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1.  Single-dose fosfomycin trometamol versus 5-day cephalexin regimen for treatment of uncomplicated lower urinary tract infections in women. 
Antimicrobial Agents and Chemotherapy  1994;38(11):2612-2614.
A randomized study was conducted to assess the clinical and microbiological efficacies of a single 3-g dose of fosfomycin trometamol for the treatment of uncomplicated lower urinary tract infections in women compared with a 5-day regimen of cephalexin at 0.5 g four times daily. One hundred twelve women, all of whom had documented infections with bacteria sensitive to both antibiotics, were included. Fifty-eight women received fosfomycin trometamol, and 54 women received cephalexin. The two groups did not differ in age, severity, or duration of current urinary tract infection, menstrual status, sexual activity, or use of contraceptives. Ninety percent of pathogens in the fosfomycin trometamol group and 81% in the cephalexin group were Escherichia coli (the difference is not significant [NS]). A clinical evaluation at the 5-day follow-up showed that 91% of the women in each group were free of symptoms, while five women in each group were considered therapy failures and were treated by another antibiotic course. A microbiological evaluation at the 5-day follow-up showed a 91% eradication rate in the fosfomycin trometamol group and an 83% eradication rate in the cephalexin group (NS). At the 1-month follow-up, a clinical evaluation demonstrated prolonged resolution in 86 and 78%, respectively, of the participating women (NS). A microbiological evaluation at 1 month demonstrated prolonged eradication in 47 (81%) women treated with fosfomycin trometamol and in 37 (68%) women treated with cephalexin (NS). Three and six women, respectively, had relapsed. No adverse reactions were reported by the fosfomycin trometamol-treated women, while three women treated with cephalexin reported mild adverse reactions but completed the study period. Fosfomycin trometamol in a single 3-g dose is as effective as a 5-day regimen of cephalexin for the treatment of uncomplicated lower urinary tract infection in women.
PMCID: PMC188250  PMID: 7872756
2.  Comparative double-blind study of cephalexin and co-trimoxazole in urinary tract infections. 
British Medical Journal  1976;1(6011):684-686.
Treatment with cephalexin 1 g twiec daily and cotrimoxazole 2 tablets twice daily was compared in a double-blind, randomised study of 100 women with urinary tract infections. CO-trimoxazole gave a significantly higher cure rate compared with cephalexin two and six weeks after the one-week course of treatment. The higher failure rate with cephalexin was not related to the age of the patient, presentation, pyelographic appearances, or type of organism in the initial infection. Among the failures all but one of the organisms were sensitive to cephalexin. With the dosage regimen and duration of treatment used in this study cotrimoxazole appears to be superior to cephalexin in the management of acute urinary infections.
PMCID: PMC1639094  PMID: 1252882
3.  Cephalexin: Absorption and Excretion as Related to Renal Function and Hemodialysis 
Infection and Immunity  1971;3(4):540-543.
Cephalexin is a new semisynthetic cephalosporin C derivative, which is well absorbed from the gastrointestinal tract and excreted in high concentration in the urine. Even in patients with impaired renal function, the concentrations of cephalexin present in the urine are adequate for the treatment of most urinary tract infections produced by Escherichia coli, Klebsiella, and Proteus mirabilis. In anephric patients, single doses of 250 or 500 mg of cephalexin resulted in high, prolonged serum concentrations. Peak levels were usually observed within 1 hr. However, in two of six anephric patients, peak levels were reached after 6 and 12 hr due to delayed absorption. Hemodialysis for 6 hr reduced the serum concentration of cephalexin by 58%.
PMCID: PMC416192  PMID: 16558013
4.  Approach to urinary tract infections 
Indian Journal of Nephrology  2009;19(4):129-139.
