157
DIAG. MICROBIOL. INFECT. DIS. 1990;13:157-160
Parenteral Ciprofloxacin Compared with Ceftazidime in the Treatment of Serious Upper and Lower Urinary Tract Infection Darwin L. Palmer and Frederick T. Koster
INTRODUCTION Uncomplicated urinary tract infection in otherwise normal adults is readily treated with simple antibiotics, usually resulting in an excellent outcome. Cure of lower urinary tract infection is often effected with a single dose or short course of oral antibiotic in both women and men (Ronald, 1984). On the other hand, the therapeutic response of complicated urinary tract infections is more problematic. Treatment may fail because of multiple or resistant pathogens or reinfection due to uncorrected genitourinary disorders. Complicated urinary tract infections occur with functional or anatomic abnormalities of the urinary tract, leading to repeated infection (Kunin, 1987). These abnormalities include obstruction, foreign bodies, neurogenic or hypotonic bladder, and malignancy. Infection with these conditions results in residual and inflammatory changes, antibiotic-resistant organisms, infection stones, and parenchymal scarring with progressively more difficult therapy. Prolonged treatment with carefully selected antibiotics may be necessary, although the data are conflicting (Stamm et al., 1987), particularly in men From the Division of Infectious Disease, Department of Medicine, University of New Mexico School of Medicine and Veterans Administration Medical Center, Albuquerque, New Mexico. Address reprint requests to: Dr. D. Palmer, Division of Infectious Disease, Department of Medicine, Veterans Administration Medical Center, 2100 Ridgecrest Drive, Southeast, Albuquerque, NM 87108. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50
(Lipsky, 1989). Agents demonstrating good tissue penetration, effective spectrum for uropathogens, decreased incidence of development of resistance, and low toxicity become of utmost importance with complicated infections. The new fluorinated quinolone antibiotics offer attractive prospects in these therapeutic settings (Clin and Ney, 1984). They are effective against most Enterobacteriaceae, even those resistant to other agents, and against Pseudomonas aeruginosa and staphylococci, which may cause urinary tract infections. The newer quinolones show a decreased frequency of resistance development during therapy than older analogs such as naladixic acid that are suitable for urinary tract infection (Hooper et al., 1987). A low rate of adverse reactions and good tissue concentrations attained in both the kidney and prostate make them good choices for chronic parenchymal urinary tract infection. They do not inhibit anaerobic organisms of the gastrointestinal tract and, hence, may allow colonization resistance to other more invasive micro-organisms during prolonged treatment (Young, 1987). This study was designed to evaluate the comparative efficacy and toxicity of parenteral ciprofloxacin (CIP) with those of ceftazidime (CTZ) in patients with serious complicated urinary tract infections. In noncomparative trials, CIP has been shown previously to be both safe and effective in patients with complicated urinary tract infection (Gasser et al., 1987); and CTZ is a third-generation cephalosporin with a high degree of efficacy against the Enterobacteriaceae, including resistant Pseudomonas. This study was conducted in patients with serious, complicated urinary tract infections, including patients with repeated urinary tract infections, bacteremia, and urosepsis.
