Treatment of invasive fungal infections in renally impaired patients with amphotericin B colloidal dispersion.

Amphotericin B colloidal dispersion (ABCD) is a new formulation of conventional amphotericin B designed to minimize drug distribution in the kidney and reduce nephrotoxicity. We studied the safety and efficacy of ABCD in 133 renally compromised patients with invasive fungal infections. Patients had either nephrotoxicity from amphotericin B or preexisting renal disease. Intravenous treatment with ABCD (4 mg/kg of body weight daily) was administered for up to 6 weeks. Evaluations included clinical response to treatment and adverse events, with emphasis on changes in serum creatinine levels. ABCD did not appear to have an adverse effect on renal function: mean serum creatinine level tended to decrease slightly with days on therapy, and increases were not dose related. Complete or partial response to treatment was reported for 50% of the 133 intent-to-treat patients and 67% of the 58 evaluable patients.

Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin.

AS101, a synthetic organotellurium compound, was found to have immunomodulating properties by initiation of cytokine production in vitro and in vivo. Phase I/II clinical trials currently in progress on AIDS and cancer patients treated with AS101 show significant increases in various immunological parameters, with minimal toxicity. Recently, AS101 and the protein kinase C (PKC) inducer, phorbol myristate acetate (PMA), were shown to synergize in the secretion of interleukin-2 (IL-2) and colony-stimulating factor (CSF) in vitro, by human and mouse lymphoid cells. The bryostatins, a group of natural macrocyclic lactones isolated from marine invertebrates (Bugula neritina) have been reported to be potent PKC activators with no tumour promoting activity. In this study, we investigated the synergistic effect of AS101 and a partially purified preparation of bryostatin on the production of several cytokines. Our data confirm the presence of synergism, which greatly enhances cell proliferation, IL-2, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) secretion by human mononuclear cells (MNC) and the production of IL-2 and TNF by mouse cells. The absence of tumour-promoting activity of the bryostatins makes them particularly good candidates, in combination with AS101, for immunomodulation in vivo in clinically immunosuppressed conditions.

Current use and future directions of adenovirus vaccine.

Adenoviruses are a major cause of respiratory illnesses in military recruits and also are common causes of respiratory and gastrointestinal infections during childhood. Forty-one serotypes of human respiratory and enteric adenoviruses have been identified. Live, oral adenovirus vaccines developed for the military and tested in large clinical trials have proved to be safe and highly effective in decreasing hospitalizations related to adenoviral acute respiratory diseases. Studies have demonstrated little horizontal transmission among military personnel but substantial transmission among family members. Use of recombinant techniques have opened new opportunities for the development of recombinant adenovirus vector vaccines against a number of viral pathogens such as hepatitis B, human immunodeficiency, herpes simplex and respiratory syncytial virus.

Risk factors for urinary tract infection.

The authors carried out a case-control study in 1982-1983 to investigate the possible influence of behavioral factors on the risk of urinary tract infection. Study participants were college women attending a student health service. Cases were 43 women with culture-confirmed urinary tract infection. There were two control groups: 149 women with upper respiratory infection and 227 women visiting the gynecology clinic. Using each set of controls, the study confirmed that sexual intercourse is a risk factor and that there is a dose-response effect for increasing levels of coital frequency. The study also found that use of the diaphragm was significantly associated with urinary tract infection (odds ratios 3.0, 2.3), an association which remained significant even after controlling for possible confounding by coital frequency. The findings did not show an association with many of the factors commonly believed to be important such as type of clothing worn and volume of fluids consumed.

