©1990 S. Karger AG, Basel 0302-2838/90/01 75-0013S2.75/0
Eur Urol 1990;17(suppl 1):13—18
Review of Norfloxacin in Lower Urinary Tract Infections
1607975
L. Micinoa, S. Goldonia, A. Tubaroa, G. Paradiso Galatiotoa, P. Gandolfib “L’Aquila University School of Medicine, L’Aquila, Italy; bLaboratory for Clinical Analysis, ‘G. Mazzini’ General Hospital, Teramo, Italy
Key Words. Norfloxacin • Uncomplicated urinary tract infections ■ Cystitis Abstract. A review of worldwide clinical trials with norfloxacin in the treatment of uncomplicated urinary tract infections (UTIs), as well as our personal experience with 21 5 assessable patients, is presented. Almost all patients received 400 mg b.i.d. for 3-15 days. Bacteriological eradication (104 CFU/ml of urine or less) was achieved in more than 90% of patients. Short-term therapy (3 days) with norfloxacin proved to be as effective and tolerable as a 10- to 14-day conventional therapeutic schedule in the treatment of lower uncomplicated UTIs. Overall incidence of drug-related adverse experiences was 2.3%.
Norfloxacin is a quinolone carboxyl acid derivative. Its efficacy and its safety profile in the treatment of uncomplicated lower urinary tract infections (UTIs) have been evaluated in many worldwide clinical trials. Norfloxacin has demonstrated excellent in vitro activity against the majority of pathogens isolated from the uri nary tract [1,2]. In vivo resistance has been observed infrequently [3, 4], Pharmacokinetic studies have shown that norfloxacin has a high urinary excretion rate, a long elimination half-life and a low incidence of side effects [5, 6], Because of these characteristics, norfloxacin ap pears to be well suited for the treatment of UTIs. So far norfloxacin has been tested in many clinical trials in the treatment of uncomplicated lower UTIs all over the world. Materials and Methods This review covers 1,070 patients treated with norfloxacin in worldwide clinical trials with uncomplicated UTIs [7-13], and our personal experience based on 215 assessable patients ( 17 males and 198 females) treated over the last 4 years [14]. Both comparative
and noncomparative trials are included, except for Japanese clinical trials, which were excluded. The data cited in this report were com plete as of October 1987. A dosage of 400 mg b.i.d. for 3-15 days was used in almost all patients. All patients included in our clinical trial had symptoms of acute UTI (dysuria, frequency or urgency) and pyuria. Exclusion criteria were as follows: pyelonephritis (flank pain, rigors or temperature Ss38°C), age less than 18 years, hypersensitivity to quinolones, structural or functional abnormalities of the urinary tract, other concomitant anti-infective treatments, and pregnancy or lactation. In-all patients the étiologie agent of infection was a microorgan ism susceptible to the drug under examination, with a minimal bac terial count of 105 colony-forming units (CFU)/ml of urine. Bacter iological cure was defined by negative (104 CFU/ml or less) urine cultures during and after treatment. Isolates were identified by stan dard procedures and tested for drug susceptibility by the KirbyBauer method. A 10-pg norfloxacin disk was used and a zone inhi bition diameter of less than or equal to 12 mm identified resistance to norfloxacin. Urine cultures with antibiograms and laboratory tests were per formed 48 h preceding the start of treatment, and 5-9 days after the end of the treatment, to evaluate bacteriological response to the drug and to identify possible modifications of hematocrit and of renal and hepatic function. Follow-up urine cultures were obtained be tween the 4th and 6th posttherapy week. Patients having less than 105 CFU/ml in the pretreatment urine culture were discontinued from antibiotic therapy and are not included in the evaluation of efficacy. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
Introduction
14
Miano/Goldoni/Tubaro/Paradiso Galatioto/Gandolfi
Table 1. Study distribution and clinical efficacy for completed trials Norfloxacin dosage
Number of norfloxacin-treated patients
400 mg b.i.d. X 3 days 400 mg b.i.d. 400 mg b.i.d.
109 61
Nalidixic acid
400 mg b.i.d. X 3 days
Noncomparative
400 400 400 400 400 400
Cured or improved (first follow-up control), %
Cured or improved for the comparative agent, %
Reference No.
96 94
100
21
92
23
20
100
100
20
91
96
82
18
Uncomplicated cystitis vs. TMP-SMZ
mg b.i.d. X 3 days mg b.i.d. X 3 days mg b.i.d. mg b.i.d. mg b.i.d. mg b.i.d.