158
MATERIALS A N D M E T H O D S Thirty-four male patients (mean age, 50.6 years) and 11 female patients (mean age, 56.8 years) over the age of 18 with complaints of dysuria, cloudy urine, fever, back pain, blood in urine, and infection confirmed by cultures (clean catch or catheterized) within 24 48 hr prior to therapy were enrolled into the study after obtaining informed consent. Patients were excluded from the study for the following reasons: history of allergy to quinolones or cephalosporins; mild infections; pregnancy or lactation; severe renal dysfunction as evidenced by a serum creatinine ~2 mg/dl; and unrelieved obstruction or indwelling bladder catheter. After enrollment, a medical history was obtained and a physical examination conducted. Patients were then randomized to receive either intravenous (IV) CIP, 200 mg every 12 hr for 2-5 days, followed by oral CIP, 500 mg twice daily for up to 14 days, or intravenous ceftazidime (CTZ), 500 mg every 8 hr for 7-14 days, followed by an appropriate oral antibiotic (other than CIP), for total treatment of up to 14 days. Laboratory evaluation consisted of urine cultures (clean catch or catheterized) prior to treatment and every 3-5 days while on therapy, plus day 5-9 and week 4 after cessation of treatment. Cultures with ~105 CFU/ml (or 104 CFU/ml, when obtained by catheter) were judged to be positive. Simultaneous blood cultures were also obtained from each patient. Organisms were identified by standard bacteriologic techniques. Antibiotic sensitivity testing was conducted with the Kirby-Bauer disk diffusion method. Other laboratory evaluations of hematologic, renal, and liver function were conducted before, during, and after therapy to monitor adverse reaction. Overall outcome was determined based on both clinical and bacteriological results. Thus, a case was assessed to be a cure if the causative pathogens were eradicated and if there was complete resolution or improvement in the signs and symptoms of infection at the 5- to 9-day post-treatment visit. If the causative bacteria persisted at the site of infection, the overall response was deemed to be a failure, regardless of the clinical response. Therapy was also assessed to be a failure if there was bacterial eradication but no clinical response. In cases where there was a superinfection (new causative pathogen emerged during the course of therapy), the overall response was designated as a failure, despite the clinical response. In cases where the bacteriological response showed initial clearance followed by later relapse (same organism) or reinfection (different bacteriologic species), the therapy was deemed a failure. For statistical purposes, cure versus all other outcomes (persistence, superinfection, relapse, reinfection) was calculated.
D.L. Palmer and F.T. Koster
TABLE 1.
Bacterial Eligibility by Treatment Group
E. coli KESa Providencia sp. Citrobacter sp. Pseudomonas sp. Proteus sp. Gram-positive cocci
CIP
CTZ
10 5 4 3 3 1 4
11 5 0 0 1 2 2
"Klebsiella-Enterobacter-Serratia sp.
The chi-square test, using Yate's correction for continuity, was used to determine statistical significance.
RESULTS A total of 63 patients were initially enrolled into the study with clinical symptoms of serious urinary tract infection. Of these, 18 were excluded from the efficacy analysis because of deficient urine cultures, protocol deviations, or insufficient follow-up. Twentyfive patients received CIP and 20 received CTZ. Twenty of the CIP patients were male and five were female. There were 14 male and 6 female patients who received CTZ. Although there were slightly more patients with urologic or other medical problems in the CIP group, these differences were not statistically significant. Table 1 presents the bacteriologic data of both groups. Because five patients in the CIP group and one patient in the CTZ group had multiple pathogens, there were more organisms than patients. One patient in both groups had simultaneous positive urine and blood cultures for Escherichia coli. Of 42 organisms tested against CIP, 40 were susceptible and 2 were moderately susceptible (1 Klebsiella, 1 enterococcus). Of 39 organisms tested against CTZ, 36 were susceptible, 1 was moderately susceptible, and 2 were resistant (2 Staphylococcus epidermidis, 1 enterococcus). Table 2 presents clinical outcome by treatment group. Because the subcategories of outcome were small, overall outcomes other than cure were grouped together. CIP-treated patients had a better overall outcome (72% cure as opposed to 55% cure with CTZ), which approached (but did not reach) statistical significance. Analysis of outcome by organism (Table 2) demonstrated a better outcome among the patients with E. coli, whether treated with CIP or CTZ. This difference was also not statistically significant.
Ciprofloxacin for Urinary Tract Infection
TABLE 2.
