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Methenamine hippurate for preventing urinary tract infections.

BACKGROUND: Methenamine salts are often used for the prevention of urinary tract infection (UTI). OBJECTIVES: To assess the effectiveness of methenamine hippurate in preventing UTI. SEARCH STRATEGY: Published and unpublished randomised controlled trials were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, Current Contents, reference lists of review articles and retrieved trials. The manufacturers' of methenamine salts were contacted for unpublished studies and contact was made with known investigators in the area. SELECTION CRITERIA: Randomised and quasi-randomised trials of methenamine hippurate used for the prevention of UTIs in all population groups were eligible for inclusion. A comparison with a control (no treatment) group was a prerequisite to selection. DATA COLLECTION AND ANALYSIS: Two reviewers (BL and TB) performed independent assessment and data extraction using a standardised format. Discrepancies, methodological and interpretative issues were discussed with JS or JC. An exploration of heterogeneity as well as a detailed description of results grouped by population was conducted. MAIN RESULTS: Eleven studies met the inclusion criteria. All trials were included in a descriptive analysis. Seven trials were included in meta-analyses. Four trials (199 patients) studied symptomatic bacteriuria and six trials (341 patients) studied bacteriuria as an outcome measure. Overall, trial quality was poor. The direction of six of the pooled trials was towards a favourable treatment effect from methenamine hippurate. Interpretation of the pooled estimates was not done in view of underlying heterogeneity. The study by Pettersson 1989 explained some, but not all, of the underlying heterogeneity. This study differed from all others by including patients with known upper renal tract abnormalities. Adverse reactions were mentioned by 10 studies. The rate of adverse events was low. REVIEWER'S CONCLUSIONS: There is not enough evidence to conclusively support the use of methenamine hippurate for urinary prophylaxis. An exploration of heterogeneity raises the (hypothesis generating) possibility that methenamine hippurate may have some efficacy in patients without but not in patients with known upper renal tract abnormality (with asymptomatic bacteriuria as the outcome measure). Due to the small sample size and methodological problems within the studies involved, interpretation of these data should be done cautiously. The rate of adverse events reported by the trials was low, which suggests that current usage is unlikely to be causing significant harm.

Anti-Infective Agents, Urinary↗

Antibiotics for acute pyelonephritis in children.

BACKGROUND: Urinary tract infection (UTI) is one of the most common bacterial infection in infants. The most severe form of UTI is acute pyelonephritis, which results in significant acute morbidity and may cause permanent renal damage. Published guidelines recommend treatment of acute pyelonephritis initially with intravenous (IV) therapy followed by oral therapy for 7-14 days though there is no consensus on the duration of either IV or oral therapy. OBJECTIVES: To determine the benefits and harms of different antibiotic regimens for the treatment of acute pyelonephritis in children. SEARCH STRATEGY: We searched the Cochrane Register of Controlled Trials (Cochrane Library Issue 3, 2002), MEDLINE (1966 - September 2002), EMBASE (1988 -September 2002), reference lists of articles and abstracts from conference proceedings without language restriction. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different antibiotic agents, routes, frequencies or durations of therapy in children aged 0-18 years with proven UTI and acute pyelonephritis were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes or weight mean difference (WMD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: Sixteen trials involving 1872 children were eligible for inclusion. No significant differences were found in persistent renal damage at six months (one trial, 306 infants: RR 1.45, 95% CI 0.69 to 3.03) or in duration of fever (WMD 0.80, 95% CI -4.41 to - 6.01) between oral cefixime therapy (14 days) and IV therapy (three days) followed by oral therapy (10 days). Similarly no significant differences in persistent renal damage (three trials, 315 children: RR 0.99, 95% CI 0.72 to 1.37) were found between IV therapy (3-4 days) followed by oral therapy and IV therapy for 7-14 days. In addition no significant differences in efficacy were found between daily and thrice daily administration of aminoglycosides (one trial, 179 children, persistent symptoms at three days: RR 1.98, 95% CI 0.37 to 10.53). REVIEWER'S CONCLUSIONS: These results suggest that children with acute pyelonephritis can be treated effectively with oral cefixime or with short courses (2-4 days) of IV therapy followed by oral therapy. If IV therapy is chosen, single daily dosing with aminoglycosides is safe and effective. Trials are required to determine the optimal total duration of therapy and if other oral antibiotics can be used in the initial treatment of acute pyelonephritis.

