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PubMed2000

Primary and acquired renal scarring in boys and girls with urinary tract infection.

OBJECTIVES: To determine when pyelonephritic renal scarring was detected in children with urinary tract infection (UTI) and characterize those with primary and acquired scarring, respectively. STUDY DESIGN: A population-based cohort of 1221 children (989 girls and 232 boys) with first recognized symptomatic UTI, aged 0 to 15 years, were diagnosed and followed up prospectively at a single children's hospital; 652 had febrile UTI. Seven hundred fifty-three were evaluated by urography. Renal scarring was classified as primary or acquired, the latter without signs of scarring at the first investigation. To evaluate the frequency of recurrent UTI in those with acquired scarring, a comparison with group-matched children without scarring was performed. RESULTS: A total of 74 children without obstruction had renal scarring (acquired in 40). Primary scarring was found in 18 of 21 (86%) of the boys and 16 of 53 (30%) of the girls (P <.001). The majority of boys with scarring had dilated reflux (67%) in contrast to girls (23%). Recurrent UTI was rare in boys, whereas girls with acquired scarring had significantly more febrile recurrences than girls without scarring. CONCLUSIONS: Most boys had primary, probably congenital, reflux-associated renal damage, whereas most girls had acquired scarring related to recurrences of febrile UTI.

Adolescent↗
PubMed2006

Macrophage migration inhibitory factor is increased in the urine of patients with urinary tract infection: macrophage migration inhibitory factor-protein complexes in human urine.

PURPOSE: MIF is a proinflammatory cytokine present in preformed stores in human urothelium. In animal models of bladder inflammation, including bacterial cystitis, MIF is up-regulated in the bladder and released from the bladder as a high molecular weight complex. We compared urine MIF amounts in patients with UTI to that in patients without UTI, and we examined and identified MIF-protein complexes in urine. MATERIALS AND METHODS: Using enzyme-linked immunosorbent assay we compared MIF levels in the urine of 14 patients with UTI to levels in 16 controls with no UTI. Western blotting under native, denaturing and reducing conditions was done to examine MIF complexes found in urine. Mass spectrometry identified MIF associated proteins in urine, while co-immunoprecipitation confirmed the associations. RESULTS: Mean urine MIF amounts +/- SEM determined by enzyme-linked immunosorbent assay were significantly greater in 14 patients with UTI compared to that in 16 controls (1.96 +/- 0.40 vs 0.59 +/- 0.09 ng/mg creatinine, p <0.01). Western blotting under denaturing conditions showed several high molecular weight complexes (100 to 165 kDa) that increased in UTI urine as well as typical, monomeric MIF (12 kDa). Mass spectrometry identified associated MIF proteins, including ceruloplasmin, albumin and uromodulin. Co-immunoprecipitation confirmed mass spectrometry findings and also identified MIF interaction with alpha-2-macroglobulin. CONCLUSIONS: Increased urine MIF amounts in patients with bacterial cystitis support our experimental evidence showing a role for MIF in pelvic visceral inflammation. The novel finding of an association of MIF with other urine proteins suggest that the physiologically relevant form of MIF may be an MIF-protein complex.

Bacterial Infections↗
PubMed1991

Epidemiology and natural history of urinary tract infections in children.

Recent retrospective surveys have supported previous investigations in demonstrating the incidence of UTI during infancy; 0.3% to 1.2% of infants develop symptomatic UTI during the first year of life. Boys are more commonly infected during the first 3 months of life. After the first year, symptomatic UTI is much more frequent among girls. Similarly, asymptomatic bacteriuria is more frequently detected in boys than in girls during the first 12 months of life. Thereafter, the incidence decreases markedly in boys but increases in girls. Recent investigations indicate that lack of circumcision is a risk factor for UTI among male infants. Recurrent UTI is common and frequently asymptomatic. The most important microbiologic factor that is associated with E. coli causing acute pyelonephritis is adherence mediated by P fimbriae. Other factors, such as capsule, lipopolysaccharide, aerobactin production, and serum resistance, also determine the invasiveness of E. coli. Vesicoureteral reflux appears to be an important host factor predisposing to UTI. Microbiologic and host factors that are determinants of renal scarring are under investigation.

Bacterial Infections↗
PubMed1991

Laboratory in the diagnosis and management of urinary tract infections.