Urinary tract infection (UTI) is the most common infection experienced by humans after respiratory and gastro-intestinal infections, and also the most common cause of both community-acquired and nosocomial infections for patients admitted to hospitals. For better management and prognosis, it is mandatory to know the possible site of infection, whether the infection is uncomplicated or complicated, re-infection or relapse, or treatment failure and its pathogenesis and risk factors. Asymptomatic bacteriuria is common in certain age groups and has different connotations. It needs to be treated and completely cured in pregnant women and preschool children. Reflux nephropathy in children could result in chronic kidney disease; otherwise, urinary tract infections do not play a major role in the pathogenesis of end-stage renal disease. Symptomatic urinary tract infections occur most commonly in women of child-bearing age. Cystitis predominates, but needs to be distinguished from acute urethral syndrome that affects both sexes and has a different management plan than UTIs. The prostatitis symptoms are much more common than bacterial prostatic infections. The treatment needs to be prolonged in bacterial prostatitis and as cure rates are not very high and relapses are common, the classification of prostatitis needs to be understood. The consensus conference convened by National Institute of Health added two more groups of patients, namely, chronic prostatitis/chronic pelvic pain syndrome and asymptomatic inflammatory prostatitis, in addition to acute and chronic bacterial prostatitis. Although white blood cells in urine signify inflammation, they do not always signify UTI. Quantitative cultures of urine provide definitive evidence of UTI. Imaging studies should be done 3-6 weeks after cure of acute infection to identify abnormalities predisposing to infection or renal damage or which may affect management. Treatment of cystitis in women should be a three-day course and if symptoms are prolonged, then a seven day course of antibiotics should be given. Selected group of patients benefits from low-dose prophylactic therapy. Upper urinary tract infection may need in-patient treatment. Treatment of acute prostatitis is 30-day therapy of appropriate antibiotics and for chronic bacterial prostatitis a low dose therapy for 6-12 months may be required. It should be noted that no attempt should be made to eradicate infection unless foreign bodies such as stones and catheters are removed and correctable urological abnormalities are taken care of. Treatment under such circumstances can result only in the emergence of resistant organisms and complicate therapy further.
PMCID: PMC2875701  PMID: 20535247
Acute urethral syndrome; bacteriuria; imaging studies; low-dose prophylaxis; urinary tract infection; urine culture
5.  Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women. 
We compared the safety and efficacy of a single 400-mg dose of ofloxacin, ofloxacin (200 mg) once daily for 3 days, and trimethoprim-sulfamethoxazole (160:800 mg) twice daily for 7 days for the treatment of acute uncomplicated cystitis (urinary tract infection [UTI]) in women. At 5 weeks posttreatment, 35 (81%) of 43 patients treated with single-dose ofloxacin, 40 (89%) of 45 treated with 3 days of ofloxacin, and 41 (98%) of 42 treated with trimethoprim-sulfamethoxazole were cured (P = 0.03, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). Retreatment for symptomatic recurrent UTI was given to 7 (16%) of 43 patients initially treated with single-dose ofloxacin, 3 (7%) of 45 patients treated with 3 days of ofloxacin, and 0 of 42 patients treated with trimethoprim-sulfamethoxazole (P = 0.01, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). There was a trend in each of the three treatment groups toward an association between persistent or recurrent episodes of significant bacteriuria and a history of UTI in the past year and with diaphragm use. Ofloxacin was more effective than trimethoprim-sulfamethoxazole in eradicating Escherichia coli from rectal cultures during or soon after therapy, but there were no differences at later follow-up visits. Adverse effects were equally common among the three treatment groups. We conclude that single-dose ofloxacin was less effective than 7 days of trimethoprim-sulfamethoxazole for treatment of uncomplicated cystitis in women, while the 3-day ofloxacin regimen and the trimethoprim-sulfamethoxazole regimen were not significantly different in efficacy.
PMCID: PMC245194  PMID: 1929311
6.  Presence of Putative Repeat-in-Toxin Gene tosA in Escherichia coli Predicts Successful Colonization of the Urinary Tract 
mBio  2011;2(3):e00066-11.
Uropathogenic Escherichia coli (UPEC) strains, which cause the majority of uncomplicated urinary tract infections (UTIs), carry a unique assortment of virulence or fitness genes. However, no single defining set of virulence or fitness genes has been found in all strains of UPEC, making the differentiation between UPEC and fecal commensal strains of E. coli difficult without the use of animal models of infection or phylogenetic grouping. In the present study, we consider three broad categories of virulence factors simultaneously to better define a combination of virulence factors that predicts success in the urinary tract. A total of 314 strains of E. coli, representing isolates from fecal samples, asymptomatic bacteriuria, complicated UTIs, and uncomplicated bladder and kidney infections, were assessed by multiplex PCR for the presence of 15 virulence or fitness genes encoding adhesins, toxins, and iron acquisition systems. The results confirm previous reports of gene prevalence among isolates from different clinical settings and identify several new patterns of gene associations. One gene, tosA, a putative repeat-in-toxin (RTX) homolog, is present in 11% of fecal strains but 25% of urinary isolates. Whereas tosA-positive strains carry an unusually high number (11.2) of the 15 virulence or fitness genes, tosA-negative strains have an average of only 5.4 virulence or fitness genes. The presence of tosA was predictive of successful colonization of a murine model of infection, even among fecal isolates, and can be used as a marker of pathogenic strains of UPEC within a distinct subset of the B2 lineage.