Adolescent↗

Antibiotics for acute pyelonephritis in children.

BACKGROUND: Urinary tract infection (UTI) is one of the most common bacterial infection in infants. The most severe form of UTI is acute pyelonephritis, which results in significant acute morbidity and may cause permanent renal damage. Published guidelines recommend treatment of acute pyelonephritis initially with intravenous (IV) therapy followed by oral therapy for seven to 14 days though there is no consensus on the duration of either IV or oral therapy. OBJECTIVES: To determine the benefits and harms of different antibiotic regimens for the treatment of acute pyelonephritis in children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference lists of articles and abstracts from conference proceedings without language restriction. Date of most recent search: June 2004. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different antibiotic agents, routes, frequencies or durations of therapy in children aged 0 to 18 years with proven UTI and acute pyelonephritis were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes or weight mean difference (WMD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: Eighteen trials (2612 children) were eligible for inclusion. No significant differences were found in persistent renal damage at six months (one trial, 306 infants: RR 1.45, 95% CI 0.69 to 3.03) or in duration of fever (WMD 0.80, 95% CI -4.41 to - 6.01) between oral cefixime therapy (14 days) and IV therapy (three days) followed by oral therapy (10 days). Similarly no significant differences in persistent renal damage (three trials, 315 children: RR 0.99, 95% CI 0.72 to 1.37) were found between IV therapy (3-4 days) followed by oral therapy and IV therapy for 7-14 days. In addition no significant differences in efficacy were found between daily and thrice daily administration of aminoglycosides (one trial, 179 children, persistent symptoms at three days: RR 1.98, 95% CI 0.37 to 10.53). AUTHORS' CONCLUSIONS: These results suggest that children with acute pyelonephritis can be treated effectively with oral cefixime or with short courses (2-4 days) of IV therapy followed by oral therapy. If IV therapy is chosen, single daily dosing with aminoglycosides is safe and effective. Trials are required to determine the optimal total duration of therapy and if other oral antibiotics can be used in the initial treatment of acute pyelonephritis.

Acute Disease↗

Precise and rapid assessment of Escherichia coli adherence to vaginal epithelial cells by flow cytometry.

BACKGROUND: In the pathogenesis of Escherichia coli urinary tract infections (UTIs) in women, infecting bacteria adhere to vaginal and periurethral epithelial cells prior to ascending to the bladder and causing infection. Complex interactions among specific bacterial adhesins and various host factors appear to influence adherence of E. coli to mucosal surfaces such as the urogenital epithelium. To conduct population-based studies assessing host epithelial cell determinants that influence bacterial attachment, a method of measuring bacterial adherence utilizing clinically derived epithelial cell samples is needed. METHODS: We developed and standardized an efficient, accurate, high-throughput method for analyzing the adherence of uropathogenic E. coli to clinical samples containing a large number of exfoliated vaginal epithelial cells (VEC). Three wild-type E. coli strains isolated from women with UTI (IA2 expressing pap-encoded, class II fimbriae only; F24 expressing pap-encoded, class II and type 1 fimbriae; and F20, without pap-encoded or type I fimbriae) were transformed with gfpmut3, encoding green fluorescent protein, incubated with VECs, and analyzed by flow cytometry. RESULTS: Enumeration of the binding of each E. coli strain to 10,000 VECs showed reproducible, highly significant strain-dependent differences in adherence to VECs. Differential analysis of the relative contributions of type 1 pili and P fimbrial-mediated binding to the adherence phenotype was performed. It demonstrated that IA2 binding was dependent entirely on P fimbriae, whereas F24 binding was dependent on both P and type 1 fimbriae. CONCLUSIONS: This method has great potential for use in high-throughput analyses of clinically derived epithelial cell samples and will be valuable in population-based investigations of host-parasite interactions in UTI utilizing VECs collected from specific patient groups.