159
Clinical and Bacteriologic Response Outcome by Treatment Groupa
CIP Cure (%) Persistence Superinfection Relapse Reinfection
18 (72) 0 1 2 4
CTZ 11 (55) 2 1 3 3
Outcome of Treatment by Initial Organism ~'in Both Groups
Organisms E. coli
All other
Cure (%)
Failure (%)
16 (76) 14 (54)
5 (24) 11 (46)
aThe differences between cure and all other outcomes approached, but did not reach, statistical significance by chisquare test. bThis difference approached, but did not reach, statistical significance by chi-square test using Yates correction for continuity. DISCUSSION This study was designed to evaluate the clinical efficacy and safety of parenteral/oral CIP compared with CTZ in patients with urinary tract infections serious enough to warrant hospitalization. In this group, case selection resulted in enrollment of patients (60%) with complicated underlying urologic problems, such as neurogenic bladder, prostatic hypertrophy, bladder cancer, ileal conduit reconstruction, and multiple recurrent urinary tract infections. Twelve patients used intermittent catheterization for bladder drainage, but none used indwelling catheters or had intractable obstructive uropathy. Other underlying medical conditions with impact on urinary tract infections, such as diabetes mellitus, stroke, malignancy, and old age, were also present in 44% of patients. The complicated underlying medical and/or urological conditions of the enrolled patients was reflected in the infecting uropathogens: Only 21 of 49 were E. coli, whereas more resistant organisms such as Providencia, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus, and Pseudomonas species were frequent. Multiple pathogens were detected in six patients and bacteremia with an identical uropathogen was found in two patients. Complex urinary tract problems and uropathogens other than E. coli were more common in the
CIP-treated group. The presence of antibiotic resistance on initial testing of all organisms revealed no superiority of CIP or CTZ and, with the small number of intermediate or resistant organisms seen (three to each drug), no apparent effect on outcome. Unlike other studies (Ryan et al., 1987), superinfection was an infrequent consequence of treatment with either drug, occurring in only one patient in each treatment group. Because of the short followup, this study does not clarify the issue of long-term treatment in decreasing relapse or preventing reinfection in these complex urologic circumstances (Stamm et al., 1987; Young, 1987; Lipsky, 1989). Overall outcome, as determined by clinical and bacteriologic response, was better in the CIP-treated groups than in the CTZ-treated group, (72% cure vs. 55% cure), but this difference was not statistically significant. As might be expected with this complex group of patients (Ronald, 1984; Kunin, 1987; Ryan et al., 1987), early reinfection (7 of 45, or 16%) was the most common cause of failure, whereas relapse with identical organisms (by species identification) was seen in 5 of 45, or 11% of patients. Initial failure of therapeutic response was seen in only two (both CTZ), and superinfection with another pathogen during treatment was seen in two (one from each group). Adverse reactions were infrequent and minimal in degree. One patient developed a transient rash while on CIP. Some changes in other laboratory parameters were seen in both groups but did not result in permanent sequelae or alteration of therapy. Both IV/oral CIP and IV CTZ appear to be excellent antibiotics in the treatment of serious urinary tract infections in patients with complex urologic problems. Ciprofloxacin showed a slightly (but not statistically significant) better outcome. No adverse effects of consequence were seen with either drug. Not unexpectedly, failure of therapy (mostly reinfection and relapse) occurred in 31% of patients. In this clinical setting, possibly more prolonged therapy with an appropriate agent would be of value, particularly in patients with prostatic or renal involvement. The initial choice of parenteral CIP would appear warranted in those patients with infections sufficiently serious to require hospitalization in whom urologic complications suggest a difficult clinical course.
REFERENCES Chin N-X, Neu HC (1989) Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 25:319325. Gasser TC, Graversen PC, Madsen PO (1987) Treatment
of complicated urinary tract infections with ciprofloxacin. Am ] Med 82(suppl 4A):278-287. Hooper DC, Wolfson JS, Ng EY, Swartz MN (1987) Mechanisms of action of and resistance to ciprofloxacin. Am ] Med 82(suppl 4A):12-20.
160
Kunin CM (1987) An overview of urinary tract infections. In Detection, Prevention and Management of Urinary Tract Infections, 4th ed. Ed., CM Kunim. Philadelphia: Lea and Febiger. pp 1-41. Lipsky BA (1989) Urinary tract infections in men: epidemiology, pathophysiology, diagnosis and treatment. Ann Intern Med 110:138-150. Ronald AR (1984) Current concepts in the management of urinary tract infections in adults. Med Ctin N Am 68:33549.
D.L. P a l m e r a n d F.T. Koster
Ryan JL, Berenson CS, Greco TP, et al (1987) Oral ciprofloxacin in resistant urinary tract infections. Am J Med 82(suppl 4A):303-306. Stamm WE, McKevitt M, Counts GW (1987) Acute renal infection in women: treatment with trimethoprim-sulfamethoxazole or ampicillin for two or six weeks. Ann Intern Med 106:341-345. Young LS (1987) The new fluorinated quinolones for infection prevention in acute leukemia. Ann Intern Med 106:144-146.