Escherichia coli is the primary cause of urinary tract infections, the most common bacterial infection of humans. Virulence of a uropathogenic strain is typically defined by the clinical source of the isolate, the ability to colonize the bladder and kidneys in a murine model, the phylogenetic group of the bacterium, and virulence gene content. Here we describe a novel single gene, the repeat-in-toxin gene tosA, the presence of which predicts virulence of E. coli isolates regardless of source. Rapid identification of uropathogenic strains of E. coli may aid in the development of therapeutic and preventive therapies.
PMCID: PMC3088117  PMID: 21540363
7.  Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: The LUTIW project 
To analyse associations between symptoms and bacteriuria in uncomplicated lower urinary tract infection in women (LUTIW) and to evaluate outcome of therapy with three different regimens of pivmecillinam or placebo.
Prospective, multicentre, randomized, double-blind, and placebo-controlled therapy study. Symptoms registered at inclusion, during therapy and at follow-up visits after 8–10 and 35–49 days. Significant bacteriuria defined according to current European guidelines.
A total of 18 primary healthcare centres in northern Sweden.
Women aged 18 years and above with symptoms of urgency, dysuria, supra pubic or loin pain.
Main outcome measures
Symptoms and bacteriuria at inclusion and course of symptoms, bacteriuria, and their combinations during and post-therapy.
At inclusion, no associations or significant differences were found between symptom scores and bacteriuria, bacterial counts, or species. The 884 patients (77%) with significant bacteriuria were followed up. All pivmecillinam therapies were superior to placebo (p < 0.001). From day six until first follow-up, the mean values of all symptoms were higher and the bacteriological cure was lower at first follow-up in the three days (84%) compared with the seven days regimens (93–94%, p < 0.001). At final follow-up clinical cure was similar in all pivmecillinam regimens (65–72%) as was bacteriological cure (83–89%). Pivmecillinam had few low to mild adverse reactions, comparable to placebo.
Symptoms are not conclusive for diagnosis of LUTIW. Pivmecillinam therapies are superior to placebo and seven days regimens are more efficient than three days. Pivmecillinam 200 mg×2×7 days is recommended as a first-line therapy for LUTIW.
PMCID: PMC3389454  PMID: 17354160
Bacteriuria; family practice; pivmecillinam; placebo; symptoms; therapy study; urinary tract infection
8.  Double-Blind Comparison of Carbenicillin Indanyl Sodium, Ampicillin, and Cephalexin in Treatment of Urinary Tract Infection 
Carbenicillin indanyl sodium, ampicillin, or cephalexin was administered orally to 61 patients with urinary tract infections. Assignment of drug was made by a computer-generated, randomized plan in a double-blind fashion. The rates of cure 4 weeks after therapy were 50, 42, and 50% for patients treated with carbenicillin, ampicillin, and cephalexin, respectively. Failure of therapy was correlated with chronicity of infection and sensitivity of the microorganism to the antibiotic used. Thirty-nine percent of the patients developed side effects, but there were no significant differences in side effects among the three antibiotics. This double-blind study demonstrates that carbenicillin indanyl sodium is as effective as ampicillin and cephalexin in treatment of urinary tract infections.
PMCID: PMC444602  PMID: 4602827
9.  Randomized, double-blind comparison of single-dose regimens of rufloxacin and pefloxacin for acute uncomplicated cystitis in women. French Multicenter Urinary Tract Infection-Rufloxacin Group. 
