1607979
EurUrol 1990;17(suppl l):34-39
©1990 S. Karger AG, Base! 0302-2838/90/0175-0034S2.75/0
Norfloxacin versus Trimethoprim-Sulfamethoxazole in the Treatment of Urinary Tract Infections Michael L. Corrado, Michael Hesney, William E. Strahle, Kenneth R. Brown, Robert H.K. Eng, Ralph Landes, Lloyd Harrison, John Ryan, O. Thomas Bolding Medical Affairs Division, Merck Sharp & Dohme Research Laboratories, West Point, Pa., USA; Division of Infectious Diseases, East Orange VA Medical Center, East Orange, N.J., USA; Danville Urologie Clinic, Danville, Va., USA; Department of Urology, Bowman Gray School of Medicine, Winston-Salem, N.C., USA; Division of Infectious Diseases, West Haven VA Medical Center, West Haven, Conn., USA; Department of Obstetrics and Gynecology, Brookwood Medical Center, Birmingham, Ala., USA
Key Words. Norfloxacin • Urinary tract infection, therapy • Urinary tract infection, antibacterial resistance Abstract. In a controlled, randomized trial of 133 patients with proven urinary tract infections (UTIs), signifi cantly more pathogens were found to be susceptible to norfloxacin than to trimethoprim-sulfamethoxazole (TMPSMZ) (p < 0.01). Among patients with pathogens susceptible to both drugs, more of those treated with norfloxacin were cured or improved (p = 0.06). When at least one patient variable, i.e., prior history of therapy, was corrected for, this difference became significant (p = 0.03). Norfloxacin eradicated 11 of 13 infections due to Pseudomonas aeru ginosa and 6 of 7 due to enterococci. Five patients treated with norfloxacin and two treated with TMP-SMZ had relapses within 6 weeks. Significantly fewer adverse experiences occurred in patients receiving norfloxacin (p < 0.01).
Norfloxacin is a new, oral, broad-spectrum, fluoro quinolone antimicrobial agent which attains high uri nary levels and is active against most uropathogens, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp, enterococci and staphylococci [1-3], A multicenter study comparing the efficacy and tolerability of norfloxacin to trimethoprim-sulfamethoxazole (TMPSMZ) was undertaken at five centers in the eastern United States. The results of that study are described in this report.
Materials and Methods Patients with urinary tract infections (UTIs) were enrolled at five centers: Brookwood Medical Center, Birmingham, Ala.; East Orange VA Medical Center, East Orange, N.J.; Bowman Gray School of Medicine, Winston-Salem, N.C.; Danville Urology Clinic, Danville, Va.; and Yale University School of Medicine, New Haven, Conn.
Men and nonpregnant women 18 years of age or older who pre sented with signs or symptoms of UTI were eligible for entry. Patients were randomized equally to either norfloxacin or TMPSMZ, except at the Danville Urologie Clinic and Brookwood Medi cal Center, where twice as many patients were treated with norflox acin. Patients signed informed consents prior to therapy, and pro vided urine cultures within 48 h of study entry. During therapy (study days 2-4), after therapy (study days 5-9) and again 4-6 weeks later, urine cultures, urinalyses, CBC and SMA (12) were per formed. The severity of the infections were classified by the investigators as mild, moderate or severe, depending on the number and intensity of complaints, urinalysis results for pyuria and hematuria and the underlying condition of the patients. Prior therapy within the pre vious 12 months and urologie procedures such as catheterization or cystoscopy conducted within 48 h of study initiation were also noted. Patients who had anatomical urologie (e.g. nephrolithiasis, be nign prostatic hypertrophy) or functional (e.g. neurogenic bladder) conditions which might either decrease the likelihood of success of antibacterial therapy alone or require more than 10 days of therapy for an optimal outcome were considered to have complicated UTIs. Patients whose pretherapy cultures grew less than 105 colony-form ing units (cfu)/ml and patients whose initial pathogens were resis-
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Introduction
Norfloxacin versus Trimethoprim-Sulfamethoxazole in UTIs
tant to the drug to which they were randomized were not considered to be evaluable and were dropped from the study. Microbiologie eradication was defined as the elimination of all organisms that were present at 105 cfu/ml pretherapy from subsequent cultures during and after therapy. An organism was considered to persist if it was still present at 104 cfu/ml in the cultures done either during therapy or at 5-9 days posttherapy. Cases were classified as clinical cures if all pretherapy signs and symptoms disappeared by the posttherapy visit, and as improved if a clear amelioration of signs and symptoms occurred. However, if microbiologie persistence occurred, the case was considered a clinical as well as a microbiologie failure, whether or not there was clinical improvement. Patients who returned for late follow-up visits (4-6 weeks post therapy) were monitored for relapses. Organisms were not serotyped, but cases in which the same species were isolated with similar antibiograms were considered relapses. Statistical Methods The X2 test or Fisher’s exact test was used to determine the fol lowing: whether the treatment groups were comparable with respect
35
to important characteristics; whether patient characteristics were related to the percentage of patients cured or improved; to compare the proportion of clinical and laboratory adverse experiences in each treatment group; to test for differences between treatment groups in the proportion of untoward effects in each treatment group; to compare the clinical outcomes in each treatment group, and to compare the distribution of patients by reason for nonevaluability. The rank sum test for ordered contingency tables was used in the analysis of the distribution of patients by treatment and category of laboratory outcome to compare the distribution of patients by dura tion of therapy. A Mantel-Haenszel test was used to determine whether the distribution of patients by treatment and category of response was consistent among investigators and to determine whether the distribution of patients by treatment and category of response was consistent among the levels of relevant stratification variables, such as prior therapy. McNemar’s test was used to analyze the proportion of pathogens susceptible to each drug. All tests were two-tailed and were done at the 5 % level of significance.