The laboratory is essential in the diagnosis and management of UTIs. The presence of pyuria and bacteriuria, the two most important indicators of UTIs, are most accurately determined by standard techniques. In quantitating pyuria, the finding of greater than or equal to 10 leukocytes/mm3 of urine by either hemocytometry or direct microscopy correlates highly with symptomatic, culture-proven UTIs. The determination of bacteriuria by direct microscopy is inaccurate, particularly at lower levels of bacteriuria; thus, quantitative urine cultures remain the most accurate measure of bacteriuria. Significant bacteriuria, previously defined as greater than or equal to 10(5) CFU/ml of urine, has been redefined with the observation that as few as 10(2) CFU/ml can be associated with significant pyuria and symptoms suggestive of cystitis. The need for routine and posttreatment urine cultures in nonpregnant women with acute dysuria remains controversial, but current data suggest that they are usually unnecessary. Rapid diagnostic tests for detection of pyuria and bacteriuria are designed to increase efficiency and decrease cost in the diagnosis of UTI. Unfortunately, none of these techniques can quantitate pyuria or bacteriuria as accurately as the standard methods, but the level of accuracy offered by the standard methods is not always necessary in the care of patients with uncomplicated UTIs. These tests are particularly well suited for screening asymptomatic high-risk populations. Noninvasive localization techniques continue to be explored as possible alternatives to invasive localization procedures, but they remain largely research tools that are not readily available to the practicing clinician. Understanding the applicability and appropriate use of newer technologies in the evaluation of patients with UTIs and how these technologies complement the standard diagnostic techniques will lead to better, more efficient, and less costly patient care.

Bacterial Infections↗
PubMed1998

Cohort study on circumcision of newborn boys and subsequent risk of urinary-tract infection.

BACKGROUND: A decrease in risk of urinary-tract infection is one of the most commonly given reasons for circumcision of newborn boys. Previous studies have reported rates of UTI to be 10-20 times higher in uncircumcised than in circumcised boys. This population-based cohort study followed neonates in Ontario, Canada, prospectively to study the relation between circumcision and subsequent UTI risk. METHODS: Eligible boys were born to residents of Ontario between April 1, 1993, and March 31, 1994. We used hospital discharge data to follow up boys until March 31, 1996. FINDINGS: Of 69,100 eligible boys, 30,105 (43.6%) were circumcised and 38,995 (56.4%) uncircumcised. 888 boys circumcised after the first month of life were excluded. 29,217 uncircumcised boys were matched to the remaining circumcised boys by date of birth. The 1-year probabilities of hospital admission for UTI were 1.88 per 1000 person-years of observation (83 cases up to end of follow-up) in the circumcised cohort and 7.02 per 1000 person-years (247 cases up to end of follow-up) in the uncircumcised cohort (p<0.0001). The estimated relative risk of admission for UTI by first-year follow-up indicated a significantly higher risk for uncircumcised boys than for circumcised boys (3.7 [2.8-4.9]). 195 circumcisions would be needed to prevent one hospital admission for UTI in the first year of life. INTERPRETATION: Although our findings support the notion that circumcision may protect boys from UTI, the magnitude of this effect may be less than previously estimated.

Circumcision, Male↗
PubMed1999

An economic analysis of antimicrobial prophylaxis against urinary tract infection in patients undergoing transurethral resection of the prostate.

Despite the high level of safety and low incidence of mortality associated with transurethral resection of the prostate (TURP), urinary tract infections (UTIs)-the most common complication associated with this procedure-continue to be an important source of postoperative morbidity and costs. However, there is controversy about whether antimicrobial agents should be used as UTI prophylaxis in patients undergoing TURP and, if so, which agents should be used and for what duration. This retrospective study used multivariate regression analysis to evaluate the different types and durations of antibiotic prophylaxis in 222 patients who underwent TURP at a Veterans Affairs hospital between January 1, 1995, and March 30, 1998. The primary outcome measures were total medical costs (ie, medication use, clinic office visits, and hospital care in the 4 weeks after the procedure), length of hospital stay (total days in hospital due to the procedure), and probability of UTI (incidence of infection in the 4 weeks after the procedure). Results showed that there was no difference in the length of hospital stay regardless of the regimen or duration of pre-TURP antibiotic therapy. Patients who received pre-TURP ampicillin plus ceftizoxime incurred moderately higher total medical costs than did patients who received the least costly drug, cefazolin (P = 0.10). Similarly, patients who received post-TURP quinolones incurred a significantly higher total medical cost than did patients who received co-trimoxazole (P = 0.06). We found no evidence of a relationship between use of specific parenteral or oral antibiotic prophylaxis for UTI in patients undergoing TURP and the rate of UTI in such patients. Thus there is no justification for the use of more expensive antibiotic regimens. At our institution, the preferred pre-TURP prophylactic regimen would be cefazolin, whereas co-trimoxazole would be the most cost-effective post-TURP prophylactic regimen. Because duration of post-TURP prophylaxis does not appear to influence the rate of UTI, 24 hours would seem adequate.