DIAG. MICROBIOL. INFECT. DIS. 1990;13:157-160
Parenteral Ciprofloxacin Compared with Ceftazidime in the Treatment of Serious Upper and Lower Urinary Tract Infection Darwin L. Palmer and Frederick T. Koster
INTRODUCTION Uncomplicated urinary tract infection in otherwise normal adults is readily treated with simple antibiotics, usually resulting in an excellent outcome. Cure of lower urinary tract infection is often effected with a single dose or short course of oral antibiotic in both women and men (Ronald, 1984). On the other hand, the therapeutic response of complicated urinary tract infections is more problematic. Treatment may fail because of multiple or resistant pathogens or reinfection due to uncorrected genitourinary disorders. Complicated urinary tract infections occur with functional or anatomic abnormalities of the urinary tract, leading to repeated infection (Kunin, 1987). These abnormalities include obstruction, foreign bodies, neurogenic or hypotonic bladder, and malignancy. Infection with these conditions results in residual and inflammatory changes, antibiotic-resistant organisms, infection stones, and parenchymal scarring with progressively more difficult therapy. Prolonged treatment with carefully selected antibiotics may be necessary, although the data are conflicting (Stamm et al., 1987), particularly in men From the Division of Infectious Disease, Department of Medicine, University of New Mexico School of Medicine and Veterans Administration Medical Center, Albuquerque, New Mexico. Address reprint requests to: Dr. D. Palmer, Division of Infectious Disease, Department of Medicine, Veterans Administration Medical Center, 2100 Ridgecrest Drive, Southeast, Albuquerque, NM 87108. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50
(Lipsky, 1989). Agents demonstrating good tissue penetration, effective spectrum for uropathogens, decreased incidence of development of resistance, and low toxicity become of utmost importance with complicated infections. The new fluorinated quinolone antibiotics offer attractive prospects in these therapeutic settings (Clin and Ney, 1984). They are effective against most Enterobacteriaceae, even those resistant to other agents, and against Pseudomonas aeruginosa and staphylococci, which may cause urinary tract infections. The newer quinolones show a decreased frequency of resistance development during therapy than older analogs such as naladixic acid that are suitable for urinary tract infection (Hooper et al., 1987). A low rate of adverse reactions and good tissue concentrations attained in both the kidney and prostate make them good choices for chronic parenchymal urinary tract infection. They do not inhibit anaerobic organisms of the gastrointestinal tract and, hence, may allow colonization resistance to other more invasive micro-organisms during prolonged treatment (Young, 1987). This study was designed to evaluate the comparative efficacy and toxicity of parenteral ciprofloxacin (CIP) with those of ceftazidime (CTZ) in patients with serious complicated urinary tract infections. In noncomparative trials, CIP has been shown previously to be both safe and effective in patients with complicated urinary tract infection (Gasser et al., 1987); and CTZ is a third-generation cephalosporin with a high degree of efficacy against the Enterobacteriaceae, including resistant Pseudomonas. This study was conducted in patients with serious, complicated urinary tract infections, including patients with repeated urinary tract infections, bacteremia, and urosepsis.