552 99 28 17 15
UTIs in men vs. TMP-SMZ 400 mg b.i.d.
97 100
92
5 14 17
88
10
80 90
4 9
68
93*
19
* p < 0.05, significantly higher cure rate in the norfloxacin group. TMP-SMZ = Trimethoprim-sulfamethoxazole.
Table 2. Clinical and laboratory adverse experiences in 1,070 treated patients Number of patients Total treated Clinical adverse experiences All Drug-related Serious (all) Laboratory adverse experiences All Drug-related Serious (all)
1,070 (-) 67 (6.1) 25 (2.2) 0(0)
Our patients were subdivided according to clinical and epidemi ologic criteria: lower uncomplicated symptomatic UTIs or recurrent lower symptomatic UTIs, and community-acquired (i.e., outpa tients) or hospital-acquired (i.e., inpatients) UTIs. Bacteriological outcome was defined as follows: eradication, negative posttherapy follow-up urine culture; relapse, temporary eradication of the original pathogen reappearing in subsequent fol low-up urine cultures; reinfection, eradication of the original patho gen but follow-up urine cultures positive for different serotypes of the same pathogen, or for different bacterial species with greater than 105 CFU/ml of urine.
11 (1.0)
1 (0.09) 0(0)
Results Figures in parentheses indicate percentage.
All
Drug-related
Gastrointestinal Skin reactions Neuropsychiatrie
32 (2.9) 9 (0.8) 26 (2.4)
11 (1.0)
Total
67 (6.1)
25 (2.2)
Figures in parentheses indicate percentage.
5 (0.4) 9 (0.8)
Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
Table 3. Clinical adverse experiences in 1,070 treated patients
Worldwide Studies Study distribution and clinical efficacy of completed trials (400 mg b.i.d.) are shown in table 1. The first studies in uncomplicated cystitis compared norfloxacin 200 mg b.i.d. with trimethoprim-sulfamethoxazole 80400 mg b.i.d., both given for 10 days. Bacteriological eradication was seen in 80-90% of patients [14, 15]. In subsequent comparative and noncomparative studies, a higher degree of efficacy was shown with 400 mg b.i.d. of norfloxacin. In all these studies, norflox acin was at least as effective as the comparative agents. Four studies were conducted to investigate the efficacy of short-course therapy (3 days) with norfloxacin. All data demonstrated that a 3-day course of norfloxacin
Norfloxacin in Uncomplicated UTIs
15
Table 4. Neuropsychiatrie adverse experiences in 1,070 treated
Table 5. Male:female patient ratio in our series
patients UTI
Patients Men
Women
Lower uncomplicated symptomatic Recurrent lower symptomatic
166 49
153 45
Number of adverse experiences drug-related
Drowsiness Headache Lightheadedness Depression Insomnia Confusion Dizziness Total
9 (0.8) 6 (0.5) 5 (0.5) 2 2 1 1
13 4
4(0.3) 1 2 1 1
(0.1) (0.2) (0.1) (0.1)
(0.2) (0.2) (0.1) (0.1)
0 (0.0) 0 (0.0)
26 (2.4)
9 (0.8)
Figures in parentheses indicate percentage.
was as effective and well tolerated as 10-14 days of con ventional therapy in the treatment of uncomplicated lower UTIs. The review of safety is based on 1,070 assessable patients treated with norfloxacin (table 2). The overall incidences of clinical and laboratory adverse experiences for all patients were 6.1 and 1 %, respectively. The inci dence of drug-related events was below 3%, and no seri ous adverse experiences were reported in any trials. The most common drug-related side effects were gas trointestinal, neuropsychiatrie, and skin reactions; the incidence of each was < 1 % (table 3). Nausea, diarrhea, and vomiting were the predominant gastrointestinal symptoms. Among the neuropsychiatrie effects, drowsi ness and headache were the most frequent in the 1,070 treated patients, while other events included light headedness, insomnia, and depression (table 4). Only one drug-related laboratory adverse experience (eosinophilia) was reported; this occurred in a patient who received therapy for 4 weeks for recurrent UTI [16]. University of L’Aquila Trial Data from the Department of Urology, University of L’Aquila, Italy, are summarized in tables 5 and 6. The male:female ratio in our series was 1:11.6, with the great majority of patients presenting as outpatients (87%). The dosage of norfloxacin was 400 mg b.i.d. in all cases. The first group of patients was treated according to a conventional therapeutic schedule of 7-10 days. Subse quently we initiated, in accordance with other centers, a short therapy protocol based on a 3-day schedule. Pa
Table 6. Patient distribution according to clinical and epidemio logic criteria
UTI
Inpatients Outpatients
Lower uncomplicated symptomatic Recurrent lower symptomatic
17
149 39
10
Table 7. Pathogens isolated from pretreatment specimens in our
senes Pathogens Gram-negative rods Escherichia coli Klebsiella pneumoniae Citrobacter freundii Proteus mirabilis Enterobacter cloacae Pseudomonas aeruginosa Gram-positive cocci Staphylococcus aureus Staphylococcus epidermide Enterococci Gram-positive rods Corynebacterium spp
Number of cases
151 9 5 5 4 4
(70.23) (4.18) (2.32) (2.32) (1.86) (1.86)
2 (0.93) 5 (2.32) 28 (13.02) 2 (0.93)
Figures in parentheses indicate percentage.