Bacterial Adhesion↗

No-touch catheterization and infection rates in a select spinal cord injured population.

A clinical trial comparing two intermittent catheterization techniques used with spinal cord injured patients at Parkwood Hospital, a long-term care facility in London, ON, Canada, was conducted to evaluate the techniques' effect on urinary tract infections (UTIs). Charts were reviewed retrospectively for 92 patients with traumatic spinal cord injury who were on intermittent catheterization between January 1985 and December 1988. Nearly 80% of these patients had more than one UTI per admission. A convenience sample of 18 patients with traumatic spinal cord injury participated in a prospective study using a no-touch method of catheterization for 7 months. Preliminary findings at the completion of the study revealed that 44.4% of this experimental group had more than one UTI per admission--a 44.5% reduction. The no-touch method using the O'Neil Sterile Field urinary catheter was successful in reducing the total number of infections and duration of infection for the experimental group. A nurse satisfaction questionnaire revealed that nursing staff preferred this method of intermittent catheterization to the traditional method.

Adult↗

A study comparing sterile and nonsterile urethral catheterization in patients with spinal cord injury.

This study was designed to determine the effect of sterile and nonsterile intermittent catheterization on the incidence of urinary tract infection (UTI) in patients after spinal cord injury. The study included 29 patients with neurogenic bladder dysfunction treated with intermittent catheterization. One group of 14 patients was on sterile catheterization; another group of 15 patients was on nonsterile catheterization. On a weekly basis, urine samples were obtained and analyzed. A total of 122 urine samples were analyzed. The patients on sterile catheterization had a 28.6% UTI incidence; the group using a nonsterile catheterization technique had a UTI incidence of 42.4%. The most common urinary pathogen in both groups was E. coli (65%). The cost of antibiotics for patients on the sterile catheterization program was only 43% of the cost of antibiotics for those on the nonsterile program. However, the sterile kits cost 371% of the cost of the catheterization kits for the patients in the nonsterile program, so the total cost of managing neurogenic bladder on the sterile program was 277% of the cost of the nonsterile program.

Bacterial Infections↗

Variation in urological practice amongst spinal injuries units in the UK and Eire.

AIMS: To investigate variations in common urological practice between the Spinal Injuries Units (SIU) of UK and Eire. METHODS: In December 2002, each of the 12 SIU in the UK and Eire were sent a questionnaire addressing basic practice relating to urological outpatient follow-up, management of urinary tract infection, upper tract surveillance, and urodynamic studies. RESULTS: Regarding frequency of urological review, two units only saw patients when specifically required. One unit reviewed patients every 6 months and six centres reviewed patients annually. The remaining three units had a patient-specific follow-up protocol. Regarding urinary tract infection, only five units had a unified departmental management protocol. Four units advocated antibiotic prophylaxis for recurrent UTI. Only one unit would routinely treat asymptomatic UTI in individuals using catheters. The range of recommended duration of treatment for symptomatic UTI was 3-14 days (mean 6.3). All units performed routine upper tract screening, ranging from annually to every 3 years. Six units did not perform routine urodynamic studies; in other units the range of frequency of urodynamics was from annually to every 3 years. CONCLUSIONS: The variation in urological practice amongst SIU in the UK and Eire is considerable. This finding supports the need for an increase in the level of collaboration and research.

Follow-Up Studies↗

1H NMR spectroscopy in the diagnosis of Klebsiella pneumoniae-induced urinary tract infection.

The (1)H NMR spectroscopic method is suggested and its utility is demonstrated for the diagnosis of Klebsiella pneumoniae (K. pneumoniae) in urinary tract infection (UTI). K. pneumoniae have the specific property of metabolizing glycerol to 1,3-propanediol (1,3-PD), acetate, ethanol and succinate. The quantity of 1,3-PD produced correlates well with the viable bacterial count. Other common bacteria causing UTI (except for Citrobacter frundii), such as Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Enterobacter aerogenes, Acinetobacter baumanii, Proteus mirabilis, Enterococcus faecalis, Streptococcus gp B and Staphylococcus aureus do not metabolize glycerol under similar conditions. Citrobacter frundii (C. frundii) also gives the same NMR results but is easily differentiated as being motile on direct microscopic examination of urine and it is not common nosocomial infectious agent in urinary tract infection. The method provides a single-step documentation of K. pneumoniae (and C. frundii) qualitatively as well as quantitatively. Out of the total 614 subjects considered, clinical diagnosis of UTI was obtained in 516 cases (84%). The NMR-based screening had a sensitivity of 90%, a specificity of 100% and a false negativity of 10% relative to the conventional quantitative culture method. In the present authors' experience, the results of NMR spectroscopy based screening show a very good correlation with the diagnosis of urinary tract infected patients.

