

Worldwide clinical experience with ofloxacin in urologic cases.

Ofloxacin is a quinolone carboxylic acid with a broad spectrum of activity for gram-negative pathogens that are common causes of urologic infections including cystitis, pyelonephritis, and prostatitis. The data in this publication will review clinical trials in urologic infections as well as the literature which dates from January 1983 through February 1989. The database includes over four hundred reports from nineteen foreign countries and involves data from more than 21,000 patients. The data from the United States were accumulated in clinical trials conducted between 1984 and 1988. Ofloxacin has certain attributes that make it a potentially useful drug in the treatment of urologic infections. These include the high bioavailability from oral administration and the fact that the product is excreted almost entirely by the kidney, primarily as the active parent compound. Urinary levels of ofloxacin two to four hours postadministration can achieve concentrations above 600 micrograms/mL after a single 400-mg dose. Urinary levels twenty-four hours after a single dose are noted to be typically around 50 micrograms/mL. Both of these concentrations are well above the minimum inhibitory concentration (MIC90) for uropathogens, which might be below 1 microgram/mL for many uropathogens. With respect to the prostate, ofloxacin penetrates prostatic tissues well and can achieve concentrations of approximately 4.5 micrograms per gram of prostate tissue as a mean peak level. Prostate levels ten hours postdose will typically be approximately 2.7 micrograms per gram of prostatic tissue. These levels exceed the MIC90 for the majority of prostatic pathogens as well.

Norfloxacin in the eradication of enteric infections in AIDS patients.

Recurrent episodes of salmonellosis, including recurrent life-threatening bacteremias, have been well-described in patients with AIDS. Because of the need to avoid sensitization to trimethoprim-sulfamethoxazole (TMP-SFX) in AIDS patients and the high frequency of ampicillin resistance of Salmonella isolates, alternative therapies must be sought. We report the treatment of nine AIDS patients, who had recurrent salmonellosis, with norfloxacin, a new oral fluoroquinolone which has excellent in vivo activity against Salmonella sp. Each patient had two to three prior distinct clinical episodes of salmonellosis which had failed to be eradicated with standard courses of ampicillin, TMP-SFX, ceftriaxone or cefotaxime. Microbiologic relapse had occurred in each patient within 2-4 weeks. Each of the enteric pathogens was susceptible in vitro to norfloxacin. Patients were treated with norfloxacin 400 mg bid orally for 30 days. Stool cultures were negative at 1 week in all patients. Nausea and headache were the only adverse reactions to norfloxacin noted. One patient had a clinical and microbiologic relapse of Salmonella 1 week after norfloxacin was stopped but responded to retreatment with norfloxacin. Norfloxacin appears effective in the treatment of enteric infections in AIDS patients and may be more useful than standard agents in eradicating the organism and preventing clinical and microbiologic relapse. Oral administration and twice daily dosing are significant advantages.

The tolerability profile of prophylactic norfloxacin in neutropenic patients.

Norfloxacin has been compared to placebo (136 patients), sulfamethoxazole plus trimethoprim (SXT, 72 patients) and oral vancomycin plus colistin (V/C, 61 patients) for the prevention of alimentary tract-associated infections during and after induction chemotherapy. These patients were evaluated for the safety and tolerability of each regimen by clinical and laboratory means. Most neutropenics involved, regardless of the regimen, experienced at least one adverse experience. The majority were felt to be unrelated to prophylactic study drug therapy. Of 139 patients who received norfloxacin, only two had drug-related adverse experiences, compared to two of 35 receiving SXT, five of 28 for VC, and none of 67 receiving placebo. In evaluating adverse experiences considered possibly drug related, 19 occurred on norfloxacin compared to 13 for placebo. Among neurologic adverse experiences, only one possibly related to norfloxacin occurred (confusion), while three occurred on placebo (confusion, decreased auditory acuity and hallucinations). Generally, no significant differences were seen between any of the regimens except for a higher frequency of diarrhea in those receiving V/C.

Norfloxacin: review of safety studies.