tients entered one of the two different treatment groups on a nonrandomized basis. Pathogens isolated from pretreatment specimens are presented in table 7: the predominant organisms were Escherichia coli (151 patients, or 70.23%), Enterococcus species (28 patients, or 13.02%) and Klebsiella pneumo niae (9 patients, or 4.18%). Success rates cross-matched with clinical presentation are reported in table 8. A high success rate was observed using the 3-day regimen in lower uncomplicated symptomatic UTIs (98.9%). In Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
all
Miano/Goldoni/Tubaro/Paradiso Galatioto/Gandolfi
Table 8. Success rates cross-matched with clinical presentation in our series of patients treated with norfloxacin Short therapy
Total
Bacteriological outcome
(3 days)
Conventional therapy (7-10 days)
number of cure patients rate, %
number of cure patients rate, %
Lower uncomplicated symptomatic 94 Recurrent lower symptomatic 23 117
100
98.9
72
91.3
26
96.1
97.4
98
98.9
Tabic 9. Success rates in patients treated with norfloxacin subdi vided according to epidemiologic criteria in our series Short therapy (3 days)
Conventional therapy (7-10 days)
number of cure patients rate. %
number of cure patients rate, %
Men Women
6
66.6
111
99.0
11 87
100.0
Inpatients Outpatients
2
115
50.0 98.2
25 73
100.0
90.9 96.0
Table 10. Norfloxacin in lower uncomplicated symptomatic UTI Bacteriological outcome Number of patients Eradication Relapse Reinfection Failure Failure (acquired resistance)
Short therapy
Conventional therapy
7-9 days 4-6 weeks
7-9 days 4-6 weeks
94 93 (99) 1(1)
72 72 (100)
65 60 (92) 2(3) 3(5)
Figures in parentheses indicate percentage.
Table 11. Norfloxacin in lower recurrent symptomatic UTI
56 52 (93) 1 (2)
3(5)
Number of patients Eradication Relapse Reinfection Failure Failure (acquired resistance)
Short therapy
Conventional therapy
7-9 days 4-6 weeks
7-9 days 4-6 weeks
23 21 (92) 1 (4) 1(4)
26 25 (96)
23 19 (83) 1 (4) 3(13)
25 21(84) 2(8) 2(8)
1 (4)
Figures in parentheses indicate percentage.
these latter patients conventional therapy did not in crease the success rate. The use of short-term norfloxacin therapy in recurrent lower symptomatic UTIs produced excellent results - a 91.3% success rate - which com pared favorably with the 96.1% success rate achieved following a 7- to 10-day course of norfloxacin. Success rates obtained using the two therapeutic schedules in the same patients, subdivided according to epidemiologic criteria, are shown in table 9. The 3-day course appears to be as effective as conventional therapy in women and against community-acquired UTI. Lower success rates were obtained when the 3-day course ther apy was used in men and against hospital-acquired infec tions. Bacteriological outcomes for the two groups of pa tients, treated with short-term or conventional therapy, are presented in tables 10 and 11. Bacteriological eradi cation was achieved in more than 90% of patients treated with either therapeutic schedule at the first (7-9 days) follow-up urine culture. At 4-6 weeks posttherapy follow-up, a few cases of recurrence (relapse or reinfec tion) occurred among patients in whom bacteriological eradication had been obtained. Escherichia coli was responsible for the great majority of recurrences in all three subgroups of patients. In patients with lower recurrent symptomatic UTI, one bacteriological failure (acquired resistance) due to Pseu domonas aeruginosa was demonstrated. Norfloxacin proved to be well tolerated, and only minor side effects were experienced. These are summarized in table 12. All abnormal blood chemistry and hematologic data could be attributed to the underlying infection. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
16
Norfloxacin in Uncomplicated UTIs
17
Table 12. Drug-related side effects in our series Total number 215 10 (4.65) 3 1 1 1 2 1 1
(1.39) (0.46) (0.46) (0.46) (0.93) (0.46) (0.46)
Few patients experienced more than one adverse experience; thus the number of adverse experiences does not equal the number of patients reporting drug-related side effects. Figures in parentheses indicate percentage.
