Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children.

BACKGROUND: Acute invasive diarrhea is a potentially serious condition in children. Because of the increasing resistance of enteric pathogens to commonly used oral antibiotics, intramuscular ceftriaxone has become the routine drug in the treatment of acute invasive diarrhea requiring an emergency visit in southern Israel. The inconvenience of this parenteral regimen created an increased need for oral pediatric formulations for the treatment of invasive diarrhea. OBJECTIVES: To evaluate the efficacy and safety of a suspension formulation of ciprofloxacin in the treatment of acute invasive diarrhea in infants and children. PATIENTS AND METHODS: From July 1996 through December 1997, 201 evaluable children ages 6 months to 10 years (35% <1 year; 70% <3 years) presenting with acute invasive diarrhea at the Pediatric Emergency Room were randomized to receive either ciprofloxacin suspension (10 mg/kg twice a day + im placebo; n = 95) or im ceftriaxone (50 mg/kg/day + placebo suspension; n = 106) for 3 days in a double blind manner. Stool cultures for Shigella, Salmonella, Campylobacter spp. and diarrheagenic Escherichia coli were obtained on Days 1, 3, 4 to 5 and 21 +/- 5. Clinical response and safety were assessed on Days 1, 2, 3, 4 to 5 and 21 +/- 5. RESULTS: We isolated 127 pathogens from 121 (60%) patients: 73 (57%) Shigella; 23 (18%) Salmonella; 18 (14%) E. coli; and 13 (10%) Campylobacter. Overall bacteriologic eradication on Day 4 to 5 was 99% for Shigella, 77% for Salmonella and 77% for Campylobacter, with no difference between the 2 groups. Clinical cure or improvement was observed in 100 and 99% of the ciprofloxacin and ceftriaxone groups, respectively. Serum ciprofloxacin values determined on Day 3 of the treatment were higher in the majority of patients than were the MIC50 and MIC90 values for the Shigella and Salmonella spp. isolated. Possible drug-related adverse events occurred in 13 patients [ciprofloxacin, 8 (8%); ceftriaxone, 5 (4.7%)] and were mild and transient. Joint examination was normal during and after completion of therapy in all patients. CONCLUSION: Oral ciprofloxacin was as safe and effective as intramuscular ceftriaxone for the empiric treatment of acute invasive diarrhea in ambulatory pediatric patients requiring an emergency room visit.

Safety of long-term therapy with ciprofloxacin: data analysis of controlled clinical trials and review.

We reviewed the literature and the manufacturer's U.S. clinical data pool for safety data on long-term administration of ciprofloxacin (Bayer, West Haven, CT). Only controlled clinical trials including patients treated for >30 days were selected. We identified 636 patients by literature search and 413 patients in the Bayer U.S. database who fulfilled our search criteria; the average treatment duration for these patients was 130 and 80 days, respectively. Main indications for long-term therapy were osteomyelitis, skin and soft-tissue infection, prophylaxis for urinary tract infection, mycobacterial infections, and inflammatory bowel disease. Adverse events, premature discontinuation of therapy, and deaths occurred at a similar frequency in both treatment arms. Most adverse events occurred early during therapy with little increase in frequency over time. As with short-term therapy, gastrointestinal events were more frequent than central nervous system or skin reactions, but pseudomembranous colitis was not observed. No previously unknown adverse events were noted. We conclude that ciprofloxacin is tolerated as well as other antibiotics when extended courses of therapy are required.

Results of a randomized trial comparing sequential intravenous/oral treatment with ciprofloxacin plus metronidazole to imipenem/cilastatin for intra-abdominal infections. The Intra-Abdominal Infection Study Group.