Table 1. Demographics of patients with UTIs treated with norfloxacin or TMP-SMZ Characteristics
All patients
Evaluable patients
NOR (n = 124)
TMP-SMZ (n = 86)
NOR (n = 79)
TMP-SMZ (n = 54)
Mean age, years All Males Females
49.6 59.8 45.0
44.8 59.2 37.5
52.5 58.1 49.4
46.6 60.9 37.5
Sex, % Males Females
31.5 68.5
33.7 66.3
35.4 64.6
38.9 61.1
UTI designation, % Complicated Uncomplicated
40.7a 59.3
23.9 76.1
46.9a 53.1
27.8 72.2
Severity, % Mild Moderate Severe
17.1 50.4 32.5a
23.5 56.5 20.0
16.5 55.7 27.9
24.1 59.3 16.7
66.1
Type of infection, % Monomicrobic Polymicrobic No organisms
12.9a 21.0
75.6 3.5 20.9
79.7 20.3a 0.0
94.4 5.6
Prior therapy, %
54.8b
41.9
60.8a
40.7
Prior procedures, %
34.7
25.6
36.7
24.1
Concomitant procedures, %
43.5C
30.2
46.8a
25.9
Mean duration of therapy, days
11.7
10.4
12.8
12.4
0.0
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NOR = Norfloxacin. a p < 0.05, significantly greater than TMP-SMZ; b p = 0.06, higher than TMP-SMZ;c p = 0.051, higher than TMP-SMZ.
36
Corrado/Hesney/Struble/Brown/Eng/Landes/Harrison/Ryan/Bolding
Table 2. In vitro susceptibility of étiologie pathogens Number of strains
Type
Susceptible to NOR only
Resistant to both TMP-SMZ only both
Gram-positive rods Gram-positive aerobic cocci Gram-negative aerobic rods
2
0
27 158
11
0
24
Totals
187
35
0
1 13 132
0 3 2
1
146
5
NOR = Norfloxacin.
Results
Pathogen Pseudomonas aeruginosa Group D streptococci Escherichia coli Klebsiella pneumoniae Staphylococcus epidermidis Proteus vulgaris Providencia rettgeri Citrobacter spp Serratia spp
Number 16 10 2
2 1 1 1 1 1
Table 4. Effect of patient characteristics on microbiologie out come Characteristic
Microbiologie eradication, % norfloxacin
TMP-SMZ
Intensity of infection Mild or moderate Severe
95
85 67
Concomitant urologie procedure Yes No
91 90
79 83
Type of infection Monomicrobic Polymicrobic
93 79
83 67
UTI designation Complicated Uncomplicated
85 95
83 82
84 100
71 90
Prior therapy Yes No
One hundred twenty-four patients were randomized to norfloxacin and 86 to TMP-SMZ. Of these patients, 79 were considered evaluable for efficacy in the norfloxacin group and 54 in the TMP-SMZ group. All patients were evaluable for safety. Table 1 shows the patient character istics of all patients and of those who were evaluable. Significantly more patients randomized to norflox acin had complicated, severe or polymicrobic UTIs, as well as histories of prior therapy and concomitant uro logie procedures. No differences were noted with respect to age, sex, percentage of patients with prior procedures or duration of study therapy. The distribution of susceptible gram-positive and gram-negative pathogens to norfloxacin and TMP-SMZ appears in table 2. While 79% (147 of 187) of pathogens were susceptible to TMP-SMZ, a significantly greater number of organisms - 97% (181 of 187) - were suscep tible to norfloxacin (p < 0.01). A single Corynebacterium organism was TMP-SMZ-susceptible and norflox acin-resistant, while 35 organisms were susceptible to norfloxacin and resistant to TMP-SMZ. A greater diversity of organisms was found in the nor floxacin arm. Of 93 pathogens treated with norfloxacin, 85 (91 %) were eradicated and 8 persisted; 2 of the latter (a P. aeruginosa and a Corynebacterium) acquired resis tance during therapy. Among the 55 pathogens treated with TMP-SMZ, 46 (84%) were eradicated and 9 per sisted, with 3 of the latter (two enterococci and one E. coli) acquiring resistance. Table 3 lists the organisms that were susceptible to norfloxacin but resistant to TMP-SMZ. The effects of patient characteristics on clinical re sponses appear in table 4. Rates of cure or improvement were lower in patients with polymicrobic infections and
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Table 3. Pathogens resistant to TMP-SMZ
37
Norfloxacin versus Trimethoprim-Sulfamethoxazole in UTIs
Table 5. Effect of prior therapy on clinical response of evaluable patients with pathogens susceptible to both drugs Prior Treatment therapy Yes
No
All
Cured
Im proved
Not Cured or improved improved, %
2
3 6 9
89 71
0 3 3
100 90 94
norfloxacin TMP-SMZ all
22 15 37
norfloxacin TMP-SMZ all
25 25 50
0 1
norfloxacin TMP-SMZ
47 40
2
0 2
1
94b 82
3 9
1
a Significantly lower than for all patients with no prior therapy (81 vs. 94%, p = 0.04). b Significantly higher than TMP-SMZ treatment group (p = 0.03) without adjustment for prior therapy (p = 0.06).
Table 6. Clinical responses of evaluable patients regardless of patient characteristics or susceptibility of pathogen Drug
Norfloxacin TMP-SMZ a
Number Cured of patients
Im proved
73 50
3
63 40
Cured or Not improved improved %
1
7 9
90a 82
No significant difference (p = 0.17).