Discussion
Norfloxacin was well tolerated, with a very low inci dence of drug-related adverse experiences. Most re ported side effects were mild and transient and were sim ilar to those seen with other antibiotics. Few neuropsy chiatrie adverse experiences were reported, and fewer than 1 % of the patients had drug-related adverse reac tions of that type. The lack of photosensitivity reactions to norfloxacin is also noteworthy, since such reactions have been reported with some of the other newer quinolones. Clinical trials have suggested that 3- and 10-day courses of therapy are comparable [22, 23]. This short regimen also has the advantage of high patient accep tance and compliance coupled with a low incidence of side effects and decreased cost [23]. When the patients in our study were subdivided according to clinical criteria, the 3-day regimen achieved a high cure rate in lower uncomplicated UTIs. In these patients conventional reg imens did not add any further advantage. Similar results were obtained in community-acquired infections in out patients, as well as in UTIs of the female. The 3-day therapy thus appears to represent the most rational schedule of norfloxacin administration in communityacquired UTIs in women, i.e., lower uncomplicated symptomatic UTI. Otherwise, a treatment course of at least 7 days seemed to be more appropriate. A review of worldwide clinical trials and data from our own experience indicate that norfloxacin is highly
References 1 Bergeron MG, Thabet M, Ray R, et al: Norfloxacin penetration into human renal and prostatic tissues. Antimicrob Agents Chemother 1985;28:349-350. 2 Bologna M, Vaggi L, Tornei E: La norfloxacina nella terapia delle infezioni del tratto urinario. Eur J Chemother Antibiot 1983:3:37-47. 3 Charlton CAC, Crowther A, Davies JC, et al: Three-day and ten-day chemotherapy of urinary tract infections in general prac tice. Br Med J 1976;i:124—126. 4 Consoli C, Ranno S: La norfloxacina nel trattamento delle infe zioni urinarie. Ter Essenz Clin 1984;1:47-49. 5 Deaney WB, Vogel R. Vandemburg MJ, et al: Norfloxacin in acute urinary tract infections. Practitioner 1984;228(1387):11 1117. 6 Downs J, Andriole VT, Ryan JL: In vitro activity of MK-0366 against clinical urinary pathogens including gentamicin resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1982; 21:670-672. 7 Fair WR, Crane DB. Peterson LJ, et al: Three-day treatment of urinary tract infections. J Urol 1980;123:717-721. 8 Giuliani FP, Quagliarini P, Giuliani G: La norfloxacina nel trat tamento delle infezioni delle vie urinarie. Rassegna Urol Nefrol 1986;24:1-5. 9 Goldoni S, Paradiso Galatioto G, Manieri C, et al: Valutazione clinica della norfloxacina nel trattamento delle infezioni urinarie non complicate. Prog Med Roma 1984;40:285-288. 10 Haase D, Urias B, Harding G, et al: Comparative in vitro activ ity of norfloxacin against urinary tract pathogens. Eur J Clin Microbiol 1983;2:235-241. 1 1 Hooper DC. Wolfson JS: The fluoroquinolones: Pharmacology, clinical uses, and toxicity in humans. Antimicrob Agents Che mother 1985;28:616-721. 12 Hooper DC, Wolfson JS, Souza KS, et al: Genetic and biochem ical characterization of norfloxacin resistance in Escherichia coli. Antimicrob Agents Chemother 1986;29:639-644. 13 Khan MY, Gruninger RP, Nelson SM, et al: Comparative in vitro activity of norfloxacin (MK-0366) and ten oral antimicro bial agents against urinary bacterial isolates. Antimicrob Agents Chemother 1982;21:848-851. 14 Kirby CP: Treatment of simple urinary tract infections in gen eral practice with a 3-day course of norfloxacin. J Antimicrob Chemother 1984; 13(suppl B): 107-112. 15 Marble DA, Bosso JA: Norfloxacin: A quinolone antibiotic. Drug Intell Clin Pharm 1986;20:261-266. 16 Miano L. Goldoni S, Racheli T: Valutazione clinica comparativa dell’efficacia di un derivato dclfacido nalidixico (MK-366) e del cotrimoxazolo nel trattamento delle infezioni urinarie basse non complicate. Boll Atti SUCMI 1980;16:213-216. 1 7 Paoletti PP, Rimondi C, Tenti S, et al: Studio sulla attività' della Norfloxacina nelle infezioni del tratto urinario inferiore. Ter Essenz Clin 1986;4:173-174. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
Assessable patients Total side effects reported Individual side effects Nausea Vomiting Loss of appetite Diarrhea Headache Dizziness Skin reactions
effective in the treatment of lower uncomplicated UTI, was generally well tolerated, and offers important advan tages over other existing available regimens.
