UROPHARMACOLOGY i
EFFICACY AND TOLERANCE OF NORFLOXACIN IN TREATMENT OF COMPLICATED URINARY TRACT INFECTION IN OUTPATIENTS WITH NEUROGENIC BLADDER SECONDARY TO SPINAL CORD INJURY KEN B. WAITES, M.D. KAY C. CANUPP, M.S. MICHAEL J. DEVIVO, DmRH.
From the Departments of Microbiology, and Rehabilitation Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
ABSTRACT--We studied the efficacy of a fourteen-day course of the fluoroquinolone, norfloxacin, in a group of 69 catheter-free spinal cord iniury (SCI) outpatients who experienced a total of seventy-nine urinary tract infection (UTI) episodes. A total of 114 bacterial strains representing twenty species, including sixteen Pseudomonas aeruginosa, all susceptible to norfloxacin, were isolated from initial urine cultures. Mid-treatment cultures in 58/79 (73 %) cases were negative. Cultures taken five to seven days after completing treatment in 42 cases (53 %) were negative. In the remaining 37 there was persistence of initial or superinfecting pathogen(s), or early reinfection with new organisms. Cultures eight to twelve weeks later in 32 cases with initial eradication showed that 27 (84 %) had either relapsed and/or become reinfected. Clinical cure occurred in 4/6 (67 %) symptomatic episodes. Side effects occurred in 6 of 73 (8%) patients who received norfloxacin, 4 of whom required withdrawal from the study. Twenty of one hundred twenty-two (16 %) bacterial strains isolated during or after treatment were resistant to norfloxacin. Given the limited oral treatment options and the constant risk of reinfection in the SCI population, norfloxacin appears to be a reasonable choice in many patients. However, as with other antimicrobials, when using norfloxacin in SCI patients, the emergence oJ resistant bacteria must be carefully monitored.
:Complicated urinary tract infections (UTIs) in persons with spinal cord injury (SCI) represent !perhaps the most complex and difficult type of i:urologic infection from a management standpoint. Such UTIs differ from infections oecur::ring in many other populations in that they are often asymptomatie, frequently polymierobial, i:eaused by bacteria which are resistant to multii!:ple antibiotics, and are likely to recur or re[!apse. 1,2 The occurrence of serious urologic [iUROLOGY /
DECEMBER 1991
complications following SCI is usually related to ascending or hematogenous spread of uncontrolled infection from a focus in the lower urinary tract to the upper tract, or even to remote organs. 1 The high costs and impracticality of parenteral therapy in nonlife-threatening UTIs encountered in an outpatient setting, coupled with the limited options of broad-spectrum oral antimierobials, particularly for Pseudomonas
/ VOLUME XXXVIII, NUMBER 6
589
',~.erugin-sa infections, and lack of prospective clinical studies in the SCI population make ~:herapeutie decisions difficult. The introdue,:ion of a new class of antimierobials, the fluoroquinolones, represents a significant advance in ~:herapeutic options for complicated UTI. The purpose of the present study was to evaluate the efficacy and tolerability of norfloxaein in the ~treatment of complicated UTIs oeurring in SCI outpatients. Material and Methods The study was conducted between July 1988 and December 1989 in the SCI outpatient clinic at Spain Rehabilitation Center at the University of Alabama at Birmingham. Outpatients who were found to have UTI while undergoing their annual urologic examination or who sought medical care because of acute symptomatic UTI were eligible for enrollment in this openlabel prospective study. The study was approved by the Institutional Review Board and a signed informed consent was obtained from all participants. Patients with a history of allergy, hypersensitivity or other adverse reaction to quinolones, clinical signs suggestive of baeteremia and/or urosepsis, prior antibiotic therapy within the previous s e v e n t y - t w o hours, d o c u m e n t e d urinary calculi, severe c o n c u r r e n t illness, seizure disorders, and/or mental incapacitation were excluded. Urinary pregnancy tests were performed in women of childbearing potential to exclude the possibility of the enrollment of patients who were pregnant. A total of '78 patients were enrolled in the study initially. Ten patients were enrolled twice during the study period because of recurrent UTI, giving a total of 88 infectious episodes. Nine patients were unevaluable because of either lack of compliance with the study protocol resulting in inadequate laboratory data (5 patients), or minor adverse experiences requiring withdrawal of the patient from the study (4 patients). Thus, there were 79 evaluable infectious episodes in 69 patients. Characteristics of the patient population are shown in Table I. On the initial clinic visit a complete medical history was elicited and physical examination performed. Urine was collected either by deancatch midstream specimen (54 patients) or sterile catheterization (15 patients), depending on whether the patient used a condom catheter or Cred6 maneuver for bladder management, 590
TABLE I.