Table 7. Frequencies of adverse clinical and laboratory experi ences Category
Norfloxacin TMP-SMZ
Adverse clinical experiences only 1 (0.8a) Adverse laboratory experience only 0b Adverse clinical and laboratory experiences 1 (0.8) Total patients with at least one adverse 2 (1.6a) experience Therapy discontinued because of adverse 1 (0.8)b experiences Total patients without adverse experiences 122 (98.0) 124 Total patients
a b
8 (9.3) 4 (4.7) 1 (1.2)
13 (15.1) 5 (6.0) 73 (84.0) 86
Figures in parentheses indicate percentage. p < 0.01, significantly lower than TMP-SMZ. p < 0.05, significantly lower than TMP-SMZ. Downloaded by: University of Exeter 144.173.6.94 - 6/6/2020 10:50:07 AM
in patients with histories of prior UTI therapy, regard less of the therapy received. Patients designated as hav ing severe infections and treated with TMP-SMZ had lower rates of cure and improvement, as well; however, this was not the case with norfloxacin. As shown in table 3, a substantial number of patients receiving norfloxacin presented with organisms resistant to TMP-SMZ. This unequal distribution of pathogens created a potential bias in comparing norfloxacin and TMP-SMZ. Table 5 corrects for this dissimilarity by analyzing only pathogens susceptible to both drugs. Another characteristic that could have introduced bias was a history of prior therapy. As indicated in table 5, patients with prior therapy had significantly lower response rates than those without prior therapy. The fact that there were significantly more norfloxacintreated patients with this characteristic created a poten tial bias which could have confounded a comparison of efficacy between the two study drugs. When corrected for spectrum alone, the cured and improved rates for norfloxacin over TMP-SMZ ap proached significance (p = 0.06). However, when prior therapy was corrected for, as well, this difference became significant (p = 0.03). When neither spectrum nor prior therapy are taken into account, 90% of norfloxacintreated patients and 82% of TMP-SMZ-treated patients had their organisms eradicated. These rates were not sta tistically different (table 6). Among evaluable patients, 90% of those treated with norfloxacin and 85% with TMP-SMZ were symptomfree by day 3 of therapy. These results were not signifi cantly different. Five patients (7%) treated with norflox acin and 2 TMP-SMZ-treated patients (5%) relapsed with the same pathogen within 6 weeks of the cessation of therapy. Among patients who were considered nonevaluable, the majority of whom did not have a microbiologically documented infection, no significant differences were noted between treatment groups with respect to clinical outcome. Safety profiles were analyzed by both clinical and lab oratory parameters in 124 patients receiving norfloxacin and 86 receiving TMP-SMZ. No adverse experiences occurred in 122 of 124 norfloxacin-treated patients, compared with 73 of 86 TMP-SMZ patients (table 7). Significantly more TMP-SMZ cases had adverse clinical experiences (p < 0.01) and adverse laboratory experi ences (p < 0.05) than did patients receiving norfloxacin. In addition, therapy was discontinued because of ad verse experiences by significantly more TMP-SMZ-
38
Corrado/Hesney/Struble/Brown/Eng/Landes/Harrison/Ryan/Bolding
treated patients than by norfloxacin patients (6 vs. 1 %, p < 0.01). Table 8 lists the specific adverse experiences associ ated with each drug, and indicates which ones were con sidered probably or definitely drug-related by the inves tigators. Significantly fewer patients in the norfloxacin group had adverse experiences that were considered related to therapy than did those in the TMP-SMZ group (none of 124 vs. 7 of 86). Table 8. Types, distributions and drug relationships of adverse experiences Adverse experience
Norfloxacin TMP-SMZ
Rash (macular) Urticaria Diarrhea Nausea Insomnia Depression Nervousness Dizziness with disorientation Leukopenia AST, ALT LDH Eosinophilia
0
3a
0 0 1 0 0 0 1 1 0 0 0
2“ 1
la
1 la 1 0 2
1 1 1
a All were felt by the investigator to be either definitely or probably drug-related. Some patients had more than one adverse experience.
One patient receiving TMP-SMZ had two adverse experiences, namely depression and insomnia, that were considered to be related to TMP-SMZ therapy. Three cases of leukopenia, 1 on norfloxacin and 2 on TMP-SMZ, occurred. None had WBC counts below 2,000/mm3.