PIP: A case study was conducted among college women using a student health service at a university in southern Michigan to identify and evaluate behavioral factors which may be determinants of urinary tract infection. Women who presented to the student health service with symptoms suggestive of urinary tract infection and found to have pyuria on urinalysis were offered the opportunity to participate in a clinical trial comparing antibiotic regimens in the treatment of their urinary infection. Women with identified structural abnormalities of the urinary tract were not admitted to the study. On their 1st visit, women enrolled in the antibiotic study were asked to complete a questionnaire for the epidemiologic study described here. Midstream specimens were obtained during the 1st visit prior to therapy and were cultured quantitatively using standard methods. A patient with symptoms of acute urinary tract infection was included as a case if the urine culture was positive or probable. 2 different control groups were used to assess risk factors for urinary tract infection. For the 1st control group, women presenting to the student health service with coryza and/or sore throat, an oral temperature of less than 38.9 degrees Centigrade, and a clinical diagnosis of uncomplicated viral upper respiratory infection were asked to complete the same questionnaire as cases. For the 2nd control group, women attending the gynecology clinic at the same student health service for routine scheduled pelvic examinations and/or contraceptive services were asked to complete the same questionnaire. Cases were entered into the study from March through December 1982. The students used as controls participated from March 1982 through March 1983. The subjects completed a standard self-administered multiple-choice questionnaire, asking primarily about activities during the 3 weeks prior to completion of the questionnaire. 47 women with presumptive urinary tract infection participated in the clinical trial. 43 cases of confirmed urinary tract infection were identified, 38 with a positive and 5 with a probable urine culture result. In all, 149 upper respiratory infection controls and 227 gynecology controls participated. The history of previous urinary tract infection was significantly greater in cases than in either of the control groups. 4 variables were included in the final logistic model: coital frequency within 3 weeks, use of the diaphragm within 3 weeks, history of previous urinary tract infection, and age. Coital frequency during the previous 3 weeks was associated strongly with illness, with generally higher risk at higher frequencies. A significant association with the diaphragm was observed in comparison with both control groups. The findings failed to show an association with many of the factors commonly believed to be important such as type of clothing worn and volume of fluids consumed.

Clinical and microbiological features of Aeromonas hydrophila-associated diarrhea.

The prevalence of Aeromonas hydrophila in stool specimens from patients with diarrhea was studied during 18 months. A. hydrophila was found in 1.1% of patients with diarrhea and in none of 533 control patients (P less than 0.02). Cases were detected 1.5 times more often during the summer months than the winter months, and most occurred in children less than 2 years of age. Clinical features included fever greater than 38 degrees C (55%), abdominal cramps (35%), vomiting (25%), and duration of illness greater than 10 days (50%). Detection of A. hydrophila in stools was facilitated by the use of sheep blood agar with 15 micrograms of ampicillin per ml which was flooded with oxidase reagent after growth. A cytotoxin was produced by 62% of the isolates, and the cytotoxic strains showed positive results in a hemolysin assay and a lysine decarboxylase reaction.

Amoxicillin-potassium clavulanate, a beta-lactamase-resistant antibiotic combination.

The chemistry, microbiology, pharmacokinetics, therapeutic use, adverse effects, and dosage of amoxicillin-potassium clavulanate, a beta-lactamase-resistant antibiotic combination, are reviewed. Clavulanic acid is a "suicide" inhibitor of bacterial beta-lactamase enzymes and has been effective in preventing destruction of penicillins by these enzymes. Clavulanic acid alone has weak antibacterial activity against most organisms. After oral administration, clavulanic acid is rapidly absorbed; amoxicillin appears to increase its absorption. Absorption of amoxicillin-clavulanic acid is not affected by food. Amoxicillin-clavulanic acid is effective in treating both acute uncomplicated and complicated urinary-tract infections and exacerbations of chronic bronchitis caused by amoxicillin-resistant organisms in adults. It appears to be comparable in efficacy to cefaclor for treating uncomplicated urinary-tract infections in adults and children, acute bronchitis and bronchopneumonia, and acute sinusitis, otitis media, and skin and soft-tissue infections in children. Other infections for which the combination has been effective include cellulitis and intra-abdominal and pelvic sepsis caused by mixed aerobic/anaerobic organisms. Amoxicillin-clavulanic acid has also successfully cured urethritis in men caused by penicillinase-producing Neisseria gonorrhoeae and is superior to amoxicillin alone for beta-lactamase-positive Haemophilus ducreyi infections (chancroid). Diarrhea or loose stools is the most common side effect seen with amoxicillin-clavulanic acid; nausea, vomiting, and skin rash may also occur. Nausea, vomiting, and diarrhea may be lessened by taking the combination with food.(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective comparison of amoxicillin-clavulanic acid and cefaclor in treatment of uncomplicated urinary tract infections.