OBJECTIVE: In a randomized, double-blind, multicenter trial, ciprofloxacin/metronidazole was compared with imipenem/cilastatin for treatment of complicated intra-abdominal infections. A secondary objective was to demonstrate the ability to switch responding patients from intravenous (IV) to oral (PO) therapy. SUMMARY BACKGROUND DATA: Intra-abdominal infections result in substantial morbidity, mortality, and cost. Antimicrobial therapy often includes a 7- to 10-day intravenous course. The use of oral antimicrobials is a recent advance due to the availability of agents with good tissue pharmacokinetics and potent aerobic gram-negative activity. METHODS: Patients were randomized to either ciprofloxacin plus metronidazole intravenously (CIP/MTZ IV) or imipenem intravenously (IMI IV) throughout their treatment course, or ciprofloxacin plus metronidazole intravenously and treatment with oral ciprofloxacin plus metronidazole when oral feeding was resumed (CIP/MTZ IV/PO). RESULTS: Among 671 patients who constituted the intent-to-treat population, overall success rates were as follows: 82% for the group treated with CIP/MTZ IV; 84% for the CIP/MTZ IV/PO group; and 82% for the IMI IV group. For 330 valid patients, treatment success occurred in 84% of patients treated with CIP/MTZ IV, 86% of those treated with CIP/MTZ IV/PO, and 81% of the patients treated with IMI IV. Analysis of microbiology in the 30 patients undergoing intervention after treatment failure suggested that persistence of gram-negative organisms was more common in the IMI IV-treated patients who subsequently failed. Of 46 CIP/MTZ IV/PO patients (active oral arm), treatment success occurred in 96%, compared with 89% for those treated with CIP/MTZ IV and 89% for those receiving IMI IV. Patients who received intravenous/oral therapy were treated, overall, for an average of 8.6 +/- 3.6 days, with an average of 4.0 +/- 3.0 days of oral treatment. CONCLUSIONS: These results demonstrate statistical equivalence between CIP/MTZ IV and IMI IV in both the intent-to-treat and valid populations. Conversion to oral therapy with CIP/MTZ appears as effective as continued intravenous therapy in patients able to tolerate oral feedings.

Definition of the role of enterococcus in intraabdominal infection: analysis of a prospective randomized trial.

BACKGROUND: The role of enterococcus in intraabdominal infection is controversial. This study examines the contribution of enterococcus to adverse outcome in a large intraabdominal infection trial. METHODS: A randomized prospective double-blind trial was performed to compare two different antimicrobial regimens in combination with surgical or percutaneous drainage in the treatment of complicated intraabdominal infections. A total of 330 valid patients was enrolled from 22 centers in North America. RESULTS: In 330 valid patients, 71 had enterococcus isolated from the initial drainage of an intraabdominal focus of infection. This finding was associated with a significantly higher treatment failure rate than that of patients without enterococcus (28% versus 14%, p < 0.01). In addition, only Acute Physiology and Chronic Health Evaluation II score and presence of enterococcus were significant independent predictors of treatment failure when stepwise logistic regression was performed (p < 0.01 and < 0.03). Risk factors for the presence of enterococcus include age, Acute Physiology and Chronic Health Evaluation II, preinfection hospital length of stay, postoperative infections, and anatomic source of infection. There was no difference between the clinical trial treatment regimens with regard to overall failure, failure associated with enterococcus, or frequency of enterococcal isolation. CONCLUSIONS: This study is the first to report enterococcus as a predictor of treatment failure in complicated intraabdominal infections. This trial also identifies several significant risk factors for the presence of enterococcus in such infections.

Combined nitrofurantoin toxicity to liver and lung.

Nitrofurantoin is an antibiotic commonly used for prophylaxis and treatment of urinary tract infections. Pulmonary and hepatic toxicity are rare side effects of this agent. The simultaneous occurrence of pulmonary fibrosis and chronic active hepatitis in a patient undergoing long-term nitrofurantoin therapy is reported. The presence of pulmonary toxicity was evidenced by infiltrates on chest radiographs and impaired diffusion capacity during pulmonary function tests. Prolonged elevation of liver enzyme concentrations together with the presence of increased antibody titers (anti-smooth muscle antibody, antinuclear antibody) was suggestive of chronic hepatitis, a diagnosis corroborated by liver biopsy findings. After discontinuation of nitrofurantoin therapy, the patient had a full recovery. The infiltrates initially found on chest radiographs disappeared, and laboratory parameters normalized without the need for corticosteroid therapy.

Quantitation of urinary Tamm-Horsfall protein in children with urinary tract infection.

It has been suggested that urinary Tamm-Horsfall protein (THP) prevents colonization of the urinary tract by binding uropathogens. We tested the hypothesis that low urinary THP levels may predispose to urinary tract infection (UTI) by measuring THP levels in children. We studied a cohort of 35 girls with uncomplicated recurrent UTI (group 1) that was compared with 27 patients with myelomeningoceles undergoing clean intermittent catheterization (group 2) and 16 female controls (group 3). We measured urinary THP in both aggregated (aTHP) and disaggregated form (dTHP), leukocyte esterase activity, urine chemistries and culture. No significant differences in dTHP or aTHP levels were seen between groups 1 and 3, but group-1 patients had higher dTHP levels than group-2 patients (p < 0.008). History of reflux or the presence of bacteriuria or pyuria at the time of urine collection did not affect dTHP levels; in contrast, pyuria or bacteriuria at the time of sampling was associated with markedly lower aTHP levels when compared with sterile samples (p < 0.0001). For all groups, measured quantities of dTHP did not correlate with aTHP levels. We conclude that excretion of dTHP in children with history of recurrent UTI is not reduced. In contrast, concentrations of aTHP are profoundly depressed in children during times of UTI, suggesting a role for THP in the pathogenesis of UTI. Assaying THP in its aggregated form may prove valuable when studying its physiologic function and merits further investigation.