Patient demographic characteristic~ (N = 69) .... No. of
Variable Male Female White Black Paraplegic Quadriplegie Complete neurologic lesion Incomplete neurologie lesion Injured < 6 months Injured >6 months Bladder management: Condom catheter Intermittent catheterization Cred6 maneuver Age range (yrs.) Av. and median age (yrs.)
Pts. 66 3 43 26 44 25 58 11 5 64 53 15 1 18-69 37
or was undergoing intermittei UTI was defined as the pres~ mL of bacteria in addition urinary leukocytes per high scopic field [ x 400]). On demonstration of UTI susceptible to norfloxacin, p taeted regarding partieipatiol informed consent was obtain plete blood counts and serur also obtained during the ini patients with a creatinine el~ min were given norfloxacin West Point, PA) 400 mg twic for fourteen days after initial firmation of UTI. Urine cull bility testing was performed after initiating treatment a seven days after completing t~ ing long-term follow-up sp twelve weeks later was atte whose post-treatment cultur, Mid-treatment and follow-t were performed using the ag~ plex Scientific, Mississauga, ( Urine was collected by the p~ oculated onto the Dip Slide University of Alabama Hospit biology Laboratory, where counts, organism identifieati bility testing were perforn standard methods. 3 Use of assess the bacteriologic statu_
UROLOGY
/
DECEMBER 1991
/
VOLUME XXXVIII,
iiL
Total Isolates (n-114)
Drug Amikacin
Ampicillin Ciprofloxacin Gentamicin Mezlocillin Nitrofurantoin Nor floxacin Piperacillin Tetracycline ~rimethoprim/Sulfa
Cephalothin Chloramphenicol 0
20
40
60
80
100
% Susceptible
FIGURE1. Comparative susceptibility rates o] bacteria isolated ]rom urine prior to treatment in patients whose initial isolates were shown to be susceptible to norfloxacin. Susceptibility data ]or 12 :.antimicrobial agents, are presented. i!
pathogen ( > 1 0 5 cfu/mL) was demonstrated; (2) relapse, if the original infecting pathogen ( > 10 5 cfu/mL) was demonstrated; (3) no infection, if a negative culture or urinary pathogen < 10 5 cfu/mL was demonstrated; and (4) unable to evaluate, when efficacy data were unavailable for any reason, including lack of performance of urine testing at this time because of prior early reinfection. Because of mixed infections and the constant risk for recurrence of UTI in this population, the various bacteriologic outcome categories are not mutually exclusive. Symptomatic infections were evaluated as follows: (1) cure, when all pretreatment signs and symptoms of UTI resolved with treatment; (2) improvement, when there was a decrease in the number and/or severity of signs and symptoms of UTI; and (3) failure, when there was no improvement after a satisfactory course of therapy, or when there was evidence of progression of the infectious process requiring a change of antibiotic regimen. Patients who were asymptomatic were graded as unable to evaluate clinically. Tolerability of the drug with regard to development of adverse experiences coincident with its administration was recorded for each patient on two occasions by telephone during the course of therapy. A minimum of ten full days of treatment with norfloxacin was required to consider a patient evaluable.