Miano/Goldoni/Tubaro/Paradiso Galatioto/Gandolfi
23 Watt B, Chait I, Kelsey MC, et al: Norfloxacin vs. co-trimoxazole in the treatment of uncomplicated urinary tract infections. A multi-center trial. J Antimicrob Chemother 1984; 13 (suppl B): 89-94. 24 Wolfson JS, Hooper DC: The fluoroquinolones: Structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 1985;28:581-586.
Prof. L. Miano Chair of Urology Department of Urology ‘G. Mazzini’ General Hospital 1-64100 Teramo (Italy)
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18 Reeves DS, Lacey RW, Hummery RV, et al: Treatment of acute urinary infection by norfloxacin or nalidixic acid/citrate: A mul ti-center comparative study. J Antimicrob Chemother 1984; 13(suppl B):99— 105. 19 Sabbaj J, Hoagland VL, Cook T: Norfloxacin versus cotrimoxazole in the treatment of recurrent urinary tract infections in men. Scand J Infect Dis 1986;48(suppl):48-53. 20 Schaeffer AJ, Sisney GA: Efficacy of norfloxacin in urinary tract infections: Biological effects on vaginal and fecal flora. J Urol 1985;133:628-630. 21 Stein GE, Hummaw W, Goldstein EJC: A multi-center compar ative trial of three-day norfloxacin vs. ten-day sulfamethoxazole and trimethoprim for the treatment of uncomplicated urinary tract infections. Arch Intern Med 1987;147:1760-1762. 22 Swanson BN, Boppana VK, Vlasses PH, et al: Norfloxacin dis position after sequentially increasing oral doses. Antimicrob Agents Chemother 1983;23:284-288.
Eur Urol 1990;17(suppl 1):13—18
Review of Norfloxacin in Lower Urinary Tract Infections
1607975
L. Micinoa, S. Goldonia, A. Tubaroa, G. Paradiso Galatiotoa, P. Gandolfib “L’Aquila University School of Medicine, L’Aquila, Italy; bLaboratory for Clinical Analysis, ‘G. Mazzini’ General Hospital, Teramo, Italy
Key Words. Norfloxacin • Uncomplicated urinary tract infections ■ Cystitis Abstract. A review of worldwide clinical trials with norfloxacin in the treatment of uncomplicated urinary tract infections (UTIs), as well as our personal experience with 21 5 assessable patients, is presented. Almost all patients received 400 mg b.i.d. for 3-15 days. Bacteriological eradication (104 CFU/ml of urine or less) was achieved in more than 90% of patients. Short-term therapy (3 days) with norfloxacin proved to be as effective and tolerable as a 10- to 14-day conventional therapeutic schedule in the treatment of lower uncomplicated UTIs. Overall incidence of drug-related adverse experiences was 2.3%.