Urinary excretion of Tamm-Horsfall protein in elderly women.

The incidence of urinary tract infection is higher in the geriatric population than in younger adults despite the exclusion of patients with known risk factors. Tamm-Horsfall protein, a renal glycoprotein excreted in urine, may constitute a natural defense mechanism against ascending urinary tract infection by binding mannose-sensitive fimbriated microorganisms. We hypothesized that the quantity of Tamm-Horsfall protein excreted is decreased in the elderly. Native aggregated Tamm-Horsfall protein was measured in urine samples from 24 young women (group 1, mean age 33 years) and 47 female nursing home patients (group 2, mean age 84 years) using enzyme-linked immunosorbent assay techniques. Another 16 elderly women (group 3, mean age 85 years) had active urinary tract infection. The aggregated Tamm-Horsfall protein was then disaggregated by dilution and quantified. Significant differences in mean urinary disaggregated Tamm-Horsfall protein concentrations were found between groups 1 (64.22 mg./l.) and 2 (35.07 mg./l.), and between groups 1 and 3 (34.71 mg./l.), respectively. In contrast, mean aggregated Tamm-Horsfall protein levels were significantly higher in group 2 (1.56 mg./l.) than in group 1 (0.92 mg./l.) or group 3 (0.97 mg./l.). Our studies show that urinary disaggregated Tamm-Horsfall protein concentration is decreased in the elderly, and that aggregated Tamm-Horsfall protein is increased compared to younger adults. The aggregated Tamm-Horsfall protein concentration is decreased in the elderly during episodes of urinary tract infection.

Effect of Tamm-Horsfall protein on chemoluminescence response of polymorphonuclear leukocytes to uropathogenic Escherichia coli.

Mannose residues on the outer membranes of polymorphonuclear leukocytes (PMNL) are capable of binding mannose-sensitive Escherichia coli. Tamm-Horsfall protein, a major urinary glycoprotein, has also been shown to bind mannose-sensitive E. coli via mannose-containing side chains. The effect of Tamm-Horsfall protein on the interaction between PMNL and mannose-sensitive E. coli was studied by measuring luminol-dependent chemoluminescence after bacterial stimulation. In the presence of 0.475, 4.75, 47.5, and 475 mg/l Tamm-Horsfall protein, chemoluminescence responses were reduced in a dose-dependent fashion by 8.7%, 38.1%, 60.3%, and 96.1%, respectively. Addition of 0.003 units/ml alpha-mannosidase reversed the effect of increasing concentrations significantly. Thus, urinary Tamm-Horsfall protein seems to compete with PMNL for mannose-sensitive E. coli in a mannose-sensitive fashion, thereby significantly reducing the role of PMNL as a defense mechanism in the urine of patients with urinary tract infection.

Quantitation of Tamm-Horsfall protein binding to uropathogenic Escherichia coli and lectins.

In quantitative experiments using ELISA, binding of Tamm-Horsfall protein (THP) to uropathogenic Escherichia coli was studied with monoclonal antibody to THP. Adherence to E. coli bearing type 1 fimbriae was proportional to THP concentration and size of the bacterial inoculum. Type 1 fimbriae-bearing E. coli bound 50 times more THP than did non-type 1-fimbriated or P-fimbriated strains. Concanavalin A and wheat germ agglutinin bound THP in a dose-dependent fashion, whereas pokeweed mitogen and Vicia villosa B4 isolectin did not. Addition of mannose and N-acetylglucosamine reduced adherence of THP to concanavalin A and wheat germ agglutinin by 50%-80%. Sugar inhibition studies suggested that the fimbrial receptor site for THP has lectin-like properties and that THP binds to fimbriae via its mannose side chains. This quantitative assay is useful for studying the interaction between THP, uroepithelial cells, and bacteria in vitro.

Urinary excretion of Tamm-Horsfall protein in women with recurrent urinary tract infections.