Patients with acute, uncomplicated urinary tract infections were treated with either amoxicillin-clavulanic acid (A-C) in fixed combination or cefaclor for 10 days in a prospective randomized comparison. The A-C group included 29 women and 1 man (mean age, 25.5 years), and the cefaclor group included 35 women and 1 man (mean age, 24.9 years). The cure rates were 26 (87%) of 30 with A-C and 26 (72%) of 36 with cefaclor (P greater than 0.20). There was one failure in each group, each caused by an isolate resistant to ampicillin. There were one relapse and two reinfections in the A-C group, compared with seven relapses and two reinfections in the cefaclor group. Side effects, including patients started on antibiotics but whose cultures did not confirm urinary tract infections, were diarrhea in 7 (16%) and rash in 1 (2%) of 44 A-C patients, compared with diarrhea in 1 (2%) and yeast vaginitis in 3 (6%) of 48 cefaclor patients. Although the A-C group had a greater proportion of antibody-coated bacterium-positive infections (22 versus 18 with cefaclor), there was a lower recurrence rate with fewer relapses in patients treated with A-C.

Reduction in mortality from gram-negative sepsis in neutropenic patients receiving trimethoprim/sulfamethoxazole therapy.

The causes of death were reviewed in 53 patients from two prospective randomized trials on the efficacy of trimethoprim/sulfamethoxazole as prophylaxis of gram-negative bacillary infection in granulocytopenic patients. Twenty-nine deaths occurred in patients treated with TMP/SMX prophylaxis while 24 occurred in patients who served as controls in the first trial. The two groups were similar, with the exception that more patients in the TMP/SMX group had acute leukemia (82 versus 50%; P less than 0.02). Microbiologically documented gram-negative rod infection preceeded death in 8/24 control patients as compared to 2/29 TMP/SMX recipients (P less than 0.02). This decrease in gram-negative related deaths was most pronounced in the patients with acute leukemia. Fatal gram-negative rod infection occurred in 7/12 control leukemic patients as compared to 2/24 TMP/SMX treated patients. Despite the reduction in numbers of gram-negative rod-related deaths, infectious deaths accounted for 16/24 and 15/29 patients in control and TMP/SMX treated patients, respectively. Similar numbers of fungal, viral, and gram-positive bacterial infections occurred in each group. Fever with pulmonary infiltrates but without proven etilogic agents were included in the category of "clinically documented infections;" 6/7 patients with fever and undiagnosed pulmonary infiltrates were in the TMP/SMX group. Prophylactic administration or oral trimethoprim/sulfamethoxazole reduces the frequency of fatal gram-negative rod infections in neutropenic patients.

Morphologic and functional effects of Clostridium difficile enterotoxin in tissue culture.

The effects of the Clostridium difficile toxin were examined in HeLa and mouse adrenal tumor (MAT) cells. Cytotoxicity was evaluated by vital dye exclusion and 51Cr release. In both HeLa and MAT cells, C. difficile toxin caused rounding of virtually 100% of cells. This rounding was distinguishable from rounding produced by the Escherichia coli heat-labile enterotoxin (LT): (1) LT was inactive in HeLa cells; (2) in MAT cells, C. difficile toxin produced uniformly rounded cells, while LT-rounded cells usually had cytoplasmic extensions and a regular background of flattened cells. In C. difficile toxin affected HeLa cells, there were less than mitotic figures per 1000 cells compared with 15-18 in controls. Clostridium difficile toxin treated HeLa cells showed less than 10% cytotoxicity in 24 h and no more than 30% by 74 h, similar to control cells. However, paralleling the suppression of mitotic figures, cell multiplication was inhibited in C. difficile toxin treated cells when subcultured in a short-term (72 h) assay compared with up to a 500% increase in control cells. This inhibition was also seen in a 6-week cloning assay in which C. difficile toxin treated cells had a cloning efficiency of less than 1% compared with approximately 10% in controls. We conclude that the major effect of the C. difficile toxin is inhibition of growth rather than immediate cell death. The relationship of this growth inhibition to colitis remains to be elucidated.