The tolerability profile of norfloxacin, the first of a new generation of fluoroquinolone carboxylic acid antibacterials, has been defined in numerous laboratory animal and human trials. Whether administered for moderate or protracted periods, norfloxacin has been relatively safe in animals over a wide range of doses. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at six to 50 times the human dose (400 mg twice daily). However, norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times the maximal human dose, resulting in peak plasma levels that are two to three times those obtained in humans. Although there are no adequate and well-controlled studies in pregnant women, norfloxacin is not recommended for use in this population because it, like other drugs in this class, causes arthropathy in immature animals. In animals, norfloxacin is neither mutagenic nor carcinogenic, and, in clinical trials, norfloxacin-related adverse experiences have been uncommon. Those that have occurred have been generally mild, requiring discontinuation of therapy in less than 1 percent of patients. The most frequently reported side effects have been nausea, dyspepsia, headache, and dizziness. Administration of 400 mg of norfloxacin at two or three times a day has been associated with reasonably good gastrointestinal tolerance.

Compassionate use of norfloxacin.

Norfloxacin, a new oral fluoroquinolone, has a spectrum of activity and pharmacology that suggest it may be useful in certain infections in which other agents are inactive or have anticipated toxicity. This report is an analysis of 61 "compassionate" requests for norfloxacin that resulted in 42 treatment courses. The reasons for use included multiresistant pathogens susceptible only to norfloxacin in 42 percent, failure of prior use of a marketed antibiotic in 34 percent, and preferred use of norfloxacin due to anticipated toxicity from an aminoglycoside in 32 percent or from other agents in 9 percent. Infections treated included 29 complicated urinary tract infections, 23 involving multiresistant Pseudomonas species, and 10 gastrointestinal infections, seven involving Salmonella species. Prophylaxis of infection was initiated in three neutropenic patients with leukemia. The duration of norfloxacin therapy ranged from eight to 28 days at a daily dose of 800 mg (400 mg twice daily). Norfloxacin treatment resulted in clinical cure or improvement in 84 percent of patients and eradicated the etiologic pathogen(s) 52 percent of the time. In Pseudomonas species infections, cure was achieved in 29 percent of patients and 57 percent showed improvement; the pathogen was eradicated in 43 percent of these infections. Resistance developed in four of the eight Pseudomonas species infections that persisted. Based on a review of compassionate therapy cases, it appears that norfloxacin is effective oral therapy for many complicated urinary and gastrointestinal infections for which other agents cannot be used because of bacterial resistance or anticipated toxicity.

Norfloxacin in the treatment of urinary tract infections in men with and without identifiable urologic complications.

A retrospective analysis of data from the treatment of 95 men with nonbacteremic urinary tract infections (UTIs) (clean-catch urinary bacterial count greater than or equal to 10(5) colony-forming units/ml) who received norfloxacin (400 mg orally twice daily) was performed. Treatment duration ranged from a required minimum of seven days to a maximum of 30 days. If an underlying anatomic or functional condition existed that might decrease the likelihood of a favorable medical response and/or require prolonged treatment, the patient's UTI was considered "complicated." In addition to eight patients with polymicrobic UTIs (usually involving enterococci or Pseudomonas aeruginosa), 48 men (i.e., 51 percent of the total population) had an identifiable complication. Complications included benign prostatic hypertrophy in 13 patients; prostatic cancer in four; urethral stricture in four; quadriplegia/paraplegia with indwelling urinary catheter in four; prostatism in three; and other conditions commonly recognized as altering the response to antibiotic treatment. Among the 95 patients treated, 76 (80 percent) were considered to have had a cure and five (5 percent) showed improvement. Fourteen patients (15 percent) failed to show a response to treatment. Of the 48 patients with UTI and defined complications, 36 (75 percent) had a cure, three (6 percent) showed improvement, and therapy failed in nine (19 percent). Ninety-seven percent (105 of 108) of the pretreatment bacterial isolates were susceptible to norfloxacin. In addition to the three resistant organisms that were present prior to therapy, three organisms (two P. aeruginosa and one Enterobacter) persisted and acquired resistance during therapy. Five adverse clinical experiences and six adverse laboratory experiences were noted. Only one of the former (mild heartburn) was thought to be drug related, and no adverse experience was considered serious or required discontinuation of treatment. Gastrointestinal tolerability of oral norfloxacin was good.