In a double-blind, randomized, multicenter study, 463 adult women with symptomatic acute uncomplicated cystitis were treated orally with either a 400-mg single dose of rufloxacin (n = 226) or an 800-mg single dose of pefloxacin (n = 237). Escherichia coli (78%) and Proteus mirabilis (7%) were the most common isolates from 350 patients with significant pretreatment bacteriuria (uropathogens, > or = 10(5) CFU/ml). In the intention-to-treat analysis of patients with significant pretreatment bacteriuria, 343 patients were assessed for bacteriological outcome and 345 were assessed for clinical outcome. The bacteriological cure rate was 88% in the rufloxacin group and 84% in the pefloxacin group (95% confidence interval [CI] for difference in proportions, -4 to 12%), while the clinical resolution rate was 85 and 84%, respectively (95% CI, -8 to 9%). The per-protocol analysis demonstrated that among the 264 assessable patients, the bacteriological cure rate obtained with rufloxacin at 4 weeks of follow-up was comparable to that with pefloxacin (91 versus 85%; 95% CI, -3 to 15%). Among 295 clinically assessable patients, the clinical resolution rate at 4 weeks of follow-up was 89% in the rufloxacin group and 88% in the pefloxacin group (95% CI, -6 to 10%). Potentially drug-related adverse events occurred in 19% of the rufloxacin patients and in 18% of the pefloxacin patients. A single oral dose of 400 mg of rufloxacin is as effective and safe as a single oral dose of 800 mg of pefloxacin for the treatment of acute uncomplicated cystitis in women.
PMCID: PMC162511  PMID: 7695309
10.  A Comparative Study of the Triphenyltetrazolium Chloride (Uroscreen) Test and Conventional Methods for the Detection of Bacteriuria 
Canadian Medical Association Journal  1965;92(22):1161-1165.
Acute urinary tract infection may be preceded by and active pyelonephritis may be associated with asymptomatic bacteriuria. Treatment of asymptomatic bacteriuria may prevent or arrest active, chronic pyelonephritis and its sequelae. Consequently, there is a need for a reliable and simple screening procedure to detect asymptomatic bacteriuria in large segments of the population.
The reliability and practicability of tests advocated for the detection of bacteriuria, including the new chemical triphenyltetrazolium chloride (T.T.C.) (Uroscreen) test, were evaluated. Reliability was assessed by correlating results of these tests with bacterial counts of tested urines. Significant bacteriuria is defined as the presence of 100,000 or more organisms per ml. of urine.
The T.T.C. (Uroscreen) test was positive in 92.5% of cases of bacteriuria; there were 7.5% false-negative and 2.8% false-positive results. Bacteria on Gram-stained smear were found in 95.5% of the cases of bacteriuria and in 14.6% of those with non-infected urine; pyuria (more than three leukocytes per high-power field), in 60% of those with bacteriuria and in 15.9% of those with presumably non-infected urine. Bacteria were conspicuous in the urinary sediment in 91.1% of cases of bacteriuria and in 3.7% of presumably non-infected urines.
The T.T.C. (Uroscreen) test fulfilled the criteria for a reliable and simple screening procedure. It should be used concomitantly with other screening tests when the urine is examined routinely.
PMCID: PMC1928330  PMID: 14285304
11.  Contribution of Proteus mirabilis urease to persistence, urolithiasis, and acute pyelonephritis in a mouse model of ascending urinary tract infection. 
Infection and Immunity  1993;61(7):2748-2754.
Proteus mirabilis, a significant cause of bacteriuria and acute pyelonephritis in humans, produces urease. This high-molecular-weight, multimeric, cytoplasmic enzyme hydrolyzes urea to ammonia and carbon dioxide. To assess the role of urease in colonization, urolithiasis, and acute pyelonephritis in an animal model of ascending urinary tract infection, we compared a uropathogenic strain of P. mirabilis with its isogenic urease-negative mutant, containing an insertion mutation within ureC, the gene encoding the large subunit of the enzyme. Mice challenged transurethrally with the parent strain developed significant bacteriuria and urinary stones. The urease-negative mutant had a 50% infective dose of 2.7 x 10(9) CFU, a value more than 1,000-fold greater than that of the parent strain (2.2 x 10(6) CFU). The urease-positive parent strain reached significantly higher concentrations and persisted significantly longer in the bladder and kidney than did the mutant. Indeed, in the kidney, the parent strain increased in concentration while the mutant concentration fell so that, by 1 week, the parent strain concentration was 10(6) times that of the mutant. Similarly, the urease-positive parent produced significantly more severe renal pathology than the mutant. The initial abnormalities were in and around the pelvis and consisted of acute inflammation and epithelial necrosis. By 1 week, pyelitis was more severe, crystals were seen in the pelvis, and acute pyelonephritis, with acute interstitial inflammation, tubular epithelial cell necrosis, and in some cases abscesses, had developed. By 2 weeks, more animals had renal abscesses and radial bands of fibrosis. We conclude that the urease of P. mirabilis is a critical virulence determinant for colonization, urolithiasis, and severe acute pyelonephritis.