Norfloxacin is a quinolone carboxyl acid derivative. Its efficacy and its safety profile in the treatment of uncomplicated lower urinary tract infections (UTIs) have been evaluated in many worldwide clinical trials. Norfloxacin has demonstrated excellent in vitro activity against the majority of pathogens isolated from the uri nary tract [1,2]. In vivo resistance has been observed infrequently [3, 4], Pharmacokinetic studies have shown that norfloxacin has a high urinary excretion rate, a long elimination half-life and a low incidence of side effects [5, 6], Because of these characteristics, norfloxacin ap pears to be well suited for the treatment of UTIs. So far norfloxacin has been tested in many clinical trials in the treatment of uncomplicated lower UTIs all over the world. Materials and Methods This review covers 1,070 patients treated with norfloxacin in worldwide clinical trials with uncomplicated UTIs [7-13], and our personal experience based on 215 assessable patients ( 17 males and 198 females) treated over the last 4 years [14]. Both comparative
and noncomparative trials are included, except for Japanese clinical trials, which were excluded. The data cited in this report were com plete as of October 1987. A dosage of 400 mg b.i.d. for 3-15 days was used in almost all patients. All patients included in our clinical trial had symptoms of acute UTI (dysuria, frequency or urgency) and pyuria. Exclusion criteria were as follows: pyelonephritis (flank pain, rigors or temperature Ss38°C), age less than 18 years, hypersensitivity to quinolones, structural or functional abnormalities of the urinary tract, other concomitant anti-infective treatments, and pregnancy or lactation. In-all patients the étiologie agent of infection was a microorgan ism susceptible to the drug under examination, with a minimal bac terial count of 105 colony-forming units (CFU)/ml of urine. Bacter iological cure was defined by negative (104 CFU/ml or less) urine cultures during and after treatment. Isolates were identified by stan dard procedures and tested for drug susceptibility by the KirbyBauer method. A 10-pg norfloxacin disk was used and a zone inhi bition diameter of less than or equal to 12 mm identified resistance to norfloxacin. Urine cultures with antibiograms and laboratory tests were per formed 48 h preceding the start of treatment, and 5-9 days after the end of the treatment, to evaluate bacteriological response to the drug and to identify possible modifications of hematocrit and of renal and hepatic function. Follow-up urine cultures were obtained be tween the 4th and 6th posttherapy week. Patients having less than 105 CFU/ml in the pretreatment urine culture were discontinued from antibiotic therapy and are not included in the evaluation of efficacy. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
Introduction
14
Miano/Goldoni/Tubaro/Paradiso Galatioto/Gandolfi
Table 1. Study distribution and clinical efficacy for completed trials Norfloxacin dosage
Number of norfloxacin-treated patients
400 mg b.i.d. X 3 days 400 mg b.i.d. 400 mg b.i.d.
109 61
Nalidixic acid
400 mg b.i.d. X 3 days
Noncomparative
400 400 400 400 400 400
Cured or improved (first follow-up control), %
Cured or improved for the comparative agent, %
Reference No.
96 94
100
21
92
23
20
100
100
20
91
96
82
18
Uncomplicated cystitis vs. TMP-SMZ
mg b.i.d. X 3 days mg b.i.d. X 3 days mg b.i.d. mg b.i.d. mg b.i.d. mg b.i.d.
552 99 28 17 15
UTIs in men vs. TMP-SMZ 400 mg b.i.d.
97 100
92
5 14 17
88
10
80 90
4 9
68
93*
19
* p < 0.05, significantly higher cure rate in the norfloxacin group. TMP-SMZ = Trimethoprim-sulfamethoxazole.
Table 2. Clinical and laboratory adverse experiences in 1,070 treated patients Number of patients Total treated Clinical adverse experiences All Drug-related Serious (all) Laboratory adverse experiences All Drug-related Serious (all)
1,070 (-) 67 (6.1) 25 (2.2) 0(0)
Our patients were subdivided according to clinical and epidemi ologic criteria: lower uncomplicated symptomatic UTIs or recurrent lower symptomatic UTIs, and community-acquired (i.e., outpa tients) or hospital-acquired (i.e., inpatients) UTIs. Bacteriological outcome was defined as follows: eradication, negative posttherapy follow-up urine culture; relapse, temporary eradication of the original pathogen reappearing in subsequent fol low-up urine cultures; reinfection, eradication of the original patho gen but follow-up urine cultures positive for different serotypes of the same pathogen, or for different bacterial species with greater than 105 CFU/ml of urine.
11 (1.0)
1 (0.09) 0(0)
Results Figures in parentheses indicate percentage.
All
Drug-related
Gastrointestinal Skin reactions Neuropsychiatrie
32 (2.9) 9 (0.8) 26 (2.4)
11 (1.0)
Total
67 (6.1)
25 (2.2)
Figures in parentheses indicate percentage.