i
tract in SCI patients has been described preMously. 4 MICs for norfloxacin were determined by the liquid micro-dilution technique (Micro !:MIC, Analytab Products, Plainview, NY). Bacteriologic outcomes five to seven days after completing treatment were graded as: (1) eradication, if either a negative culture was ;demonstrated or if the colony count of the in:letting organism present in urine was < 10 5 cfu/ rnL; (2) persistence, if the number of pretreatrnent organisms present in urine remained ~10 5 cfu/mL; (3) superinfection, if a new iurinary tract pathogen ( > 1 0 5 cfu/mL) was demonstrated in urine cultures obtained at any point during treatment; and (4) early reinfection, if a new urinary tract pathogen (> 10 5 cfu/ rnL) was isolated within the five to seven days following discontinuation of therapy. Late bacteriologic outcomes were obtained eight to twelve weeks after completion of therapy in pa:tients whose five- to seven-day post-therapy cultures were negative. Late outcomes were g r a d e d as: (1) late reinfection, if a new urinary
UROLOGY
/
DECEMBER 1991
/
Results One hundred fourteen bacterial strains, representing at least twenty species, all susceptible to norfloxacin, were isolated from urine in 79 evaluable eases of UTI prior to norfloxacin therapy. Comparative susceptibilities of these one hundred fourteen strains of bacteria are shown in Figure 1. Of the initial 79 UTIs, 52 (66 % ) were monomierobial and 27 (34 %) were polymicrobial. Cultures collected two to four days into treatment were negative in 58 of 79 (73 % ) eases. Table II shows the number of isolates of each species and the eradication rates for each based on cultures obtained five to seven days after discontinuation of norfloxaein. Escheriehia coli was the most common organism isolated in the initial cultures and was eradicated in all twenty-four UTIs. This was in contrast to eradication rates for Serratia marcescens (50 %), Enteroeoeeus species (57%), Aeinetobacter caleoaeetieus (67 %), Klebsiella pneumoniae (72%), Pseudomonas aeruginosa
VOLUME XXXVIII, NUMBER 6
591
TABLE II. Bacterial species isolated from initial urine cultures and organism eradication rates 5-7 days after completing norfloxacin (N = 114) Isolates Eradicated Organism (No.) (No.) % 24 24 100 Eseherichia coli 18 13 72 Klebsiella pneumoniae 16 12 75 Pseudomonas aeruginosa 11 10 91 Proteus mirabilis 8 4 50 Serratia marcescens Enterocoecus species 7 4 57 4 4 100 Providencia stuartii 4 4 100 Citrobacter freundii 3 3 100 Providencia rettgeri Aeinetobacter calcoaeeticus 3 2 67 Morganella morganii 3 3 100 Citrobacter diversus 2 2 100 2 2 100 Staphylococcus aureus Enterobacter aerogenes 2 2 100 2 2 100 Diphtheroid species 1 1 100 Enterobacter cloacae Xanthomonas maltophila 1 1 100 1 1 100 Streptococcus agalactiae Other Pseudomonas species 1 1 100 Other Staphylococcus species 1 1 100
TABLE III. Bacteriologic outcomes o~ urinary tract infections 5-7 days post-treatment (N = 79) Outcome Infection eradicated Culture positive (> l0 s efu/mL) Early reinfection alone Persistence alone Superinfection alone Combinations of early reinfection, persistence, and/or superinfection
No. of Cases
%
42 37 11 8 6
53 47 14 10 8
12
15
(75 % ), and Proteus mirabilis (91% ) infections, in which persistence was more likely. Bacteriologic outcomes based on urine cultures collected five to seven days after completion of norfloxacin are shown in Table III. Eradication was observed in 42 cases (53 %), while the remaining 37 (47%) had evidence of infection ( > 10 s cfu/mL) in one or more of the categories listed. Among eighty-six bacterial strains encountered either during treatment or within five to seven days after discontinuation of norfloxacin, A. calcoaeetieus was the most common organism isolated, documented in sixteen speci-
592
mens, in contrast to only three isolates of thi6,~ organism noted in the initial one hundred fourteen bacterial isolates obtained prior to treat~ ment with norfloxaein (p
EFFICACY AND TOLERANCE OF NORFLOXACIN IN TREATMENT OF COMPLICATED URINARY TRACT INFECTION IN OUTPATIENTS WITH NEUROGENIC BLADDER SECONDARY TO SPINAL CORD INJURY KEN B. WAITES, M.D. KAY C. CANUPP, M.S. MICHAEL J. DEVIVO, DmRH.