PMCID: PMC280917  PMID: 8514376
12.  Single-dose cefonicid therapy for urinary tract infections. 
The efficacy of single-dose therapy with cefonicid (1 g intramuscularly) and multidose therapy with amoxicillin (500 mg orally three times a day for 7 days) was compared for the treatment of uncomplicated lower urinary tract infection in women. Of 50 patients with symptoms of lower urinary tract infection randomized to receive either cefonicid or amoxicillin, 39 were infected with greater than or equal to 10(5) bacteria per ml. At early posttherapy follow-up (5 to 18 days), 19 of 21 (90%) cefonicid-treated patients and 16 of 18 (89%) amoxicillin-treated patients were cured. At late posttherapy follow-up (6 to 7 weeks), 16 of 18 (89%) cefonicid-treated patients and 14 of 15 (93%) amoxicillin-treated patients were cured. One patient was lost to follow-up in each late follow-up group. There were fewer side effects in the cefonicid-treated group. There were significantly more organisms resistant to amoxicillin than to cefonicid in the study population. Considering the small size of the series, single-dose therapy with cefonicid for lower urinary tract infection in women appears to be as safe and effective as conventional multidose therapy with amoxicillin.
PMCID: PMC184971  PMID: 6555015
13.  Urinary Tract Infections and Asymptomatic Bacteriuria in Renal Transplant Recipients 
Asymptomatic bacteriuria and urinary tract infection are common complications after kidney transplantation. In this population, if urinary tract infection occurred in the first six months post procedure, it carries a grave impact on both graft and patient survival. Renal transplant recipients with urinary tract infection are often clinically asymptomatic as a consequence of immunosuppression. Urinary tract infection, however, may progress to acute pyelonephritis, bacteremia and the full blown picture of urosepsis. PubMed and Cochrane databases were searched. The purpose of this review is to discuss the screening and treatment of urinary tract infection and asymptomatic bacteriuria in renal transplant recipients and to evaluate the guidelines on the basis of a review of published evidence.
PMCID: PMC3249996  PMID: 22224004
Asymptomatic bacteriuria; Graft survival; Renal transplantation; Screening; Urinary tract infection; Uropathogens
14.  Double-blind study comparing 3-day regimens of cefixime and ofloxacin in treatment of uncomplicated urinary tract infections in women. 
This double-blind randomized study compared 3-day regimens of cefixime (400 mg once daily) and ofloxacin (200 mg twice a day) in the treatment of urinary tract infections in women. The respective clinical cure rates for the two groups of women were 89 and 92% after 7 days and 81 and 84% after 4 weeks. The respective microbiological cure rates (free of bacteriuria) for the two groups of women were 83 and 86% after 7 days and 77 and 80% after 28 days. A 3-day cefixime regimen seems to be as efficient as a 3-day ofloxacin regimen in the treatment of uncomplicated cystitis in women.
PMCID: PMC188173  PMID: 8067759
15.  Three-day and ten-day chemotherapy for urinary tract infections in general practice. 
British Medical Journal  1976;1(6002):124-126.
The length of a course of antibiotic treatment for urinary tract infection varies with the habits of the prescriber. Many patients do not complete a course of treatment once their symptoms have subsided. In uncomplicated urinary tract infection among women seen in general practice a three-day course of amoxycillin was as effective as a 10-day course of the same drug in the same dose. Relief of symptoms was equal in both groups and bacteriuria was eliminated equally successfully in both regimens. There was no significant difference between the two groups in the incidence of side effects from the drugs. The financial saving which could accrue from adopting this therapeutic regimen would be significant.
PMCID: PMC1638616  PMID: 764915
16.  Efficacy and Safety of a Novel Once-Daily Extended-Release Ciprofloxacin Tablet Formulation for Treatment of Uncomplicated Urinary Tract Infection in Women 
Antimicrobial Agents and Chemotherapy  2005;49(10):4137-4143.