Bacteria↗

(1)H NMR spectroscopy in the diagnosis of Pseudomonas aeruginosa-induced urinary tract infection.

The utility of (1)H NMR spectroscopy is suggested and demonstrated for the diagnosis of Pseudomonas aeruginosa in urinary tract infection (UTI). The specific property of P. aeruginosa of metabolizing nicotinic acid to 6-hydroxynicotinic acid (6-OHNA) is exploited. The quantity of 6-OHNA produced correlates well with the viable bacterial count. Other common bacteria causing UTI such as Escherichia coli, Klebsiella pneumonia, Enterobacter aerogenes, Acinetobacter baumanii, Proteus mirabilis, Citrobacter frundii, Enterococcus faecalis, Streptococcus gp B and Staphylococcus aureus do not metabolize nicotinic acid under similar conditions. The method provides a single-step documentation of P. aeruginosa qualitatively as well as quantitatively. The NMR method is demonstrated on urine samples from 30 patients with UTI caused by P. aeruginosa.

Biomarkers↗

Physician speciality and adherence to guidelines for the treatment of unsubstantiated uncomplicated urinary tract infection among women.

PURPOSE: To evaluate the variance in rates of physician adherence to guidelines for the empiric treatment of uncomplicated urinary tract infection (UTI) in women recommending either trimethoprim-sulfamethoxazole (TMP-SMX) or nitrofurantoin, in all relevant physician subspecialities practising in a managed care community setting in Israel. METHODS: Data were derived from the computerised medical records of Maccabi Healthcare Services, a health maintenance organisation (HMO) in Israel providing care to more than 1.6 million members nation-wide. The study population included women aged 18-75 years without risk factors for complicated UTI who were treated empirically with antibiotics for a diagnosis of acute cystitis or UTI. The data set consisted of 64,236 initial physician-patient encounters from July 2000 to June 2002. Physician adherence to guidelines was calculated by comparing the proportion of cases treated with each individual drug. A binary regression model was used to evaluate factors associated with suboptimal adherence to the guidelines. RESULTS: Nitrofurantoin was the most frequently prescribed drug (18.51%), followed by TMP-SMX (17.04%) for a crude rate of adherence of 35.6%. Adherence was observed to be highest in cases treated by urologists (OR=2.8, 95%CI: 2.4, 3.3), followed by gynaecologists (OR=1.9, 95%CI: 1.7, 2.31), with family practice as the referent speciality. The medical school attended was also found to be significant. CONCLUSIONS: Physician speciality was found to be significantly associated with rate of adherence to guidelines, with higher rates being observed amongst specialities such as urologists who presumably have greater familiarity with the subject matter.

Adolescent↗

Significance of urinary endotoxin concentration in patients with urinary tract infection.

Endotoxin is a component of the outer membrane of gram-negative rods (GNR). Since GNR are responsible for the majority of urinary tract infection (UTI), we measured the concentration of endotoxin in urine using chromogenic endotoxin-specific assay and examined its diagnostic utility in patients with suspected UTI. In all 18 urine samples with an endotoxin concentration exceeding 350 pg/ml and 2 samples with 10-350 pg/ml of endotoxin concentration, GNR were detected at a count of 10(4) cfu/ml. Negative for endotoxin were 3 samples of culture positive for gram-positive cocci (GPC), 2 samples containing various bacterial contaminants and all 37 samples with no growth on culture. Two urine samples collected 5 h after antibiotic dosage showed negative culture for GNR but a significant concentration of endotoxin. In an in vitro experiment, a residual concentration of antibiotic in urine inhibited bacterial growth, leading to a false-negative culture. These results suggest that chromogenic endotoxin assay is a reliable method for diagnosing UTI caused by GNR and detecting false-negative culture of GNR.