158
MATERIALS A N D M E T H O D S Thirty-four male patients (mean age, 50.6 years) and 11 female patients (mean age, 56.8 years) over the age of 18 with complaints of dysuria, cloudy urine, fever, back pain, blood in urine, and infection confirmed by cultures (clean catch or catheterized) within 24 48 hr prior to therapy were enrolled into the study after obtaining informed consent. Patients were excluded from the study for the following reasons: history of allergy to quinolones or cephalosporins; mild infections; pregnancy or lactation; severe renal dysfunction as evidenced by a serum creatinine ~2 mg/dl; and unrelieved obstruction or indwelling bladder catheter. After enrollment, a medical history was obtained and a physical examination conducted. Patients were then randomized to receive either intravenous (IV) CIP, 200 mg every 12 hr for 2-5 days, followed by oral CIP, 500 mg twice daily for up to 14 days, or intravenous ceftazidime (CTZ), 500 mg every 8 hr for 7-14 days, followed by an appropriate oral antibiotic (other than CIP), for total treatment of up to 14 days. Laboratory evaluation consisted of urine cultures (clean catch or catheterized) prior to treatment and every 3-5 days while on therapy, plus day 5-9 and week 4 after cessation of treatment. Cultures with ~105 CFU/ml (or 104 CFU/ml, when obtained by catheter) were judged to be positive. Simultaneous blood cultures were also obtained from each patient. Organisms were identified by standard bacteriologic techniques. Antibiotic sensitivity testing was conducted with the Kirby-Bauer disk diffusion method. Other laboratory evaluations of hematologic, renal, and liver function were conducted before, during, and after therapy to monitor adverse reaction. Overall outcome was determined based on both clinical and bacteriological results. Thus, a case was assessed to be a cure if the causative pathogens were eradicated and if there was complete resolution or improvement in the signs and symptoms of infection at the 5- to 9-day post-treatment visit. If the causative bacteria persisted at the site of infection, the overall response was deemed to be a failure, regardless of the clinical response. Therapy was also assessed to be a failure if there was bacterial eradication but no clinical response. In cases where there was a superinfection (new causative pathogen emerged during the course of therapy), the overall response was designated as a failure, despite the clinical response. In cases where the bacteriological response showed initial clearance followed by later relapse (same organism) or reinfection (different bacteriologic species), the therapy was deemed a failure. For statistical purposes, cure versus all other outcomes (persistence, superinfection, relapse, reinfection) was calculated.
D.L. Palmer and F.T. Koster
TABLE 1.
Bacterial Eligibility by Treatment Group
E. coli KESa Providencia sp. Citrobacter sp. Pseudomonas sp. Proteus sp. Gram-positive cocci
CIP
CTZ
10 5 4 3 3 1 4
11 5 0 0 1 2 2
"Klebsiella-Enterobacter-Serratia sp.
The chi-square test, using Yate's correction for continuity, was used to determine statistical significance.
RESULTS A total of 63 patients were initially enrolled into the study with clinical symptoms of serious urinary tract infection. Of these, 18 were excluded from the efficacy analysis because of deficient urine cultures, protocol deviations, or insufficient follow-up. Twentyfive patients received CIP and 20 received CTZ. Twenty of the CIP patients were male and five were female. There were 14 male and 6 female patients who received CTZ. Although there were slightly more patients with urologic or other medical problems in the CIP group, these differences were not statistically significant. Table 1 presents the bacteriologic data of both groups. Because five patients in the CIP group and one patient in the CTZ group had multiple pathogens, there were more organisms than patients. One patient in both groups had simultaneous positive urine and blood cultures for Escherichia coli. Of 42 organisms tested against CIP, 40 were susceptible and 2 were moderately susceptible (1 Klebsiella, 1 enterococcus). Of 39 organisms tested against CTZ, 36 were susceptible, 1 was moderately susceptible, and 2 were resistant (2 Staphylococcus epidermidis, 1 enterococcus). Table 2 presents clinical outcome by treatment group. Because the subcategories of outcome were small, overall outcomes other than cure were grouped together. CIP-treated patients had a better overall outcome (72% cure as opposed to 55% cure with CTZ), which approached (but did not reach) statistical significance. Analysis of outcome by organism (Table 2) demonstrated a better outcome among the patients with E. coli, whether treated with CIP or CTZ. This difference was also not statistically significant.
Ciprofloxacin for Urinary Tract Infection
TABLE 2.