5 (0.4) 9 (0.8)
Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
Table 3. Clinical adverse experiences in 1,070 treated patients
Worldwide Studies Study distribution and clinical efficacy of completed trials (400 mg b.i.d.) are shown in table 1. The first studies in uncomplicated cystitis compared norfloxacin 200 mg b.i.d. with trimethoprim-sulfamethoxazole 80400 mg b.i.d., both given for 10 days. Bacteriological eradication was seen in 80-90% of patients [14, 15]. In subsequent comparative and noncomparative studies, a higher degree of efficacy was shown with 400 mg b.i.d. of norfloxacin. In all these studies, norflox acin was at least as effective as the comparative agents. Four studies were conducted to investigate the efficacy of short-course therapy (3 days) with norfloxacin. All data demonstrated that a 3-day course of norfloxacin
Norfloxacin in Uncomplicated UTIs
15
Table 4. Neuropsychiatrie adverse experiences in 1,070 treated
Table 5. Male:female patient ratio in our series
patients UTI
Patients Men
Women
Lower uncomplicated symptomatic Recurrent lower symptomatic
166 49
153 45
Number of adverse experiences drug-related
Drowsiness Headache Lightheadedness Depression Insomnia Confusion Dizziness Total
9 (0.8) 6 (0.5) 5 (0.5) 2 2 1 1
13 4
4(0.3) 1 2 1 1
(0.1) (0.2) (0.1) (0.1)
(0.2) (0.2) (0.1) (0.1)
0 (0.0) 0 (0.0)
26 (2.4)
9 (0.8)
Figures in parentheses indicate percentage.
was as effective and well tolerated as 10-14 days of con ventional therapy in the treatment of uncomplicated lower UTIs. The review of safety is based on 1,070 assessable patients treated with norfloxacin (table 2). The overall incidences of clinical and laboratory adverse experiences for all patients were 6.1 and 1 %, respectively. The inci dence of drug-related events was below 3%, and no seri ous adverse experiences were reported in any trials. The most common drug-related side effects were gas trointestinal, neuropsychiatrie, and skin reactions; the incidence of each was < 1 % (table 3). Nausea, diarrhea, and vomiting were the predominant gastrointestinal symptoms. Among the neuropsychiatrie effects, drowsi ness and headache were the most frequent in the 1,070 treated patients, while other events included light headedness, insomnia, and depression (table 4). Only one drug-related laboratory adverse experience (eosinophilia) was reported; this occurred in a patient who received therapy for 4 weeks for recurrent UTI [16]. University of L’Aquila Trial Data from the Department of Urology, University of L’Aquila, Italy, are summarized in tables 5 and 6. The male:female ratio in our series was 1:11.6, with the great majority of patients presenting as outpatients (87%). The dosage of norfloxacin was 400 mg b.i.d. in all cases. The first group of patients was treated according to a conventional therapeutic schedule of 7-10 days. Subse quently we initiated, in accordance with other centers, a short therapy protocol based on a 3-day schedule. Pa
Table 6. Patient distribution according to clinical and epidemio logic criteria
UTI
Inpatients Outpatients
Lower uncomplicated symptomatic Recurrent lower symptomatic
17
149 39
10
Table 7. Pathogens isolated from pretreatment specimens in our
senes Pathogens Gram-negative rods Escherichia coli Klebsiella pneumoniae Citrobacter freundii Proteus mirabilis Enterobacter cloacae Pseudomonas aeruginosa Gram-positive cocci Staphylococcus aureus Staphylococcus epidermide Enterococci Gram-positive rods Corynebacterium spp
Number of cases
151 9 5 5 4 4
(70.23) (4.18) (2.32) (2.32) (1.86) (1.86)
2 (0.93) 5 (2.32) 28 (13.02) 2 (0.93)
Figures in parentheses indicate percentage.