The efficacy and safety of a novel once-daily extended-release ciprofloxacin (ciprofloxacin ER) 500-mg dose were compared with those of an immediate-release ciprofloxacin (ciprofloxacin IR) 250-mg twice-daily dose, each administered orally for 3 days in the treatment of acute uncomplicated urinary tract infection (uUTI) in women. Adult female outpatients (mean age, 39 years) with clinical signs and symptoms of acute uUTI and a positive pretreatment urine culture (≥105 CFU/ml) were enrolled in a multicenter, randomized, double-blind, noninferiority trial. Patients were assessed at a test-of-cure visit (4 to 11 days posttreatment) and a late-posttreatment visit (4 to 6 weeks posttreatment) for microbiological and clinical outcomes and safety. The primary efficacy endpoint and microbiological eradication rate at the test-of-cure visit in the ciprofloxacin ER group (254/272; 93.4%) were noninferior to those in the ciprofloxacin IR group (225/251; 89.6%) (95% confidence interval [CI] of difference, −0.99%, 8.59%). Clinical-cure rates at the test-of-cure visit were 85.7% (233/272) for ciprofloxacin ER and 86.1% (216/251) for ciprofloxacin IR (95% CI of difference, −6.37%, 5.57%). At the late-posttreatment visit, microbiological and clinical outcomes were similar for the two treatments and consistent with test-of-cure results. Both treatments were well tolerated, but the frequencies of nausea and diarrhea were lower in the ciprofloxacin ER group than in the ciprofloxacin IR group (nausea, ER, 0.6%; IR, 2.2%; P = 0.033; diarrhea, ER, 0.2%; IR, 1.4%; P = 0.037). Once-daily ciprofloxacin ER was safe, effective, and noninferior to twice-daily ciprofloxacin IR in the treatment of acute uUTI. Additionally, ciprofloxacin ER was associated with significantly reduced frequencies of nausea and diarrhea.
PMCID: PMC1251530  PMID: 16189090
17.  Comparative study of amoxicillin-clavulanic acid and cephalexin in the treatment of bacteriuria during pregnancy. 
A comparative clinical trial of amoxicillin-clavulanic acid and cephalexin was carried out in 80 women with bacteriuria of pregnancy. Treatment was randomly allocated and consisted of either one tablet of amoxicillin plus clavulanic acid (250 and 125 mg, respectively) three times daily or cephalexin (250 mg) three times daily for 7 days. Overall bacteriological cure rates at 2 weeks were 77% in the amoxicillin-clavulanic acid group and 74% in the cephalexin group. At 6 weeks the respective rates were 76 and 60%. Twenty-five episodes of infection were with ampicillin-resistant strains; cure rates were 82% (2 weeks) and 80% (6 weeks) in the amoxicillin-clavulanic acid group and 85 and 64%, respectively, in the cephalexin group. Differences in cure rates were not statistically significant. No significant difference in the rate of side effects was found. In particular, no toxicity to the fetus was seen which could be ascribed to either drug. Amoxicillin-clavulanic acid would appear to be a safe and effective treatment for bacteriuria of pregnancy.
PMCID: PMC180085  PMID: 4004191
18.  Paradoxical activity of beta-lactam antibiotics against Proteus vulgaris in experimental infection in mice. 
In previous papers (Y. Ikeda and T. Nishino, Antimicrob. Agents Chemother. 32:1073-1077, 1988; Y. Ikeda, T. Nishino, and T. Tanino, Antimicrob. Agents Chemother. 31:865-869, 1987), we reported that many of the 7-aminothiazolyl cephalosporins, such as cefmenoxime, showed paradoxically reduced activity against Proteus vulgaris at higher concentrations, whereas these paradoxical effects were not observed for other types of cephalosporins, such as cefbuperazone and cefoperazone. In this study, we compare the therapeutic effect of cefmenoxime with that of cefbuperazone and explore the in vivo paradoxical effect of cefmenoxime by using an experimental infection model in mice. In an intraperitoneal infection with P. vulgaris 11, the survival rate with cefmenoxime was increased to 43% at 3.13 mg/kg but was lower at higher doses. On the other hand, cefbuperazone did not show such a paradoxical therapeutic effect. In mice infected with P. vulgaris 11, cefmenoxime levels in both serum and peritoneal washings were rapidly reduced and beta-lactamase activities in the peritoneal cavity were increased at higher cefmenoxime doses. These findings suggested that high levels of cefmenoxime at the infection site induced increased production of beta-lactamase, which then rapidly inactivated the antibiotic. We conclude that the paradoxical therapeutic effect of cefmenoxime against P. vulgaris occurs by the same mechanisms as the in vitro effect and that the high beta-lactamase inducibility and low beta-lactamase stability may account for the paradoxical therapeutic effect of cefmenoxime against P. vulgaris.