Discussion
The fluoroquinolones are bactericidal, have a novel site of action specific for bacteria (i.e. inhibition of bac terial DNA-gyrase) and do not appear to be susceptible to plasmid-mediated resistance [3, 4], While it is impos sible to predict the degree to which resistance to the fluoroquinolones will develop in the future, at the present time norfloxacin affords physicians the ability to treat, on an outpatient basis, UTIs caused by organisms that are resistant to many other drugs. This is supported by the observation that 21% of pathogens encountered in this trial were resistant to TMP-SMZ, while only 3% were norfloxacin-resistant. Almost all TMP-SMZ-resistant isolates belonged to three groups of organisms: P. aeruginosa, enterococci and Enterobacteriaceae. Many recurrent UTIs are due to organisms other than E. coli. A review of all cases of recurrent (3 or more/year) uncomplicated cystitis in women who were treated in norfloxacin trials from 1982 to 1986 revealed that 190 women had 216 étiologie pathogens, of which 34% were
Table 9. Susceptibilities of UTI pathogens Numbers susceptible/numbers tested norfloxacin
TMP-SMZ
ampicillin
Escherichia coli Klebsiella pneumoniae Proteus mirabilis Enterococci Staphylococcus epiderm idis Staphylococcus saprophyticus Citrobacter freundii Pseudomonas aeruginosa Enterobacter aerogenes Enterobacter cloacae Providencia rettgeri Klebsiella oxytoca Miscellaneous gram-negative rods Staphylococcus aureus Providencia stuardi
141/143 17/20 17/17 6/6 5/5 4/4 4/4 4/4 3/3
119/143 13/20
79/141 3/20 11/17 6/6 2/5 3/4 2/4 0/4 3/3
Totals
211/216 (97.7%)
2/2 2/2 2/2 2/2 1/1 1/1
14/17
3/6 1/5 4/4 3/4 1/4 3/3 1/2
0/2 0/2 1/2 1/1 0/1
164/216 (75.9%)
0/2 1/2
0/2 2/2 1/1 0/1
113/214 (52.8%) Downloaded by: University of Exeter 144.173.6.94 - 6/6/2020 10:50:07 AM
Organism
Norfloxacin versus Trimethoprim-Sulfamethoxazole in UTIs
ment of a broad array of UTIs. In fact, in two recent studies [7, 8], in which oral norfloxacin was compared to broad-spectrum parenteral antibiotics, including the aminoglycosides, the cure rate of nosocomial UTIs by norfloxacin was equivalent to that by the parenteral antibiotics. Tolerability is as important as efficacy. The data from this study are in general agreement with those of another trial [5], in which norfloxacin was associated with signif icantly fewer adverse experiences requiring discontinua tion of therapy than TMP-SMZ. In the present study, TMP-SMZ therapy caused a higher incidence of adverse experiences, the most common of which were rashes and elevated liver function tests. This series underscores the important variables which may affect the successful treatment of UTIs, and con firms the findings of other studies regarding the high degrees of efficacy and tolerability of norfloxacin in a broad range of patients. References
1
2
3
4
5
6
7
8
Khan MY, Gruninger RP, Nelson SM, et al: Comparative in vitro activity of norfloxacin (M 0366) and ten other antimicro bial agents against urinary bacterial isolates. Antimicrob Agents Chemother 1982;5:848-851. Corigliano BE, Appleman MD, Heseltine PNR, et al: Compara tive in vitro activities of norfloxacin (MK 0366) and six com monly used antimicrobial agents against 199 urinary isolates showing various degrees of antibiotic resistance. Diagn Micro biol Infect Dis 1984;2:101-106. Corrado ML, Chérubin CE, Shulman M: The comparative activ ity of norfloxacin with other antimicrobial agents against gram positive and gram-negative bacteria. J Antimicrob Chemother 1983;11:369-376. Burman LG: Apparent absence of transferable resistance to nal idixic acid in pathogenic gram negative bacteria. J Antimicrob Chemother 1977;3:509-516. Sabbaj J, Hoagland VL, Shih WJ: Multiclinic comparative study of norfloxacin and trimethoprim-sulfamethoxazole for the treat ment of urinary tract infections. Antimicrob Agents Chemother 1985;27:297-301. Sabbaj J, Hoagland VL, Cook T: Norfloxacin versus co-trimoxazole in the treatment of recurring urinary tract infections in men. Scand J Infect Disease 1986 (suppl 48):48-53. Chérubin C, Stilwell S: Norfloxacin versus parenteral therapy in the treatment of complicated urinary tract infections and resis tant organisms. Scand J Infect Dis 1986 (suppl 48):32-37. Cox CE, McCabe RE, Grad LC: Oral norfloxacin vs. parenteral therapy for nosocomial urinary tract infections. Am J Med 1987; 82(suppl 6B):59-64. Dr. Kenneth R. Brown Merck Sharp & Dohme Research Laboratories Blue Bell, PA 19422 (USA)
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organisms other than E. coli. During the preceding 12 months, these women had had recurrent therapies con sisting of two to nine courses of antibiotics, which might have influenced the distribution of pathogens. This study demonstrates how the type of patient treated has a bearing on the outcome of therapy. Patients who had multiple courses of antibacterial therapy for UTIs over a 12-month period had lower eradication rates than patients with no prior therapy (table 5). It is tempting to attribute this finding to the selection of resistant pathogens following the previous courses of therapy, as the review of 216 isolates suggests. Ninetyeight percent of those pathogens were identified as nor floxacin-susceptible, compared with 76% for TMP-SMZ and 53% for ampicillin (table 9). However, this hypoth esis cannot fully explain the results of the present study, in which patients were disqualified from evaluation of efficacy if the pathogens isolated were resistant to the study drug to which they had been randomized. It is pos sible that, while within the susceptible range, pathogens from such patients may have been relatively more resis tant than pathogens from patients with their first UTI. Another explanation for the disparate outcomes of patients with and without prior therapy lies in the patients themselves. All but one of the investigators involved in this multicenter trial were either urologists or infectious disease specialists. Therefore, it is not surprising that many of their patients had polymicrobic, complicated or recurrent UTIs. Perhaps patients with therapeutic failures or mul tiple relapses or reinfections are more likely to fail future courses of therapy, as well. However, despite the impact of prior therapy on out come, patients with histories of prior therapy who were randomized to norfloxacin did as well as patients with out histories of prior therapy who were treated with TMP-SMZ. This finding is consistent with those of two previous trials [5, 6], which reported significantly higher cure rates for norfloxacin than for TMP-SMZ. Even after cor recting for the distribution of both pathogen type and patients with histories of prior therapy, this study dem onstrates a significantly higher pathogen eradication rate among patients treated with norfloxacin than among those treated with TMP-SMZ. The fact that 11 of 13 P. aeruginosa cases and six of seven enterococcal infections treated with norfloxacin during this trial were eradicated, but were excluded from this analysis because of their resistance to TMP-SMZ, further supports the utility of norfloxacin in the treat