Anti-Bacterial Agents↗
PubMed1999

Feedback to nursing staff as an intervention to reduce catheter-associated urinary tract infections.

Because of high incidence of catheter-related urinary tract infections (UTIs) in our Veterans Affairs medical center, we began providing nursing staff with unit-specific UTI rates. In our preintervention period, the first quarter of 1995, 38 infections occurred in 1186 catheter-patient-days or 32/1000 catheter-patient-days (95% CI, 22.9-43.7). Thereafter, nursing staff members were provided with a quarterly report with catheter-related UTI rates depicted graphically by unit. In the 18 months after this intervention, the mean UTI rate decreased to 17.4/1000 catheter-patient-days (95% CI, 14.6-20.6, P =.002). We estimated a cost savings of $403,000. We conclude that unit-specific feedback of nosocomial UTI rates to nursing staff is a highly effective method of reducing infection rates and reducing costs associated with nosocomial UTI.

Cross Infection↗
PubMed2003

[Role of bacteria associated with sexually transmitted infections in the etiology of lower urinary tract infection in primary care].

INTRODUCTION: Urinary tract infections (UTI) are the second most frequent type of infectious pathology treated in primary care clinics. The participation of microorganisms associated with sexually transmitted infection has been reported as a cause of UTI; nevertheless this concept is still controversial. To gather data on this subject, we carried out a search for Gardnerella vaginalis, Ureaplasma urealyticum, Mycoplasma hominis and Streptococcus agalactiae besides the common microorganisms involved in UTI. METHODS: A total of 1507 urine cultures from patients with a clinical diagnosis of low UTI were analyzed. Samples were inoculated onto 5% sheep blood agar and McConkey agar, as well as HBT medium for G. vaginalis, and U9B broth and agar E broth for M. hominis and U. urealyticum. The following parameters were analyzed as possible risk factors: age, sex, pregnancy and diabetes status. RESULTS. There were 436 (28.9%) positive urine cultures. Escherichia coli was isolated in 44.34% of cases. Microorganisms associated with sexually transmitted disease were found in 162 (37%): G. vaginalis (25.7%), U. urealyticum (5.9%), S. agalactiae (3.4%) and M. hominis (2%). UTI were more frequent among the 20 to 40 year-old age group, in women and in diabetic patients. CONCLUSIONS: Microorganisms associated with sexually transmitted disease were found in a large percentage of cultures, indicating the need for studies to clarify their role in the etiology of UTI.

Adolescent↗
PubMed2002

Antibiotic prescribing and urinary tract infection.

The aim of this study was to evaluate the diagnostic and therapeutic approach to urinary tract infections (UTIs) by primary care physicians, in Samsun, Turkey. Data were obtained from the records of 2083 visits at eight primary care areas. Trained research students were stationed on site at each of the eight primary care centres between 1 June, 1999 and 1 July, 1999. Patients who had acute cystitis, recurrent UTIs, acute pyelonephritis and acute urethritis were included in the study. A total of 2083 office visits were recorded and 419 (20.1%) of the patients had UTIs and acute urethritis. Antibiotics were prescribed for 94.7% of the patients with UTIs and urethritis. Some 74% of prescriptions were consistent with current recommendation, but only 41% of the antibiotic prescriptions were rational according to dosage, dosage interval and duration of therapy. Urinary antiseptic agents were prescribed to 75% of patients with UTIs. These data indicate that polypharmacy is widespread in our region; primary care physicians need to review their knowledge about the diagnosis and treatment of UTIs and acute urethritis.