PMCID: PMC171526  PMID: 2183712
19.  Efficacy of single-dose therapy of urinary tract infection in infants and children: a review. 
The role of single-dose therapy was evaluated by pooling data on 320 infants and children included in 12 clinical trials that differed from each other in many variables. Single-dose therapy achieved an overall cure rate of 89%, but varied with different antimicrobial agents. Intramuscular aminoglycosides were the best (cure rate: 96%) closely followed by trimethoprim-sulfamethoxazole or a sulfa drug with a cure rate of 90%. The cure rate with amoxicillin (75%) was significantly less. Single-dose therapy was most effective (cure rate: 90%) in well-documented lower urinary tract infections (UTIs) and slightly less effective (cure rate: 89%) among those in whom upper UTI could not be excluded. In patients with a normal urinary tract, single-dose therapy was significantly more effective (cure rate: 93%) than in the group of 36 patients with a urinary tract malformation (cure rate: 69%). Single-dose therapy can be used with confidence in patients with lower UTIs and in those with normal urinary tracts. In patients with abnormal urinary tracts and lower UTIs, single-dose therapy may be used with caution, preferably using aminoglycosides. Further studies are required to establish a definitive role of single-dose therapy in patients with urinary tract malformation.
PMCID: PMC2607573  PMID: 7966433
20.  Complete Genome Sequence of Uropathogenic Proteus mirabilis, a Master of both Adherence and Motility▿ †  
Journal of Bacteriology  2008;190(11):4027-4037.
The gram-negative enteric bacterium Proteus mirabilis is a frequent cause of urinary tract infections in individuals with long-term indwelling catheters or with complicated urinary tracts (e.g., due to spinal cord injury or anatomic abnormality). P. mirabilis bacteriuria may lead to acute pyelonephritis, fever, and bacteremia. Most notoriously, this pathogen uses urease to catalyze the formation of kidney and bladder stones or to encrust or obstruct indwelling urinary catheters. Here we report the complete genome sequence of P. mirabilis HI4320, a representative strain cultured in our laboratory from the urine of a nursing home patient with a long-term (≥30 days) indwelling urinary catheter. The genome is 4.063 Mb long and has a G+C content of 38.88%. There is a single plasmid consisting of 36,289 nucleotides. Annotation of the genome identified 3,685 coding sequences and seven rRNA loci. Analysis of the sequence confirmed the presence of previously identified virulence determinants, as well as a contiguous 54-kb flagellar regulon and 17 types of fimbriae. Genes encoding a potential type III secretion system were identified on a low-G+C-content genomic island containing 24 intact genes that appear to encode all components necessary to assemble a type III secretion system needle complex. In addition, the P. mirabilis HI4320 genome possesses four tandem copies of the zapE metalloprotease gene, genes encoding six putative autotransporters, an extension of the atf fimbrial operon to six genes, including an mrpJ homolog, and genes encoding at least five iron uptake mechanisms, two potential type IV secretion systems, and 16 two-component regulators.
PMCID: PMC2395036  PMID: 18375554
21.  Epidemiology of urinary tract diseases in general practice 
British Medical Journal  1969;4(5680):390-394.
During a one-year morbidity survey of urinary tract diseases in general practice 741 cases were diagnosed. Only about half of all the patients with symptoms of urinary tract infection had significant bacteriuria. In young women urinary tract infections and symptoms from the urinary tract without bacteriuria—in particular urethritis—were found to predominate. In middle-aged women, the urinary tract symptoms were ascribed increasingly to genital prolapse, while incidence of urolithiasis was the highest in any group, and urinary tract infections became less frequent. The prevalence of urinary tract infection showed another increase in elderly women, and recurrent/chronic pyelonephritis, which occurs with a steadily increasing prevalence throughout all age groups, became common.