Toxin-producing bacteria in infants. Lack of an association with sudden infant death syndrome.

After finding enterotoxigenic (ET) Escherichia coli in two consecutive cases of sudden infant death syndrome (SIDS), we initiated a prospective search for ET E coli in SIDS in Manitoba; in addition, we looked for toxigenic Clostridium botulinum and C difficile. In a 21-month period, small- and large-bowel contents were obtained in 33 cases of SIDS, from 32 control subjects, and in ten suspected cases of SIDS. Neither C botulinum nor ET E coli was isolated from any of these; C difficile was cultured from postmortem bowel contents of two SIDS and seven control cases. The overall isolation rate of C difficile was 17%. Despite the fact that two of these cases had toxin detectable in the bowel contents, no evidence of colitis was found in any of the cases with C difficile. We conclude that C botulinum or ET E coli have only a small role, if any, in the etiology of SIDS, and that C difficile is found relatively commonly in the gastrointestinal tract of infants without apparent local or systemic effects.

Prospective, randomized comparative study of clindamycin, chloramphenicol, and ticarcillin, each in combination with gentamicin, in therapy for intraabdominal and female genital tract sepsis.

The results of a prospective, randomized comparative study of the efficacy and toxicity of clindamycin, chloramphenicol, and ticarcillin in the treatment, concomitantly with gentamicin to ensure complete aerobic coverage, of 175 patients with serious mixed aerobic/anaerobic intraabdominal or female genital tract sepsis are reported. In the group with intraabdominal sepsis, 33 (79%) of 42 treated with clindamycin, 43 (81%) of 53 treated with chloramphenicol, and 35 (90%) of 39 treated with ticarcillin were cured. In the group with genital tract sepsis, 16 (94%) of 17 treated with clindamycin, 11 (100%) of 11 treated with chloramphenicol, and 12 (92%) of 13 treated with ticarcillin were cured. Diarrhea occurred most frequently in patients treated with clindamycin (P < 0.001), hematologic suppression occurred most frequently in patients treated with chloramphenicol (P < 0.01), and hypokalemia occurred most frequently in patients treated with ticarcillin (P < 0.01). Clindamycin, chloramphenicol, and ticarcillin, each in combination with gentamicin, are equally effective in therapy for intraabdominal or female genital tract sepsis.

Cytotoxic enterotoxin produced by Aeromonas hydrophila: relationship of toxigenic isolates to diarrheal disease.

Ninety-six Aeromonas hydrophila isolates were tested for cytotoxin and hemolysin production. Sixty-six (69%) of the isolates were both cytotoxic and hemolytic, whereas the rest produced neither cytotoxin nor hemolysin. No evidence of a separate cytotonic activity could be found in any of the isolates. Cytotoxin activity correlated with enterotoxic activity. Of four cytotoxin-producing strains tested in the isolated rabbit ileal loop, three were definitely positive and one was borderline, whereas two nontoxigenic strains were negative. Cytotoxin activity appeared to be a stable property and could not be assoicated with any common identified plasmid; only 10 of 21 cytotoxin-producing strains could be shown to have any plasmid by agarose gel electrophoresis. Cytotoxin production correlated with a positive lysine decarboxylase phenotype (98%) or a positive Voges-Proskauer phenotype (94%), compared to 27% lysine decarboxylase-positive and 23% Voges-Proskauer-positive, cytotoxin-negative isolates (P less than 0.001 for both). In fecal samples, cytotoxin production correlated with diarrheal disease; of 40 diarrheal isolates, 32 (80%) were toxigenic compared to 9 (41%) of 22 nondiarrheal isolates (P = 0.004). It appears that A. hydrophila can be a cause of diarrhea and that this enteropathogenic potential is mediated by a cytotoxic enterotoxin.

A prospective controlled investigation of prophylactic trimethoprim/sulfamethoxazole in hospitalized granulocytopenic patients.