39
EurUrol 1990;17(suppl l):34-39
©1990 S. Karger AG, Base! 0302-2838/90/0175-0034S2.75/0
Norfloxacin versus Trimethoprim-Sulfamethoxazole in the Treatment of Urinary Tract Infections Michael L. Corrado, Michael Hesney, William E. Strahle, Kenneth R. Brown, Robert H.K. Eng, Ralph Landes, Lloyd Harrison, John Ryan, O. Thomas Bolding Medical Affairs Division, Merck Sharp & Dohme Research Laboratories, West Point, Pa., USA; Division of Infectious Diseases, East Orange VA Medical Center, East Orange, N.J., USA; Danville Urologie Clinic, Danville, Va., USA; Department of Urology, Bowman Gray School of Medicine, Winston-Salem, N.C., USA; Division of Infectious Diseases, West Haven VA Medical Center, West Haven, Conn., USA; Department of Obstetrics and Gynecology, Brookwood Medical Center, Birmingham, Ala., USA
Key Words. Norfloxacin • Urinary tract infection, therapy • Urinary tract infection, antibacterial resistance Abstract. In a controlled, randomized trial of 133 patients with proven urinary tract infections (UTIs), signifi cantly more pathogens were found to be susceptible to norfloxacin than to trimethoprim-sulfamethoxazole (TMPSMZ) (p < 0.01). Among patients with pathogens susceptible to both drugs, more of those treated with norfloxacin were cured or improved (p = 0.06). When at least one patient variable, i.e., prior history of therapy, was corrected for, this difference became significant (p = 0.03). Norfloxacin eradicated 11 of 13 infections due to Pseudomonas aeru ginosa and 6 of 7 due to enterococci. Five patients treated with norfloxacin and two treated with TMP-SMZ had relapses within 6 weeks. Significantly fewer adverse experiences occurred in patients receiving norfloxacin (p < 0.01).
Norfloxacin is a new, oral, broad-spectrum, fluoro quinolone antimicrobial agent which attains high uri nary levels and is active against most uropathogens, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp, enterococci and staphylococci [1-3], A multicenter study comparing the efficacy and tolerability of norfloxacin to trimethoprim-sulfamethoxazole (TMPSMZ) was undertaken at five centers in the eastern United States. The results of that study are described in this report.
Materials and Methods Patients with urinary tract infections (UTIs) were enrolled at five centers: Brookwood Medical Center, Birmingham, Ala.; East Orange VA Medical Center, East Orange, N.J.; Bowman Gray School of Medicine, Winston-Salem, N.C.; Danville Urology Clinic, Danville, Va.; and Yale University School of Medicine, New Haven, Conn.
Men and nonpregnant women 18 years of age or older who pre sented with signs or symptoms of UTI were eligible for entry. Patients were randomized equally to either norfloxacin or TMPSMZ, except at the Danville Urologie Clinic and Brookwood Medi cal Center, where twice as many patients were treated with norflox acin. Patients signed informed consents prior to therapy, and pro vided urine cultures within 48 h of study entry. During therapy (study days 2-4), after therapy (study days 5-9) and again 4-6 weeks later, urine cultures, urinalyses, CBC and SMA (12) were per formed. The severity of the infections were classified by the investigators as mild, moderate or severe, depending on the number and intensity of complaints, urinalysis results for pyuria and hematuria and the underlying condition of the patients. Prior therapy within the pre vious 12 months and urologie procedures such as catheterization or cystoscopy conducted within 48 h of study initiation were also noted. Patients who had anatomical urologie (e.g. nephrolithiasis, be nign prostatic hypertrophy) or functional (e.g. neurogenic bladder) conditions which might either decrease the likelihood of success of antibacterial therapy alone or require more than 10 days of therapy for an optimal outcome were considered to have complicated UTIs. Patients whose pretherapy cultures grew less than 105 colony-form ing units (cfu)/ml and patients whose initial pathogens were resis-
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Introduction
Norfloxacin versus Trimethoprim-Sulfamethoxazole in UTIs
tant to the drug to which they were randomized were not considered to be evaluable and were dropped from the study. Microbiologie eradication was defined as the elimination of all organisms that were present at 105 cfu/ml pretherapy from subsequent cultures during and after therapy. An organism was considered to persist if it was still present at 104 cfu/ml in the cultures done either during therapy or at 5-9 days posttherapy. Cases were classified as clinical cures if all pretherapy signs and symptoms disappeared by the posttherapy visit, and as improved if a clear amelioration of signs and symptoms occurred. However, if microbiologie persistence occurred, the case was considered a clinical as well as a microbiologie failure, whether or not there was clinical improvement. Patients who returned for late follow-up visits (4-6 weeks post therapy) were monitored for relapses. Organisms were not serotyped, but cases in which the same species were isolated with similar antibiograms were considered relapses. Statistical Methods The X2 test or Fisher’s exact test was used to determine the fol lowing: whether the treatment groups were comparable with respect
35
to important characteristics; whether patient characteristics were related to the percentage of patients cured or improved; to compare the proportion of clinical and laboratory adverse experiences in each treatment group; to test for differences between treatment groups in the proportion of untoward effects in each treatment group; to compare the clinical outcomes in each treatment group, and to compare the distribution of patients by reason for nonevaluability. The rank sum test for ordered contingency tables was used in the analysis of the distribution of patients by treatment and category of laboratory outcome to compare the distribution of patients by dura tion of therapy. A Mantel-Haenszel test was used to determine whether the distribution of patients by treatment and category of response was consistent among investigators and to determine whether the distribution of patients by treatment and category of response was consistent among the levels of relevant stratification variables, such as prior therapy. McNemar’s test was used to analyze the proportion of pathogens susceptible to each drug. All tests were two-tailed and were done at the 5 % level of significance.