159
Clinical and Bacteriologic Response Outcome by Treatment Groupa
CIP Cure (%) Persistence Superinfection Relapse Reinfection
18 (72) 0 1 2 4
CTZ 11 (55) 2 1 3 3
Outcome of Treatment by Initial Organism ~'in Both Groups
Organisms E. coli
All other
Cure (%)
Failure (%)
16 (76) 14 (54)
5 (24) 11 (46)
aThe differences between cure and all other outcomes approached, but did not reach, statistical significance by chisquare test. bThis difference approached, but did not reach, statistical significance by chi-square test using Yates correction for continuity. DISCUSSION This study was designed to evaluate the clinical efficacy and safety of parenteral/oral CIP compared with CTZ in patients with urinary tract infections serious enough to warrant hospitalization. In this group, case selection resulted in enrollment of patients (60%) with complicated underlying urologic problems, such as neurogenic bladder, prostatic hypertrophy, bladder cancer, ileal conduit reconstruction, and multiple recurrent urinary tract infections. Twelve patients used intermittent catheterization for bladder drainage, but none used indwelling catheters or had intractable obstructive uropathy. Other underlying medical conditions with impact on urinary tract infections, such as diabetes mellitus, stroke, malignancy, and old age, were also present in 44% of patients. The complicated underlying medical and/or urological conditions of the enrolled patients was reflected in the infecting uropathogens: Only 21 of 49 were E. coli, whereas more resistant organisms such as Providencia, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus, and Pseudomonas species were frequent. Multiple pathogens were detected in six patients and bacteremia with an identical uropathogen was found in two patients. Complex urinary tract problems and uropathogens other than E. coli were more common in the
CIP-treated group. The presence of antibiotic resistance on initial testing of all organisms revealed no superiority of CIP or CTZ and, with the small number of intermediate or resistant organisms seen (three to each drug), no apparent effect on outcome. Unlike other studies (Ryan et al., 1987), superinfection was an infrequent consequence of treatment with either drug, occurring in only one patient in each treatment group. Because of the short followup, this study does not clarify the issue of long-term treatment in decreasing relapse or preventing reinfection in these complex urologic circumstances (Stamm et al., 1987; Young, 1987; Lipsky, 1989). Overall outcome, as determined by clinical and bacteriologic response, was better in the CIP-treated groups than in the CTZ-treated group, (72% cure vs. 55% cure), but this difference was not statistically significant. As might be expected with this complex group of patients (Ronald, 1984; Kunin, 1987; Ryan et al., 1987), early reinfection (7 of 45, or 16%) was the most common cause of failure, whereas relapse with identical organisms (by species identification) was seen in 5 of 45, or 11% of patients. Initial failure of therapeutic response was seen in only two (both CTZ), and superinfection with another pathogen during treatment was seen in two (one from each group). Adverse reactions were infrequent and minimal in degree. One patient developed a transient rash while on CIP. Some changes in other laboratory parameters were seen in both groups but did not result in permanent sequelae or alteration of therapy. Both IV/oral CIP and IV CTZ appear to be excellent antibiotics in the treatment of serious urinary tract infections in patients with complex urologic problems. Ciprofloxacin showed a slightly (but not statistically significant) better outcome. No adverse effects of consequence were seen with either drug. Not unexpectedly, failure of therapy (mostly reinfection and relapse) occurred in 31% of patients. In this clinical setting, possibly more prolonged therapy with an appropriate agent would be of value, particularly in patients with prostatic or renal involvement. The initial choice of parenteral CIP would appear warranted in those patients with infections sufficiently serious to require hospitalization in whom urologic complications suggest a difficult clinical course.
REFERENCES Chin N-X, Neu HC (1989) Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 25:319325. Gasser TC, Graversen PC, Madsen PO (1987) Treatment
of complicated urinary tract infections with ciprofloxacin. Am ] Med 82(suppl 4A):278-287. Hooper DC, Wolfson JS, Ng EY, Swartz MN (1987) Mechanisms of action of and resistance to ciprofloxacin. Am ] Med 82(suppl 4A):12-20.
160
Kunin CM (1987) An overview of urinary tract infections. In Detection, Prevention and Management of Urinary Tract Infections, 4th ed. Ed., CM Kunim. Philadelphia: Lea and Febiger. pp 1-41. Lipsky BA (1989) Urinary tract infections in men: epidemiology, pathophysiology, diagnosis and treatment. Ann Intern Med 110:138-150. Ronald AR (1984) Current concepts in the management of urinary tract infections in adults. Med Ctin N Am 68:33549.
D.L. P a l m e r a n d F.T. Koster
Ryan JL, Berenson CS, Greco TP, et al (1987) Oral ciprofloxacin in resistant urinary tract infections. Am J Med 82(suppl 4A):303-306. Stamm WE, McKevitt M, Counts GW (1987) Acute renal infection in women: treatment with trimethoprim-sulfamethoxazole or ampicillin for two or six weeks. Ann Intern Med 106:341-345. Young LS (1987) The new fluorinated quinolones for infection prevention in acute leukemia. Ann Intern Med 106:144-146.