Oral trimethoprim/sulfamethoxazole (TMP/SMZ) therapy was investigated in the prophylaxis of infections in granulocytopenia. Hospitalized granulocytopenic patients were allocated at random to receive TMP/SMZ (group 1) or to a control group (group 2). The percentage of febrile granulocytopenic days was significantly reduced in group 1, 19 per cent compared to 39 per cent in group 2 (P less than 0.01). In group 1, there were no bacteremias in 59 episodes of granulocytopenia (909 days). In group 2, there were nine bacteremias in 52 episodes of granulocytopenia (796 days)(P = 0.001). Disseminated candidiasis developed in two patients in each group. Candida occurred in similar numbers in surveillance cultures in both groups; Staphylococcus aureus and Pseudomonas aeruginosa were slightly decreased, and Enterobacteriaceae resistant to TMP slightly increased in group 1. This study suggest that oral prophylactic TMP/SMZ therapy is an effective, well tolerated, easily administered alternative to "gut sterilization" with nonabsorbable antibiotics.

Granulocytopenia in hospitalized patients: I. Prognostic factors and etiology of fever.

The clinical course of 126 hospitalized patients during 192 episodes of granulocytopenia and fever was studied. Fever was a regular accompaniment of granulocytopenia, occurring in 94 per cent of granulocytopenic episodes. The mean duration of granulocytopenia (less than 1,000/mm3) was 18 days, with fever (temperature greater than 38 degrees C) being present during 44 per cent of those days. Fever was present during 69 per cent of days with a granulocyte count less than 10/mm3. A presumed infection was present in 86 of 128 febrile granulocytopenic episodes in adults and in 19 of 64 febrile granulocytopenic episodes in children. A fungal infection was found in 11 patients; a viral infection in 23 patients. Bacteremia occurred during 44 granulocytopenic episodes with 16.8 bacteremias/1,000 days of granulocytopenia in adults and 12.7 bacteremias/1,000 days in children. The mortality was 33 per cent per granulocytopenic episode in adults and only 8 per cent per episode in children.

Gastroenteritis in children: a two-year review in Manitoba. I. Etiology.

During two years, 1,217 children hospitalized with gastroenteritis at the Children's Centre in Winnipeg, Manitoba, Canada were studied. Bacterial pathogens were present in 25% of these children: enteropathogenic Escherichia coli in 120, Shigella in 139, Salmonella in 24, and multiple pathogens in 18. Rotavirus was detected in 54 (11%) of 472 patients examined. Rotavirus and enteropathogenic E. coli were the most common pathogens in infants, and Shigella was the most common in older children. Bacterial diarrhea occurred more commonly in summer, whereas rotavirus infection occurred more commonly in winter. Among 276 children screened, enterotoxigenic E. coli was found in three, and Aeromonas shigelloides that produced a similar toxin in two others. Enteroinvasive E. coli was not detected in 70 children. Organisms producing toxins "cytotoxic" to HeLa cells were isolated from three of 90 children. Screening for enterotoxigenic or enteroinvasive organisms was not productive of a significant number of pathogens, and, although screening for rotavirus did improve the number of etiologic diagnoses, the etiology of the majority of cases of diarrhea remained unknown.

Clinical and laboratory study of tobramycin in the treatment of infections due to gram-negative organisms.

Tobramycin, an aminoglycoside antibiotic, was used to treat 52 infections due to gram-negative organisms in 51 patients. Complicated urinary tract infections, bacteremia and pyelonephritis accounted for 80% of the infections. The rate of immediate satisfactory response was 79%. During therapy with tobramycin, resistant organisms emerged in four patients--two Pseudomonas aeruginosa and two Escherichia coli strains. There were four superinfections with tobramycin-resistant Providencia sp. In four seriously ill patients the serum creatinine concentration increased 1 mg/dL or more; in three the increase was transient. No auditory toxicity was noted in the 19 patients in whom serial audiograms were made. In vitro testing of isolates from these patients showed that tobramycin and gentamicin had equal activity against Enterobacteriaceae. Tobramycin was two to four times more active against susceptible P. aeruginosa.

Clinical and laboratory assessment of the pathogenicity of serotyped enteropathogenic Escherichia coli.