Adult↗

Antiseptic catheter gel and urinary tract infection after short-term postoperative catheterization in women.

This paper compares the rates of postoperative urinary tract infection (UTI) when an antiseptic lubricating gel was used at catheter insertion in 132 women and not used in 387 women. 519 consecutive patients admitted for elective gynaecological surgery were studied prospectively. Antibiotics were not used. Mean catheterization time was 1.4 days (range 1-3). Postoperative UTI occurred in 17.4% and 18.3% of the patients, respectively (p = 0.95). Therefore, using antiseptic anaesthetic gel at catheter insertion does not appear to reduce the risk of UTI associated with short-term transurethral catheterization after gynecological surgery.

Adult↗

Amoxicillin promotes vaginal colonization with adhering Escherichia coli present in faeces.

This study is aimed at a better understanding of the pathogenesis of urinary tract infection (UTI) by examining factors influencing the bacterial ecology of the genital tract. It comprises two sets of experiments in a monkey model. In the first the persistence and transmission between individuals of a P-fimbriated Escherichia coli (strain DS17) in faeces was examined and in the second we studied the influence of amoxicillin on the occurrence of this strain in the vagina. Orally administered E. coli DS17 was shown to spread to cage mates and to persist in the gut for at least 17-18 months. One of four monkeys so colonized developed three separate UTIs with the DS17 strain. The second set of experiments comprised four other monkeys, who either harboured the E. coli DS17 strain in the faeces and/or in small amounts in the vagina, probably through contamination during defaecation. Amoxicillin induced a persistent vaginal E. coli DS17 colonization in nine of ten experiments. The study thus shows that uropathogenic E. coli may persist for long time in the faeces and that, in this situation, amoxicillin may promote an abnormal, vaginal E. coli colonization similar to that characteristic of females prone to recurrent UTI and often preceding manifest urinary infections.

Amoxicillin↗

Fluconazole for treatment of fungal infections of the urinary tract in children.

Two children with fungal urinary tract infections (UTI) were treated with fluconazole. One had bilateral megaureters, an almost non-functioning right kidney, and a moderately functioning left kidney because of severe vesicoureteric reflux. He underwent a ureteric reimplantation procedure but developed a fungal UTI postoperatively. The other child had bilateral refluxing megaureters, one of which appeared to open ectopically into the urethra. He acquired a fungal infection during intensive and prolonged antibiotic therapy for a bacterial UTI and septicaemia in the neonatal period. Both fungal infections were cured successfully. We recommend fluconazole as a safe and effective antifungal agent that may be used as a drug of choice for this difficult problem.

Antifungal Agents↗

[Comparative study of cefaclor versus amoxicillin in urinary tract infections (author's transl)].

In a comparative, prospective, open randomised clinical study, the efficacy and tolerance of cefaclor (3 x 500 mg) and amoxicillin (3 x 750 mg) in the treatment of urinary tract infection (UTI) were investigated and compared. A total of 110 patients (51 males and 59 females) age 10 to 83 years were treated for a period of five to 14 days (average 10 days). Fifty-nine of the patients had complicated, and 51 uncomplicated UTI. In all patients , organisms were cultured from the urine which were sensitive to both antibiotics in vitro. In each group there were three cases of mixed infection and 35 cases of Escherichia coli monoinfection. The distribution of pathogens in the other patients was likewise very similar. Better results, i.e. a reduction in the cell count to < 10(4)/ml immediately after completion of therapy, were obtained in patients treated with cefaclor. This is largely due to a statistically significantly higher rate of elimination in E. coli infections. The long-term results at follow-up examinations 14 to 60 days after completion of therapy in both groups with uncomplicated infections were, however, equally as good in about half the cases. In complicated infections therapy was successful overall in only about a quarter of the cases, better results being obtained in the amoxicillin group. It must be taken into account that among the patients treated, the groups with complicated UTI are difficult to compare, relapses primarily being determined by underlying disease. Both antibiotics were tolerated well.