Table 1. Demographics of patients with UTIs treated with norfloxacin or TMP-SMZ Characteristics
All patients
Evaluable patients
NOR (n = 124)
TMP-SMZ (n = 86)
NOR (n = 79)
TMP-SMZ (n = 54)
Mean age, years All Males Females
49.6 59.8 45.0
44.8 59.2 37.5
52.5 58.1 49.4
46.6 60.9 37.5
Sex, % Males Females
31.5 68.5
33.7 66.3
35.4 64.6
38.9 61.1
UTI designation, % Complicated Uncomplicated
40.7a 59.3
23.9 76.1
46.9a 53.1
27.8 72.2
Severity, % Mild Moderate Severe
17.1 50.4 32.5a
23.5 56.5 20.0
16.5 55.7 27.9
24.1 59.3 16.7
66.1
Type of infection, % Monomicrobic Polymicrobic No organisms
12.9a 21.0
75.6 3.5 20.9
79.7 20.3a 0.0
94.4 5.6
Prior therapy, %
54.8b
41.9
60.8a
40.7
Prior procedures, %
34.7
25.6
36.7
24.1
Concomitant procedures, %
43.5C
30.2
46.8a
25.9
Mean duration of therapy, days
11.7
10.4
12.8
12.4
0.0
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NOR = Norfloxacin. a p < 0.05, significantly greater than TMP-SMZ; b p = 0.06, higher than TMP-SMZ;c p = 0.051, higher than TMP-SMZ.
36
Corrado/Hesney/Struble/Brown/Eng/Landes/Harrison/Ryan/Bolding
Table 2. In vitro susceptibility of étiologie pathogens Number of strains
Type
Susceptible to NOR only
Resistant to both TMP-SMZ only both
Gram-positive rods Gram-positive aerobic cocci Gram-negative aerobic rods
2
0
27 158
11
0
24
Totals
187
35
0
1 13 132
0 3 2
1
146
5
NOR = Norfloxacin.
Results
Pathogen Pseudomonas aeruginosa Group D streptococci Escherichia coli Klebsiella pneumoniae Staphylococcus epidermidis Proteus vulgaris Providencia rettgeri Citrobacter spp Serratia spp
Number 16 10 2
2 1 1 1 1 1
Table 4. Effect of patient characteristics on microbiologie out come Characteristic
Microbiologie eradication, % norfloxacin
TMP-SMZ
Intensity of infection Mild or moderate Severe
95
85 67
Concomitant urologie procedure Yes No
91 90
79 83
Type of infection Monomicrobic Polymicrobic
93 79
83 67
UTI designation Complicated Uncomplicated
85 95
83 82
84 100
71 90
Prior therapy Yes No
One hundred twenty-four patients were randomized to norfloxacin and 86 to TMP-SMZ. Of these patients, 79 were considered evaluable for efficacy in the norfloxacin group and 54 in the TMP-SMZ group. All patients were evaluable for safety. Table 1 shows the patient character istics of all patients and of those who were evaluable. Significantly more patients randomized to norflox acin had complicated, severe or polymicrobic UTIs, as well as histories of prior therapy and concomitant uro logie procedures. No differences were noted with respect to age, sex, percentage of patients with prior procedures or duration of study therapy. The distribution of susceptible gram-positive and gram-negative pathogens to norfloxacin and TMP-SMZ appears in table 2. While 79% (147 of 187) of pathogens were susceptible to TMP-SMZ, a significantly greater number of organisms - 97% (181 of 187) - were suscep tible to norfloxacin (p < 0.01). A single Corynebacterium organism was TMP-SMZ-susceptible and norflox acin-resistant, while 35 organisms were susceptible to norfloxacin and resistant to TMP-SMZ. A greater diversity of organisms was found in the nor floxacin arm. Of 93 pathogens treated with norfloxacin, 85 (91 %) were eradicated and 8 persisted; 2 of the latter (a P. aeruginosa and a Corynebacterium) acquired resis tance during therapy. Among the 55 pathogens treated with TMP-SMZ, 46 (84%) were eradicated and 9 per sisted, with 3 of the latter (two enterococci and one E. coli) acquiring resistance. Table 3 lists the organisms that were susceptible to norfloxacin but resistant to TMP-SMZ. The effects of patient characteristics on clinical re sponses appear in table 4. Rates of cure or improvement were lower in patients with polymicrobic infections and
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Table 3. Pathogens resistant to TMP-SMZ
37
Norfloxacin versus Trimethoprim-Sulfamethoxazole in UTIs
Table 5. Effect of prior therapy on clinical response of evaluable patients with pathogens susceptible to both drugs Prior Treatment therapy Yes
No
All
Cured
Im proved
Not Cured or improved improved, %
2
3 6 9
89 71
0 3 3
100 90 94
norfloxacin TMP-SMZ all
22 15 37
norfloxacin TMP-SMZ all
25 25 50
0 1
norfloxacin TMP-SMZ
47 40
2
0 2
1
94b 82
3 9
1
a Significantly lower than for all patients with no prior therapy (81 vs. 94%, p = 0.04). b Significantly higher than TMP-SMZ treatment group (p = 0.03) without adjustment for prior therapy (p = 0.06).
Table 6. Clinical responses of evaluable patients regardless of patient characteristics or susceptibility of pathogen Drug
Norfloxacin TMP-SMZ a
Number Cured of patients
Im proved
73 50
3
63 40
Cured or Not improved improved %
1
7 9
90a 82
No significant difference (p = 0.17).