Safety and efficacy of imipenem/cilastatin in treatment of complicated urinary tract infections.

Forty-three patients were treated with imipenem/cilastatin for urinary tract infections. The patients were predominantly men (77 percent), 60 years of age or older (81 percent), and had infections caused by Pseudomonas aeruginosa (58 percent). Forty of 43 cases were complicated (including tumor, stone, obstruction, and renal insufficiency). Approximately 33 percent of patients were febrile (temperature greater than 100.4 degrees). All patients received 500 mg of imipenem/cilastatin intravenously every eight hours. Microbiologic eradication was defined as a sterile urine culture sample obtained from two consecutive urine cultures, one during therapy and one five to nine days after therapy. All patients experienced clinical improvement with microbiologic eradication. No patients experienced drug-related clinical adverse effects.

Chronic mycotic meningitis with spinal involvement (arachnoiditis): a report of five cases.

Five patients developed mycotic spinal arachnoiditis-meningitis causing signs and symptoms of spinal cord neoplasm. Four had cryptococcal infection, the fifth had aspergillosis. In three patients, diagnosis was made at surgery; all three developed acute fungal meningitis postoperatively and two died. The diagnosis was made nonsurgically in two patients and was followed by medical cure. These five and twelve other reported patients with mycotic spinal arachnoiditis shared features that suggested the diagnosis. In contrast to most patients with spinal tumors, those reported here tended to be young (mean age, 32 years), to lack evidence for a primary tumor, and to have a fluctuating history of spinal symptoms for several months. Frequent associated findings were recent pregnancy; the abuse of alcohol, narcotics, or both; and the presence of headache and fever. Plain roentgenograms of the spine were normal. No single finding was diagnostic, but the combination of several would be rare with spinal tumor.

Mycobacterium thermoresistibile: a new pathogen for humans.

The first evidence of the potential pathogenicity of Mycobacterium thermoresistibile is presented. This mycobacterium, initially identified as Mycobacterium gordonae, was isolated repeatedly from sputum, a bronchoscopy specimen. and later, an open lung biopsy. The distinctive characteristics are described, including the unique ability of the organism to grow at 52 degrees C.

Infections caused by Actinomyces viscosus.

Two cases of Actinomyces viscosus infection of the lungs were seen in nonimmunosuppressed patients. One patient had a peripheral actinomycotic lung mass resembling a tumor. Both patients responded to a long course of penicillin therapy. Reports of A. viscosus infections are rare, although the organism colonizes the mouths of most adult humans. Only ten cases have previously been described. There is no characteristic of A. viscosus infection that can distinguish it from Actinomyces israelii or Actinomyces bovis infections. The illness usually manifests as a chronic disease weeks to months before the diagnosis, which can only be made by identification of the organism from a clinical specimen uncontaminated by sputum or mouth flora. Ignorance of the biochemical reactions and growth characteristics of this organism have in the past hindered its isolation and identification. At least three weeks of antibiotic therapy using agents to which A. viscosus is sensitive in vitro are required for cure.

Subcutaneous infection with phialophora richardsiae and its susceptibility to 5-fluorocytosine, amphotericin B and miconazole.

Two patients are described with subcutaneous infections due to Phialophora richardsiae. Both were diabetics and originally came from subtropical areas. One of the patients had a cystic lesion which was well encapsulated while the other had a large ulcerating lesion with draining sinus tracts. The organisms were found to be susceptible to cycloheximide but resistant to 5-fluorocytosine, miconazole and amphotericin B. There was some variability in the degree of resistance depending upon whether the primary or secondary phialoconidia were tested. While simple excision appears curative for the solitary cystic type of lesion, therapy of the ulcerating form of the disease remains problematic.