Adult↗
PubMed2003

Significant elevation of urinary trypsin inhibitor in patients with brain contusion--a preliminary report.

Urinary trypsin inhibitor (UTI) is a protease inhibitor, which is produced in the liver. The correlation between UTI level and head injury has not been evaluated. This study was designed to investigate UTI levels in patients with severe head injury. We measured UTI in the urine of patients with brain contusion. UTI was significantly higher in those patients compared to the control group. The results suggest that UTI may be useful for assessing the severity of head injury and also as a treatment marker in patients with brain contusion.

Adult↗
PubMed2000

Purification, characterization, and relation to bikunin of rat urinary trypsin inhibitors.

Two forms of urinary trypsin inhibitor (UTI-1 and UTI-2) were purified from pooled urine of normal male rats to apparent homogeneity by salting out, affinity chromatography, gel filtration, and reverse-phase HPLC. UTIs-1 and 2 were shown to be thermostable glycoproteins with the respective molecular weights of 22,000 and 18,000 estimated by SDS-PAGE. These inhibitors combined with bovine trypsin in a 1:1 molar ratio: the Kd values were 2.5 x 10(-10) and 2.3 x 10(-10) M, respectively. Amino acid composition and sequence analysis indicated that UTI-1 corresponded to rat bikunin of which the amino acid sequence was deduced from a rat liver cDNA clone encoding alpha1-microglobulin [Lindqvist et al. (1992), Biochim. Biophys. Acta 1130, 63-67] except that the protein sequence seemed to lack C-terminal serine, and UTI-2 corresponded to UTI-1 lacking N-terminal 21 amino acid residues.

Amino Acid Sequence↗
PubMed1995

Anti-metastatic therapy by urinary trypsin inhibitor in combination with an anti-cancer agent.

We have demonstrated that urinary trypsin inhibitor (UTI) purified from human urine is able to inhibit lung metastasis of mouse Lewis lung carcinoma (3LL) cells in experimental and spontaneous metastasis models. In this study, we have investigated whether UTI in combination with an anti-cancer drug, etoposide, can prevent tumour metastasis and show an enhanced therapeutic effect. Subcutaneous (s.c.) implantation of 3LL cells (1 x 10(6) cells) in the abdominal wall of C57BL/6 female mice resulted in macroscopic lung metastasis within 21 days. Microscopic lung metastasis was established by day 14 after tumour cell inoculation, and surgical treatment alone after this time resulted in no inhibition of lung metastasis. The number of lung tumour colonies in the group of mice which received surgery at day 21 was greater than in mice which had tumours left in situ (P = 0.0017). Surgical treatment on day 7, followed by UTI administration (s.c.) for 7 days, led to a decrease in lung metastasis compared with untreated animals. A significant inhibition of the formation of pulmonary metastasis was obtained with daily s.c. injections of UTI for 7 days immediately after tumour cell inoculation. UTI administration did not affect the primary tumour size at the time of operation. In addition, etoposide treatment alone led to a smaller primary tumours and yielded reduction of the formation of lung metastasis in the group of mice which received surgery at day 14 (P = 0.0026). Even in mice which received surgical treatment on day 14, followed by the combination of UTI (500 micrograms per mouse, days 14, 15, 16, 17, 18, 19 and 20) with etoposide (40 mg kg-1, days 14, 18 and 22), there was significant reduction of the formation of lung metastasis (P = 0.0001). Thus, the combination of an anti-metastatic agent with an anti-cancer drug, etoposide, might provide a therapeutically promising basis for anti-metastatic therapy.

Abdominal Muscles↗
PubMed1997

Physical predictors of infection in patients treated with clean intermittent catheterization: a prospective 7-year study.