From the Departments of Microbiology, and Rehabilitation Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
ABSTRACT--We studied the efficacy of a fourteen-day course of the fluoroquinolone, norfloxacin, in a group of 69 catheter-free spinal cord iniury (SCI) outpatients who experienced a total of seventy-nine urinary tract infection (UTI) episodes. A total of 114 bacterial strains representing twenty species, including sixteen Pseudomonas aeruginosa, all susceptible to norfloxacin, were isolated from initial urine cultures. Mid-treatment cultures in 58/79 (73 %) cases were negative. Cultures taken five to seven days after completing treatment in 42 cases (53 %) were negative. In the remaining 37 there was persistence of initial or superinfecting pathogen(s), or early reinfection with new organisms. Cultures eight to twelve weeks later in 32 cases with initial eradication showed that 27 (84 %) had either relapsed and/or become reinfected. Clinical cure occurred in 4/6 (67 %) symptomatic episodes. Side effects occurred in 6 of 73 (8%) patients who received norfloxacin, 4 of whom required withdrawal from the study. Twenty of one hundred twenty-two (16 %) bacterial strains isolated during or after treatment were resistant to norfloxacin. Given the limited oral treatment options and the constant risk of reinfection in the SCI population, norfloxacin appears to be a reasonable choice in many patients. However, as with other antimicrobials, when using norfloxacin in SCI patients, the emergence oJ resistant bacteria must be carefully monitored.
:Complicated urinary tract infections (UTIs) in persons with spinal cord injury (SCI) represent !perhaps the most complex and difficult type of i:urologic infection from a management standpoint. Such UTIs differ from infections oecur::ring in many other populations in that they are often asymptomatie, frequently polymierobial, i:eaused by bacteria which are resistant to multii!:ple antibiotics, and are likely to recur or re[!apse. 1,2 The occurrence of serious urologic [iUROLOGY /
DECEMBER 1991
complications following SCI is usually related to ascending or hematogenous spread of uncontrolled infection from a focus in the lower urinary tract to the upper tract, or even to remote organs. 1 The high costs and impracticality of parenteral therapy in nonlife-threatening UTIs encountered in an outpatient setting, coupled with the limited options of broad-spectrum oral antimierobials, particularly for Pseudomonas
/ VOLUME XXXVIII, NUMBER 6
589
',~.erugin-sa infections, and lack of prospective clinical studies in the SCI population make ~:herapeutie decisions difficult. The introdue,:ion of a new class of antimierobials, the fluoroquinolones, represents a significant advance in ~:herapeutic options for complicated UTI. The purpose of the present study was to evaluate the efficacy and tolerability of norfloxaein in the ~treatment of complicated UTIs oeurring in SCI outpatients. Material and Methods The study was conducted between July 1988 and December 1989 in the SCI outpatient clinic at Spain Rehabilitation Center at the University of Alabama at Birmingham. Outpatients who were found to have UTI while undergoing their annual urologic examination or who sought medical care because of acute symptomatic UTI were eligible for enrollment in this openlabel prospective study. The study was approved by the Institutional Review Board and a signed informed consent was obtained from all participants. Patients with a history of allergy, hypersensitivity or other adverse reaction to quinolones, clinical signs suggestive of baeteremia and/or urosepsis, prior antibiotic therapy within the previous s e v e n t y - t w o hours, d o c u m e n t e d urinary calculi, severe c o n c u r r e n t illness, seizure disorders, and/or mental incapacitation were excluded. Urinary pregnancy tests were performed in women of childbearing potential to exclude the possibility of the enrollment of patients who were pregnant. A total of '78 patients were enrolled in the study initially. Ten patients were enrolled twice during the study period because of recurrent UTI, giving a total of 88 infectious episodes. Nine patients were unevaluable because of either lack of compliance with the study protocol resulting in inadequate laboratory data (5 patients), or minor adverse experiences requiring withdrawal of the patient from the study (4 patients). Thus, there were 79 evaluable infectious episodes in 69 patients. Characteristics of the patient population are shown in Table I. On the initial clinic visit a complete medical history was elicited and physical examination performed. Urine was collected either by deancatch midstream specimen (54 patients) or sterile catheterization (15 patients), depending on whether the patient used a condom catheter or Cred6 maneuver for bladder management, 590
TABLE I.