In younger male urological patients diseases with symptoms of urinary tract infection without bacteriuria were predominant, whereas prostatitis and urinary tract infections were less frequent. In middle-aged men, urolithiasis was especially frequent, while an increasing proportion of elderly men had prostatic hypertrophy, urinary tract infections, and recurrent/chronic pyelonephritis.
PMCID: PMC1629787  PMID: 4187693
22.  Subcellular distribution of daptomycin given alone or with tobramycin in renal proximal tubular cells. 
Previous studies in experimental animals showed that daptomycin, a lipopeptide antibiotic, protects against aminoglycoside nephrotoxicity (C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. N. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989; D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew, and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990). In order to better understand the mechanism involved in this protective effect, the subcellular distribution of daptomycin was investigated in the proximal tubular cells of animals treated with daptomycin alone or in combination with tobramycin. A first group of female Sprague-Dawley rats received a single intravenous injection of daptomycin at a dose of 100 mg/kg of body weight and were killed at 10 min, 1 h, or 24 h after the injection. Other groups of rats were treated during 10 days with saline (NaCl, 0.9%), tobramycin at dosages of 20 mg/kg/12 h, daptomycin at dosages of 10 mg/kg/12 h, or the combination tobramycin-daptomycin at the same dosages. At the time of sacrifice, the renal cortex of the right kidney of each animal was dissected, and small blocks of tissue were fixed, dehydrated, and embedded in Araldite 502 epoxy resin. The subcellular distribution of daptomycin and tobramycin was determined on ultrathin sections by immunogold labeling. Ten minutes after the injection of daptomycin alone, gold particles were seen over the brush border membrane and on the membranes of the endocytic vacuoles of proximal tubular cells. One hour after the injection, a similar distribution was seen and numerous gold particles were found over the lysosomes of proximal tubular cells. The results suggest that daptomycin might protect against aminoglycoside nephrotoxicity by interfering with the interaction between the aminoglycoside and phospholipids inside the lysosomes of proximal tubular cells.
PMCID: PMC284424  PMID: 8192441
23.  Pharmacodynamics of Daptomycin in a Murine Thigh Model of Staphylococcus aureus Infection 
Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29–40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 μg/ml. In mouse serum, the MICs were 1.0 μg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid Emax (maximum effect) curve (r = 0.974; P ≪ 0.001). The density of S. aureus in untreated controls was 8.26 log10 CFU/g, and the Emax was 3.97 log10 CFU/g. The 50% effective dose (ED50) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED30, ED60, and ED80 doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.
PMCID: PMC90383  PMID: 11181370
24.  Urinary tract infections treated with single dose of short-acting sulphonamide. 
British Medical Journal  1979;1(6172):1175-1176.
In a prospective study 29 patients with urinary tract infections caused by sulphonamide-sensitive organisms were treated with a single oral dose of the short-acting sulphonamide sulphafurazole. Twenty-seven (93%) of the 29 patients--and possibly all 29--were cured of their infections. There was no difference in the recurrence rates after single-dose treatment and treatment for 10 days or more. Six out of eight strains of Escherichia coli causing early recurrences were sensitive to sulphonamides. These results suggest that uncomplicated infections may safely and successfully be treated by a single oral dose of a short-acting sulphonamide.
PMCID: PMC1599338  PMID: 444997
25.  Urinalysis and Urinary Tract Infection: Update for Clinicians 
Dysuria is a common presenting complaint of women and urinalysis is a valuable tool in the initial evaluation of this presentation. Clinicians need to be aware that pyuria is the best determinate of bacteriuria requiring therapy and that values significant for infection differ depending on the method of analysis. A hemocytometer yields a value of ≥ 10 WBC/ mm3 significant for bacteriuria, while manual microscopy studies show ≥ 8 WBC/high-power field reliably predicts a positive urine culture. In cases of uncomplicated symptomatic urinary tract infection, a positive value for nitrites and leukocyte esterase by urine dipstick can be treated without the need for a urine culture. Automated urinalysis used widely in large volume laboratories provides more sensitive detection of leukocytes and bacteria in the urine.With automated microscopy, a value of > 2 WBC/hpf is significant pyuria indicative of inflammation of the urinary tract. In complicated cases such as pregnancy, recurrent infection or renal involvement, further evaluation is necessary including manual microscopy and urine culture with sensitivities.
PMCID: PMC1784655  PMID: 11916184

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