Only one of 167 separate isolates of enteropathogenic Escherichia coli (EEC) was shown to produce enterotoxin, and none of the 167 isolates were invasive. Clinical features of 123 hospitalized children with EEC were compared with those of 917 infants with nonbacterial gastroenteritis and 145 infants infected with Shigella. The average duration of diarrhea (five or more stools per day) in hospitalized children with EEC, nonbacterial gastroenteritis, Shigella flexneri, and Shigella sonnei was 4.6, 2.4, 5.1, and 2.5 days, respectively. The average duration of fever in these four groups was 1.4, 1.2, 2.1, and 1.2 days, respectively. The difference in duration of diarrhea between children with EEC and those with nonbacterial gastroenteritis was significant (P less than 0.001), even when age and rural/urban origin were controlled by analysis of variance. Nevertheless, the EEC group tended to be younger and to have a higher proportion of infants of rural origin. Although it appears that EEC serotypes rarely identify invasive or enterotoxin-producing organisms, clinical features of infants with EEC-associated gastroenteritis suggest that these infants may represent a distinctive and clinically important group with gastroenteritis of greater severity than nonbacterial gastroenteritis.

Amoxicillin therapy of acute urinary infections in adults.

Fifty-two patients, 48 females and 4 males, with suspected urinary infection were treated with amoxicillin. Twenty-two females with presumed bladder infection were treated with amoxicillin, 250 mg three times a day for 7 days; 26 females and 4 males with presumed renal infection were treated with amoxicillin, 500 mg three times a day for 14 days. Five patients were immediate treatment failures, with positive urine cultures during therapy. All five patients had been infected with amoxicillin-resistant urinary pathogens. Three patients, treated as for bladder infections, reinfected during 6 weeks of follow-up, and only one relapsed. Two patients, treated as for renal infections, reinfected, whereas four relapsed. During therapy, amoxicillin-susceptible gram-negative rods were eradicated from the periurethral area in all but one patient. Of 28 patients studied, 19 acquired a predominant growth of either resistant aerobic gram-negative rods or Candida albicans from periurethral cultures. Our findings suggest that these two regimens of amoxicillin achieve satisfactory cure rates in urinary infection, but both regimens significantly alter the normal periurethral flora.

Diarrhea associated with clindamycin and ampicillin therapy: preliminary results of a cooperative study.

Patients treated with clindamycin were monitored for development of diarrhea and colitis in a cooperative study at three hospitals in Edmonton, Toronto, and Winnipeg, Canada. Ampicillin-treated patients were matched with clindamycin-treated patients. Diarrhea occurred in 62 (18%) of 343 clindamycin-treated patients compared with 16 (5%) of 315 ampicillin-treated patients (P less than 0.001). Among the three hospitals, the rate of diarrhea associated with clindamycin therapy ranged from 10% to 23% compared with 0 to 10% for ampicillin therapy. The only identified risk factor in the development of diarrhea was increased age; clindamycin-associated diarrhea occurred in 18 (46%) of 39 patients greater than or equal to 60 years old. No correlation was observed between the risk of diarrhea and the duration of treatment, total dosage of drug, route of administration, or type of underlying disease. Pseudomembranous colitis was diagnosed in seven (2%) of 343 patients treated with clindamycin and in one (0.3%) of 315 patients treated with ampicillin.

Bacteremia due to Bacteroidacceae: a review of 92 cases.

The clinical courses of 92 patients who had bacteremia due to Bacteroidaceae were reviewed. The overall mortality rate was 21% (19 patients). There was no significant difference between mortality rates when patients were grouped by anticipated clinical course of underlying disease (nonfatal, ultimately fatal, and rapidly fatal) and when they were grouped by type of antibacterial therapy (appropriate, including clindamycin, chloramphenicol, lincomycin, and carbenicillin; or inappropriate, signifying no antibiotic treatment or treatment with antibiotics other than the four listed above). However, there was a correlation between recovery of the patient and portal of entry of the infectious agent; patients whose source of infection was the gastrointestinal tract had a mortality rate of 29% (17 of 58 patients), whereas there were no deaths among the 26 women whose presumed source of bacteremia was the genital tract. Increasing age appeared to be an important factor as well; 17 of 19 deaths occurred in patients who were older than 40 years. There was no significant difference between the mortality rate of patients who were treated with clindamycin (15%, eight of 52 patients) and that of patients who were treated with chloramphenicol (44%, four of nine).