Adolescent↗

In vitro activity, pharmacokinetics, clinical safety and therapeutic efficacy of enoxacin in the treatment of patients with complicated urinary tract infections.

Minimal inhibitory concentrations (MIC) of enoxacin, nalidixic acid, pipemidic acid, norfloxacin, ciprofloxacin, ofloxacin and pefloxacin against isolates from 400 urological in-patients with complicated urinary tract infections (UTI) were determined by means of an agar dilution technique (10(4) cfu, multipointer). 28 patients (21 male, seven female) aged 36 to 84 years with complicated UTI due to sensitive bacteria were treated orally with 200 mg enoxacin b.i.d. for six to 14 days. Plasma and urine samples were collected from 19 patients, at intervals prior to and following a 400 mg dose of enoxacin, and enoxacin concentrations were determined by a high pressure liquid chromatography (HPLC) method. The MICs of enoxacin against all but one of the gram-negative isolates cultured from 265 urological patients were between 0.03 and 4 mg/l. The MICs against 134 gram-positive isolates were between 0.25 and 16 mg/l except two strains of streptococci. At a concentration of 4 mg/l (8 mg/l), 90.3% (98%) of the total spectrum of isolates were inhibited by enoxacin. Of the quinolones tested, ciprofloxacin appeared to be the most active compound in vitro and cinoxacin the least active antimicrobial agent. The in vitro activity of enoxacin was comparable to that of norfloxacin, ofloxacin and pefloxacin. Oral administration of 400 mg enoxacin to elderly patients resulted in peak serum concentrations between 0.7 and 6.3 mg/l (mean 3.6 mg/l) attained between 1.0 and 6.0 h following drug ingestion. The mean urinary recovery of parent drug within 24 h was 31.2% of the administered dose. 25 of 28 patients treated orally with enoxacin could be followed-up for five to 14 days after the end of treatment. Enoxacin therapy in these patients resulted in 18 cures, one failure and six relapses (same species). The drug was well tolerated and there was no evidence of renal, hepatic or haematological toxicity. Enoxacin appears to be well suited for the treatment of complicated UTI.

Administration, Oral↗

Urinary tract infections in primary biliary cirrhosis and other chronic liver diseases.

In a study to determine the prevalence of urinary tract infections (UTI) in primary biliary cirrhosis, midstream specimens of urine from 97 females with primary biliary cirrhosis and 85 females with other chronic liver diseases were investigated prospectively for urinary pathogens and Mycobacterium gordonae. No significant differences between primary biliary cirrhosis and the two groups were observed in the prevalence of significant bacteriuria (11.3% vs. 7.1%), the prevalence of Escherichia coli UTI (9.3% vs. 7.1%) or the colony morphology of Escherichia coli. No mycobacterial species were grown from any sample. In both groups, the prevalence of UTI was higher in patients with cirrhosis (20% in both) than in those without.

Adult↗

Clinical significance and spread of fluoroquinolone resistant uropathogens in hospitalised urological patients.

The minimum inhibitory concentrations (MIC) of ciprofloxacin were determined for 441 uropathogens from patients with complicated and/or hospital acquired urinary tract infections (UTI). None of the Enterobacteriaceae was resistant (MIC > or = 4 mg/l), but 21.7% of enterococci, 28.3% of Pseudomonas spp. and 38.5% of staphylococci were. Subtyping of the strains revealed that with staphylococci there was no clonal spread of resistant strains. In the case of enterococci and Pseudomonas spp., however, cross infections played a major role (46% and 40% respectively). In a retrospective analysis of 370 UTI episodes caused by Pseudomonas aeruginosa (74), enterococci (185) or staphylococci (111) there was no difference between sensitive and resistant strains with respect to clinical aspects and rates of elimination by appropriate anti-bacterial therapy. The rates of spontaneous disappearance without antibacterial therapy ranged from 28% in the case of P. aeruginosa up to 63% in the case of coagulase-negative staphylococci. This implies that especially in UTI caused by gram-positive cocci an indication for antibacterial therapy should be weighted thoroughly and fluoroquinolones should only be used in accordance with sensitivity testing.

Anti-Infective Agents↗