OBJECTIVE: To study urinary tract complications in patients treated using long-term clean intermittent catheterization (CIC), and to evaluate the physical factors which might be implicated in these complications. PATIENTS AND METHODS: During 1995, 170 patients (84 men and 86 women, mean age 56.9 years) with a mean duration of use of CIC for 8.8 years were assessed for complications related to CIC. The same patients had participated in a thorough follow-up study during 1988-9 and were examined again using questionnaires and the analysis of urine samples. CIC was practised by two-thirds of the patients because they had neurogenic bladder dysfunction and for non-neurogenic dysfunction in the remainder. RESULTS: In this prevalence study, 111 patients (65%) had no signs of clinical urinary tract infection (UTI), while 10 patients (6%) had pronounced symptoms. The remaining 29% had only minor signs of UTI. There were three predictive factors of clinical UTI: women reported more infections than men, the patients most affected by UTI in the present study were those suffering UTI during the 1988-9 study and patients with UTI had the highest mean catheterization volume now, and the highest increase in mean catheterization volume from 1989 to 1995. Bacteriuria was found in 61% of the urine samples, with Escherichia coli the dominant species among women and Gram-positive cocci among men. Patients who did not use anti-infective agents had a 31% rate of sterile urine while the corresponding value among those using antibiotics was 54%. The frequency of catheterization was the only variable predictive of bacteriuria apart from the use of antibiotics. CONCLUSION: This study confirms previous reports showing CIC to be an excellent procedure for minimizing urinary tract complications and supports the current recommendations, e.g., restricting the use of antibiotics in patients using CIC and ensuring that they catheterize sufficiently often to ensure that the mean volume of each catheterization is kept to < 400 mL in adults.

Adult↗
PubMed2000

In vitro contractile responses of detrusor to carbachol and neurokinin A, in children with recurrent urinary tract infection or day wetting.

OBJECTIVE: To investigate whether a history of recurrent urinary tract infection (UTI) and/or the presence of day-wetting/urge symptoms might influence the contractile responses to the cholinergic agonist carbachol or to the sensory neuropeptide neurokinin A (NKA) in the urinary bladder in children. PATIENTS AND METHODS: Small detrusor strips were taken from the margin of the cystotomy incision of the bladder dome during surgery to correct vesico-ureteric reflux (VUR) in 62 children (aged 4 months to 12 years) or for unrelated bladder conditions in five controls (aged 3 months to 13 years). Concentration-response curves to carbachol and NKA were constructed using organ-bath techniques, and results compared for age, sex, weight of the detrusor strip, UTI history or day-wetting syndrome. RESULTS: The contractile responses to NKA were no different for any of the features investigated. The contractile response to carbachol and NKA in detrusor from control and VUR patients was not significantly different. The children with a history of UTI were significantly older than those without. The contractility in response to carbachol was greater in older girls (aged 4-12 years) than younger girls (< 4 years) and than in all boys (< 4 years and 4-12 years; ANOVA P = 0.013). The mean (SEM) maximum contractile response to carbachol in the group of 20 young children (4-30 months) with previous UTI was 3.0 (0.3) g, whereas the maximum response in the age-matched group of 11 without UTI was 1.8 (0.3) g (P = 0.046). There were no significant differences in maximum responses between those with day-wetting and those without (aged > 4 years), although there was a significant difference in pD2 value, at 6.19 (0.13) and 5.58 (0.14), respectively (P = 0.018). CONCLUSION: Carbachol produced a larger contractile response in detrusor from children with a history of UTI than from those without, indicating possible alterations in muscarinic receptor characteristics. An increased sensitivity to muscarinic stimulation in day-wetting children was also suggested, whereas NKA is unlikely to be involved in any of these pathophysiological conditions.

Adolescent↗
PubMed2000

Could the incidence of postoperative urinary tract infection be reduced by reversing the sequence of vaginal cleansing and urethral catheterization?

Postoperative urinary tract infection (UTI) is a common hospital infection after gynaecological operations. A prospective randomized study was performed to examine whether the incidence of UTI could be reduced by reversing the sequence of vaginal cleansing and urethral catheterization. Subjects were randomly allocated to: (1) urethral catheterization before vaginal cleansing; and (2) urethral catheterization after vaginal cleansing. Urine cultures were performed immediately after the procedures as the baseline, on the day of catheter removal, and two days after catheter removal. Patients were examined daily after the operation for any urinary symptoms and fever. The incidences of preoperative asymptomatic bacteriuria were similar in both groups, seven of 84 in group 1 vs. eight of 83 in group 2. Among those with negative urine culture before the operation, 77 in group 1 and 75 in group 2, there was no significant difference in postoperative bacteriuria at catheter removal (23 vs. 22) and two days later (35 vs. 42). No significant difference was noted in the incidence of UTI (5 vs. 10, P = 0.25), with a trend towards less UTI in group 1. Voiding discomfort was more common, and fever less common in group 1. There were significant associations between urine culture results at three different occasions. Bacteriuria at catheter removal is associated with a 7.2 times risk of bacteriuria two days later, 2.4 times risk of urinary symptoms and 3.2 times risk of UTI. Routine surveillance at catheter removal is not cost-effective. We conclude that postoperative bacteriuria and UTI are common. Reversing the sequence of the procedures cannot reduce the incidence. There is no evidence to change the status quo.