Table 7. Frequencies of adverse clinical and laboratory experi ences Category
Norfloxacin TMP-SMZ
Adverse clinical experiences only 1 (0.8a) Adverse laboratory experience only 0b Adverse clinical and laboratory experiences 1 (0.8) Total patients with at least one adverse 2 (1.6a) experience Therapy discontinued because of adverse 1 (0.8)b experiences Total patients without adverse experiences 122 (98.0) 124 Total patients
a b
8 (9.3) 4 (4.7) 1 (1.2)
13 (15.1) 5 (6.0) 73 (84.0) 86
Figures in parentheses indicate percentage. p < 0.01, significantly lower than TMP-SMZ. p < 0.05, significantly lower than TMP-SMZ. Downloaded by: University of Exeter 144.173.6.94 - 6/6/2020 10:50:07 AM
in patients with histories of prior UTI therapy, regard less of the therapy received. Patients designated as hav ing severe infections and treated with TMP-SMZ had lower rates of cure and improvement, as well; however, this was not the case with norfloxacin. As shown in table 3, a substantial number of patients receiving norfloxacin presented with organisms resistant to TMP-SMZ. This unequal distribution of pathogens created a potential bias in comparing norfloxacin and TMP-SMZ. Table 5 corrects for this dissimilarity by analyzing only pathogens susceptible to both drugs. Another characteristic that could have introduced bias was a history of prior therapy. As indicated in table 5, patients with prior therapy had significantly lower response rates than those without prior therapy. The fact that there were significantly more norfloxacintreated patients with this characteristic created a poten tial bias which could have confounded a comparison of efficacy between the two study drugs. When corrected for spectrum alone, the cured and improved rates for norfloxacin over TMP-SMZ ap proached significance (p = 0.06). However, when prior therapy was corrected for, as well, this difference became significant (p = 0.03). When neither spectrum nor prior therapy are taken into account, 90% of norfloxacintreated patients and 82% of TMP-SMZ-treated patients had their organisms eradicated. These rates were not sta tistically different (table 6). Among evaluable patients, 90% of those treated with norfloxacin and 85% with TMP-SMZ were symptomfree by day 3 of therapy. These results were not signifi cantly different. Five patients (7%) treated with norflox acin and 2 TMP-SMZ-treated patients (5%) relapsed with the same pathogen within 6 weeks of the cessation of therapy. Among patients who were considered nonevaluable, the majority of whom did not have a microbiologically documented infection, no significant differences were noted between treatment groups with respect to clinical outcome. Safety profiles were analyzed by both clinical and lab oratory parameters in 124 patients receiving norfloxacin and 86 receiving TMP-SMZ. No adverse experiences occurred in 122 of 124 norfloxacin-treated patients, compared with 73 of 86 TMP-SMZ patients (table 7). Significantly more TMP-SMZ cases had adverse clinical experiences (p < 0.01) and adverse laboratory experi ences (p < 0.05) than did patients receiving norfloxacin. In addition, therapy was discontinued because of ad verse experiences by significantly more TMP-SMZ-
38
Corrado/Hesney/Struble/Brown/Eng/Landes/Harrison/Ryan/Bolding
treated patients than by norfloxacin patients (6 vs. 1 %, p < 0.01). Table 8 lists the specific adverse experiences associ ated with each drug, and indicates which ones were con sidered probably or definitely drug-related by the inves tigators. Significantly fewer patients in the norfloxacin group had adverse experiences that were considered related to therapy than did those in the TMP-SMZ group (none of 124 vs. 7 of 86). Table 8. Types, distributions and drug relationships of adverse experiences Adverse experience
Norfloxacin TMP-SMZ
Rash (macular) Urticaria Diarrhea Nausea Insomnia Depression Nervousness Dizziness with disorientation Leukopenia AST, ALT LDH Eosinophilia
0
3a
0 0 1 0 0 0 1 1 0 0 0
2“ 1
la
1 la 1 0 2
1 1 1
a All were felt by the investigator to be either definitely or probably drug-related. Some patients had more than one adverse experience.
One patient receiving TMP-SMZ had two adverse experiences, namely depression and insomnia, that were considered to be related to TMP-SMZ therapy. Three cases of leukopenia, 1 on norfloxacin and 2 on TMP-SMZ, occurred. None had WBC counts below 2,000/mm3.