Patient demographic characteristic~ (N = 69) .... No. of
Variable Male Female White Black Paraplegic Quadriplegie Complete neurologic lesion Incomplete neurologie lesion Injured < 6 months Injured >6 months Bladder management: Condom catheter Intermittent catheterization Cred6 maneuver Age range (yrs.) Av. and median age (yrs.)
Pts. 66 3 43 26 44 25 58 11 5 64 53 15 1 18-69 37
or was undergoing intermittei UTI was defined as the pres~ mL of bacteria in addition urinary leukocytes per high scopic field [ x 400]). On demonstration of UTI susceptible to norfloxacin, p taeted regarding partieipatiol informed consent was obtain plete blood counts and serur also obtained during the ini patients with a creatinine el~ min were given norfloxacin West Point, PA) 400 mg twic for fourteen days after initial firmation of UTI. Urine cull bility testing was performed after initiating treatment a seven days after completing t~ ing long-term follow-up sp twelve weeks later was atte whose post-treatment cultur, Mid-treatment and follow-t were performed using the ag~ plex Scientific, Mississauga, ( Urine was collected by the p~ oculated onto the Dip Slide University of Alabama Hospit biology Laboratory, where counts, organism identifieati bility testing were perforn standard methods. 3 Use of assess the bacteriologic statu_
UROLOGY
/
DECEMBER 1991
/
VOLUME XXXVIII,
iiL
Total Isolates (n-114)
Drug Amikacin
Ampicillin Ciprofloxacin Gentamicin Mezlocillin Nitrofurantoin Nor floxacin Piperacillin Tetracycline ~rimethoprim/Sulfa
Cephalothin Chloramphenicol 0
20
40
60
80
100
% Susceptible
FIGURE1. Comparative susceptibility rates o] bacteria isolated ]rom urine prior to treatment in patients whose initial isolates were shown to be susceptible to norfloxacin. Susceptibility data ]or 12 :.antimicrobial agents, are presented. i!
pathogen ( > 1 0 5 cfu/mL) was demonstrated; (2) relapse, if the original infecting pathogen ( > 10 5 cfu/mL) was demonstrated; (3) no infection, if a negative culture or urinary pathogen < 10 5 cfu/mL was demonstrated; and (4) unable to evaluate, when efficacy data were unavailable for any reason, including lack of performance of urine testing at this time because of prior early reinfection. Because of mixed infections and the constant risk for recurrence of UTI in this population, the various bacteriologic outcome categories are not mutually exclusive. Symptomatic infections were evaluated as follows: (1) cure, when all pretreatment signs and symptoms of UTI resolved with treatment; (2) improvement, when there was a decrease in the number and/or severity of signs and symptoms of UTI; and (3) failure, when there was no improvement after a satisfactory course of therapy, or when there was evidence of progression of the infectious process requiring a change of antibiotic regimen. Patients who were asymptomatic were graded as unable to evaluate clinically. Tolerability of the drug with regard to development of adverse experiences coincident with its administration was recorded for each patient on two occasions by telephone during the course of therapy. A minimum of ten full days of treatment with norfloxacin was required to consider a patient evaluable.