Bacteriuria↗
PubMedDate not supplied

[Ultrasonography in urinary tract infection in infancy].

In a prospective study 77 infants (35 boys) with a mean age of 5.23 months were studied to determine the value of sonography for detection of renal parenchymal involvement in urinary tract infection (UTI). Sonography was performed during UTI and about one month later. UTI was classified as upper and lower UTI according to the clinical and laboratory findings; radiological investigations (voiding cystoureterography = MCU) were performed in all infants. 40 infants were classified to have upper UTI. There was a high sensitivity (80%) and specificity (97%) for detection of renal involvement by sonography. Incidence for vesicoureteral reflux (VUR) was significantly higher in infants with repeated pathological findings on sonography. In contrast, no VUR was detected on MCU in all 12 infants with normal findings in both sonographic examinations. Yet, sonography without catheterization could not detect VUR in all infants with radiologically confirmed reflux. Our results show, that sonography is of definite value in infants with UTI, but cannot replace radiological work up.

Female↗
PubMed2003

Urinary tract infection: traditional pharmacologic therapies.

Urinary tract infections (UTIs) are common bacterial infections, particularly in women. Antimicrobial therapy is seldom indicated for asymptomatic infection, but antimicrobial therapy is usually indicated for amelioration of symptoms. Management of acute uncomplicated UTI (cystitis) is generally straightforward, with a predictable distribution of uropathogens isolated. First-line treatment of acute uncomplicated UTI has traditionally involved a 3-day regimen of trimethoprim-sulfamethoxazole (TMP-SMX) or TMP alone for patients with sulfa allergies. Increasing resistance among community-acquired Escherichia coli to TMP-SMX worldwide has led to a reassessment of the most appropriate empiric therapy for these infections. Alternative first-line agents include the fluoroquinolones, nitrofurantoin, and fosfomycin. Factors to be considered in the selection of appropriate antimicrobial therapy include pharmacokinetics, spectrum of activity of the antimicrobial agent, resistance prevalence for the community, potential for adverse effects, and duration of therapy. Ideal antimicrobial agents for UTI management have primary excretion routes through the urinary tract to achieve high urinary drug levels. In addition, there are special considerations in the management of UTI among selected populations, including postmenopausal and pregnant women, and for women with frequent recurrent UTIs.

Adolescent↗
PubMed2003

The expanding role of fluoroquinolones.

There has been a growing rate of resistance among common urinary tract pathogens, such as Escherichia coli, to traditional antimicrobial therapies including the "gold standard" trimethoprim-sulfamethoxazole (TMP-SMX). Consequently, fluoroquinolone antimicrobial agents have taken on an expanding management role for UTIs. In fact, the recent Infectious Diseases Society of America clinical management guidelines for UTI recommend fluoroquinolones as first-line therapy for uncomplicated UTI in areas where resistance is likely to be of concern. Fluoroquinolones have demonstrated high bacteriologic and clinical cure rates, as well as low rates of resistance, among most common uropathogens. There are currently 7 fluoroquinolones with indications for UTI in the United States. However, only 3 are commonly used: levofloxacin, ciprofloxacin, and, to a lesser extent, gatifloxacin. Many of the fluoroquinolone agents have once-daily dosing regimens, enhancing patient adherence. In addition, levofloxacin and gatifloxacin have same-dose bioequivalency between their intravenous and oral formulations, allowing for "switch" or step-down therapy from parenteral to oral formulations of the same agent at the same dose. Fluoroquinolones are indicated for the management of acute uncomplicated UTIs, as well as complicated and severe UTI and pyelonephritis, in adults. They are the first-line treatment of acute uncomplicated cystitis in patients who cannot tolerate sulfonamides or TMP, who live in geographic areas with known resistance >10% to 20% to TMP-SMX, or who have risk factors for such resistance. Fluoroquinolone properties include a broad spectrum of coverage, low rates of resistance, and good safety profiles.

Anti-Infective Agents↗