Discussion
The fluoroquinolones are bactericidal, have a novel site of action specific for bacteria (i.e. inhibition of bac terial DNA-gyrase) and do not appear to be susceptible to plasmid-mediated resistance [3, 4], While it is impos sible to predict the degree to which resistance to the fluoroquinolones will develop in the future, at the present time norfloxacin affords physicians the ability to treat, on an outpatient basis, UTIs caused by organisms that are resistant to many other drugs. This is supported by the observation that 21% of pathogens encountered in this trial were resistant to TMP-SMZ, while only 3% were norfloxacin-resistant. Almost all TMP-SMZ-resistant isolates belonged to three groups of organisms: P. aeruginosa, enterococci and Enterobacteriaceae. Many recurrent UTIs are due to organisms other than E. coli. A review of all cases of recurrent (3 or more/year) uncomplicated cystitis in women who were treated in norfloxacin trials from 1982 to 1986 revealed that 190 women had 216 étiologie pathogens, of which 34% were
Table 9. Susceptibilities of UTI pathogens Numbers susceptible/numbers tested norfloxacin
TMP-SMZ
ampicillin
Escherichia coli Klebsiella pneumoniae Proteus mirabilis Enterococci Staphylococcus epiderm idis Staphylococcus saprophyticus Citrobacter freundii Pseudomonas aeruginosa Enterobacter aerogenes Enterobacter cloacae Providencia rettgeri Klebsiella oxytoca Miscellaneous gram-negative rods Staphylococcus aureus Providencia stuardi
141/143 17/20 17/17 6/6 5/5 4/4 4/4 4/4 3/3
119/143 13/20
79/141 3/20 11/17 6/6 2/5 3/4 2/4 0/4 3/3
Totals
211/216 (97.7%)
2/2 2/2 2/2 2/2 1/1 1/1
14/17
3/6 1/5 4/4 3/4 1/4 3/3 1/2
0/2 0/2 1/2 1/1 0/1
164/216 (75.9%)
0/2 1/2
0/2 2/2 1/1 0/1
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Organism
Norfloxacin versus Trimethoprim-Sulfamethoxazole in UTIs
ment of a broad array of UTIs. In fact, in two recent studies [7, 8], in which oral norfloxacin was compared to broad-spectrum parenteral antibiotics, including the aminoglycosides, the cure rate of nosocomial UTIs by norfloxacin was equivalent to that by the parenteral antibiotics. Tolerability is as important as efficacy. The data from this study are in general agreement with those of another trial [5], in which norfloxacin was associated with signif icantly fewer adverse experiences requiring discontinua tion of therapy than TMP-SMZ. In the present study, TMP-SMZ therapy caused a higher incidence of adverse experiences, the most common of which were rashes and elevated liver function tests. This series underscores the important variables which may affect the successful treatment of UTIs, and con firms the findings of other studies regarding the high degrees of efficacy and tolerability of norfloxacin in a broad range of patients. References
1
2
3
4
5
6
7
8
Khan MY, Gruninger RP, Nelson SM, et al: Comparative in vitro activity of norfloxacin (M 0366) and ten other antimicro bial agents against urinary bacterial isolates. Antimicrob Agents Chemother 1982;5:848-851. Corigliano BE, Appleman MD, Heseltine PNR, et al: Compara tive in vitro activities of norfloxacin (MK 0366) and six com monly used antimicrobial agents against 199 urinary isolates showing various degrees of antibiotic resistance. Diagn Micro biol Infect Dis 1984;2:101-106. Corrado ML, Chérubin CE, Shulman M: The comparative activ ity of norfloxacin with other antimicrobial agents against gram positive and gram-negative bacteria. J Antimicrob Chemother 1983;11:369-376. Burman LG: Apparent absence of transferable resistance to nal idixic acid in pathogenic gram negative bacteria. J Antimicrob Chemother 1977;3:509-516. Sabbaj J, Hoagland VL, Shih WJ: Multiclinic comparative study of norfloxacin and trimethoprim-sulfamethoxazole for the treat ment of urinary tract infections. Antimicrob Agents Chemother 1985;27:297-301. Sabbaj J, Hoagland VL, Cook T: Norfloxacin versus co-trimoxazole in the treatment of recurring urinary tract infections in men. Scand J Infect Disease 1986 (suppl 48):48-53. Chérubin C, Stilwell S: Norfloxacin versus parenteral therapy in the treatment of complicated urinary tract infections and resis tant organisms. Scand J Infect Dis 1986 (suppl 48):32-37. Cox CE, McCabe RE, Grad LC: Oral norfloxacin vs. parenteral therapy for nosocomial urinary tract infections. Am J Med 1987; 82(suppl 6B):59-64. Dr. Kenneth R. Brown Merck Sharp & Dohme Research Laboratories Blue Bell, PA 19422 (USA)
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organisms other than E. coli. During the preceding 12 months, these women had had recurrent therapies con sisting of two to nine courses of antibiotics, which might have influenced the distribution of pathogens. This study demonstrates how the type of patient treated has a bearing on the outcome of therapy. Patients who had multiple courses of antibacterial therapy for UTIs over a 12-month period had lower eradication rates than patients with no prior therapy (table 5). It is tempting to attribute this finding to the selection of resistant pathogens following the previous courses of therapy, as the review of 216 isolates suggests. Ninetyeight percent of those pathogens were identified as nor floxacin-susceptible, compared with 76% for TMP-SMZ and 53% for ampicillin (table 9). However, this hypoth esis cannot fully explain the results of the present study, in which patients were disqualified from evaluation of efficacy if the pathogens isolated were resistant to the study drug to which they had been randomized. It is pos sible that, while within the susceptible range, pathogens from such patients may have been relatively more resis tant than pathogens from patients with their first UTI. Another explanation for the disparate outcomes of patients with and without prior therapy lies in the patients themselves. All but one of the investigators involved in this multicenter trial were either urologists or infectious disease specialists. Therefore, it is not surprising that many of their patients had polymicrobic, complicated or recurrent UTIs. Perhaps patients with therapeutic failures or mul tiple relapses or reinfections are more likely to fail future courses of therapy, as well. However, despite the impact of prior therapy on out come, patients with histories of prior therapy who were randomized to norfloxacin did as well as patients with out histories of prior therapy who were treated with TMP-SMZ. This finding is consistent with those of two previous trials [5, 6], which reported significantly higher cure rates for norfloxacin than for TMP-SMZ. Even after cor recting for the distribution of both pathogen type and patients with histories of prior therapy, this study dem onstrates a significantly higher pathogen eradication rate among patients treated with norfloxacin than among those treated with TMP-SMZ. The fact that 11 of 13 P. aeruginosa cases and six of seven enterococcal infections treated with norfloxacin during this trial were eradicated, but were excluded from this analysis because of their resistance to TMP-SMZ, further supports the utility of norfloxacin in the treat
39