Since MS-fimbriated bacteria adhere to Tamm-Horsfall protein, it has been suggested that Tamm-Horsfall protein may trap urinary pathogens and prevent them from colonizing the mucosal surfaces of the urinary tract. To test the hypothesis that low urinary Tamm-Horsfall protein excretion rates predispose to urinary tract infection we obtained serial urine samples from 17 women with and 18 without a history of recurrent urinary tract infection. None of the women had known structural abnormalities of the urinary tract. Concentrations of Tamm-Horsfall protein in urine were measured with a sensitive enzyme-linked immunosorbent assay method. On the average, 3 urine samples per person collected within 3 to 6 months were analyzed. The mean Tamm-Horsfall protein excretion of women with recurrent urinary tract infection was 57.0 mg./l. and that of controls was 66.3 mg./l.; this difference was not statistically significant. The mean coefficient of variation was 44.2 and 62.1%, respectively. We conclude that urinary Tamm-Horsfall protein concentration is not significantly decreased in women with recurrent urinary tract infection compared with controls, and that excretion varies widely in repeat samples obtained from the same individual.

A new ELISA method for the rapid quantification of Tamm-Horsfall protein in urine.

The authors present a simplified enzyme-linked immunosorbent assay (ELISA) technique for the quantitative measurement of urinary Tamm-Horsfall protein (THP). Microtiter plates are coated with THP and urine samples at various dilutions without the need for a capture antibody. The bound glycoprotein is then incubated with a monoclonal anti-THP antibody and an alkaline phosphatase conjugated anti-IgG antibody. The assay was validated and gave reproducible results over a wide range of absorbance values. The sensitivity of the assay for THP was 2-5 micrograms/L, the coefficient of variation between assays 7.5%, and the day-to-day variability 11.1% for THP concentrations between 6.25 and 200 micrograms/L. THP excretion was assayed in five volunteers over five days comparing THP concentration in spot urines and in 24-hour urine collections.

Liver abscess caused by Streptococcus milleri.

There is now convincing evidence that Streptococcus milleri is an important cause of pyogenic liver abscesses. The clinical course is no different from that of pyogenic infections of the liver arising from other causes. A positive blood culture should alert the clinician to the possibility of hepatic suppuration. Treatment consists of drainage by laparotomy or percutaneous aspiration combined with approximately 6 weeks of penicillin administration. Patients with liver abscesses who receive metronidazole may not respond if S. milleri is the infecting organism.

Prosthetic valve endocarditis caused by Trichosporon beigelii.

A case of Trichosporon beigelii prosthetic valve endocarditis is described. Prosthetic valve endocarditis developed in the patient, a 58-year-old woman with a history of rheumatic heart disease, 10 months after mitral valve surgery. A large left atrial fungus ball was present. Cultures of blood and valvular tissue were positive for T. beigelii. The organism was sensitive to amphotericin B, 5-fluorocytosine, ketoconazole, and miconazole.

Specificity and mechanism of in vitro adherence of Candida albicans.

Adherence of 14C-glucose labeled Candida albicans to vaginal epithelial cells was measured in the presence of 10 potential inhibitory sugars at concentrations of 5 to 150 mg per ml for 90 minutes at 37 degrees C. In competitive inhibition experiments, no inhibition of adherence was seen with any sugar at any concentration. On the contrary, with the exception of the aminosugars glucosamine, galactosamine, and mannosamine, increased attachment of Candida to vaginal epithelial cells was found in the presence of dextrose, galactose, mannose, alpha-methyl-mannoside, N-acetyl-glucosamine, N-acetyl-galactosamine, and N-acetyl-mannosamine. Increased adherence was not associated with recognizable changes in the electron microscopic appearance of Candida cell surface or alterations in fungal cell hydrophobicity as measured by interaction chromatography. Measurement of nonreceptor-specific adherence of Candida to glass beads revealed similar increased attachment in the presence of the test sugars, suggesting that adherence of Candida may not require specific yeast adhesin-cell receptor interaction.

A new method of measuring skin humidity.

A device suitable for the long-time measurement of relative skin humidity is described. This is a simple circuit with a resistance bridge for lithium chloride sensors connected to a digitally steered logic circuit, which causes dried air to stream intermittently through a measuring chamber placed on the skin in such a way that the relative humidity over the skin is maintained at a constant level. The number of switching time periods is proportional to the relative humidity (secretion performance) of the skin and can be counted, recorded, or directly fed into a digital calculator. The apparatus, including a two-channel version with skin temperature recording, has proved useful in sleep investigations under extreme climatic conditions.