i
tract in SCI patients has been described preMously. 4 MICs for norfloxacin were determined by the liquid micro-dilution technique (Micro !:MIC, Analytab Products, Plainview, NY). Bacteriologic outcomes five to seven days after completing treatment were graded as: (1) eradication, if either a negative culture was ;demonstrated or if the colony count of the in:letting organism present in urine was < 10 5 cfu/ rnL; (2) persistence, if the number of pretreatrnent organisms present in urine remained ~10 5 cfu/mL; (3) superinfection, if a new iurinary tract pathogen ( > 1 0 5 cfu/mL) was demonstrated in urine cultures obtained at any point during treatment; and (4) early reinfection, if a new urinary tract pathogen (> 10 5 cfu/ rnL) was isolated within the five to seven days following discontinuation of therapy. Late bacteriologic outcomes were obtained eight to twelve weeks after completion of therapy in pa:tients whose five- to seven-day post-therapy cultures were negative. Late outcomes were g r a d e d as: (1) late reinfection, if a new urinary
UROLOGY
/
DECEMBER 1991
/
Results One hundred fourteen bacterial strains, representing at least twenty species, all susceptible to norfloxacin, were isolated from urine in 79 evaluable eases of UTI prior to norfloxacin therapy. Comparative susceptibilities of these one hundred fourteen strains of bacteria are shown in Figure 1. Of the initial 79 UTIs, 52 (66 % ) were monomierobial and 27 (34 %) were polymicrobial. Cultures collected two to four days into treatment were negative in 58 of 79 (73 % ) eases. Table II shows the number of isolates of each species and the eradication rates for each based on cultures obtained five to seven days after discontinuation of norfloxaein. Escheriehia coli was the most common organism isolated in the initial cultures and was eradicated in all twenty-four UTIs. This was in contrast to eradication rates for Serratia marcescens (50 %), Enteroeoeeus species (57%), Aeinetobacter caleoaeetieus (67 %), Klebsiella pneumoniae (72%), Pseudomonas aeruginosa
VOLUME XXXVIII, NUMBER 6
591
TABLE II. Bacterial species isolated from initial urine cultures and organism eradication rates 5-7 days after completing norfloxacin (N = 114) Isolates Eradicated Organism (No.) (No.) % 24 24 100 Eseherichia coli 18 13 72 Klebsiella pneumoniae 16 12 75 Pseudomonas aeruginosa 11 10 91 Proteus mirabilis 8 4 50 Serratia marcescens Enterocoecus species 7 4 57 4 4 100 Providencia stuartii 4 4 100 Citrobacter freundii 3 3 100 Providencia rettgeri Aeinetobacter calcoaeeticus 3 2 67 Morganella morganii 3 3 100 Citrobacter diversus 2 2 100 2 2 100 Staphylococcus aureus Enterobacter aerogenes 2 2 100 2 2 100 Diphtheroid species 1 1 100 Enterobacter cloacae Xanthomonas maltophila 1 1 100 1 1 100 Streptococcus agalactiae Other Pseudomonas species 1 1 100 Other Staphylococcus species 1 1 100
TABLE III. Bacteriologic outcomes o~ urinary tract infections 5-7 days post-treatment (N = 79) Outcome Infection eradicated Culture positive (> l0 s efu/mL) Early reinfection alone Persistence alone Superinfection alone Combinations of early reinfection, persistence, and/or superinfection
No. of Cases
%
42 37 11 8 6
53 47 14 10 8
12
15
(75 % ), and Proteus mirabilis (91% ) infections, in which persistence was more likely. Bacteriologic outcomes based on urine cultures collected five to seven days after completion of norfloxacin are shown in Table III. Eradication was observed in 42 cases (53 %), while the remaining 37 (47%) had evidence of infection ( > 10 s cfu/mL) in one or more of the categories listed. Among eighty-six bacterial strains encountered either during treatment or within five to seven days after discontinuation of norfloxacin, A. calcoaeetieus was the most common organism isolated, documented in sixteen speci-
592
mens, in contrast to only three isolates of thi6,~ organism noted in the initial one hundred fourteen bacterial isolates obtained prior to treat~ ment with norfloxaein (p