tients entered one of the two different treatment groups on a nonrandomized basis. Pathogens isolated from pretreatment specimens are presented in table 7: the predominant organisms were Escherichia coli (151 patients, or 70.23%), Enterococcus species (28 patients, or 13.02%) and Klebsiella pneumo niae (9 patients, or 4.18%). Success rates cross-matched with clinical presentation are reported in table 8. A high success rate was observed using the 3-day regimen in lower uncomplicated symptomatic UTIs (98.9%). In Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
all
Miano/Goldoni/Tubaro/Paradiso Galatioto/Gandolfi
Table 8. Success rates cross-matched with clinical presentation in our series of patients treated with norfloxacin Short therapy
Total
Bacteriological outcome
(3 days)
Conventional therapy (7-10 days)
number of cure patients rate, %
number of cure patients rate, %
Lower uncomplicated symptomatic 94 Recurrent lower symptomatic 23 117
100
98.9
72
91.3
26
96.1
97.4
98
98.9
Tabic 9. Success rates in patients treated with norfloxacin subdi vided according to epidemiologic criteria in our series Short therapy (3 days)
Conventional therapy (7-10 days)
number of cure patients rate. %
number of cure patients rate, %
Men Women
6
66.6
111
99.0
11 87
100.0
Inpatients Outpatients
2
115
50.0 98.2
25 73
100.0
90.9 96.0
Table 10. Norfloxacin in lower uncomplicated symptomatic UTI Bacteriological outcome Number of patients Eradication Relapse Reinfection Failure Failure (acquired resistance)
Short therapy
Conventional therapy
7-9 days 4-6 weeks
7-9 days 4-6 weeks
94 93 (99) 1(1)
72 72 (100)
65 60 (92) 2(3) 3(5)
Figures in parentheses indicate percentage.
Table 11. Norfloxacin in lower recurrent symptomatic UTI
56 52 (93) 1 (2)
3(5)
Number of patients Eradication Relapse Reinfection Failure Failure (acquired resistance)
Short therapy
Conventional therapy
7-9 days 4-6 weeks
7-9 days 4-6 weeks
23 21 (92) 1 (4) 1(4)
26 25 (96)
23 19 (83) 1 (4) 3(13)
25 21(84) 2(8) 2(8)
1 (4)
Figures in parentheses indicate percentage.
these latter patients conventional therapy did not in crease the success rate. The use of short-term norfloxacin therapy in recurrent lower symptomatic UTIs produced excellent results - a 91.3% success rate - which com pared favorably with the 96.1% success rate achieved following a 7- to 10-day course of norfloxacin. Success rates obtained using the two therapeutic schedules in the same patients, subdivided according to epidemiologic criteria, are shown in table 9. The 3-day course appears to be as effective as conventional therapy in women and against community-acquired UTI. Lower success rates were obtained when the 3-day course ther apy was used in men and against hospital-acquired infec tions. Bacteriological outcomes for the two groups of pa tients, treated with short-term or conventional therapy, are presented in tables 10 and 11. Bacteriological eradi cation was achieved in more than 90% of patients treated with either therapeutic schedule at the first (7-9 days) follow-up urine culture. At 4-6 weeks posttherapy follow-up, a few cases of recurrence (relapse or reinfec tion) occurred among patients in whom bacteriological eradication had been obtained. Escherichia coli was responsible for the great majority of recurrences in all three subgroups of patients. In patients with lower recurrent symptomatic UTI, one bacteriological failure (acquired resistance) due to Pseu domonas aeruginosa was demonstrated. Norfloxacin proved to be well tolerated, and only minor side effects were experienced. These are summarized in table 12. All abnormal blood chemistry and hematologic data could be attributed to the underlying infection. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
16
Norfloxacin in Uncomplicated UTIs
17
Table 12. Drug-related side effects in our series Total number 215 10 (4.65) 3 1 1 1 2 1 1
(1.39) (0.46) (0.46) (0.46) (0.93) (0.46) (0.46)
Few patients experienced more than one adverse experience; thus the number of adverse experiences does not equal the number of patients reporting drug-related side effects. Figures in parentheses indicate percentage.
Discussion
Norfloxacin was well tolerated, with a very low inci dence of drug-related adverse experiences. Most re ported side effects were mild and transient and were sim ilar to those seen with other antibiotics. Few neuropsy chiatrie adverse experiences were reported, and fewer than 1 % of the patients had drug-related adverse reac tions of that type. The lack of photosensitivity reactions to norfloxacin is also noteworthy, since such reactions have been reported with some of the other newer quinolones. Clinical trials have suggested that 3- and 10-day courses of therapy are comparable [22, 23]. This short regimen also has the advantage of high patient accep tance and compliance coupled with a low incidence of side effects and decreased cost [23]. When the patients in our study were subdivided according to clinical criteria, the 3-day regimen achieved a high cure rate in lower uncomplicated UTIs. In these patients conventional reg imens did not add any further advantage. Similar results were obtained in community-acquired infections in out patients, as well as in UTIs of the female. The 3-day therapy thus appears to represent the most rational schedule of norfloxacin administration in communityacquired UTIs in women, i.e., lower uncomplicated symptomatic UTI. Otherwise, a treatment course of at least 7 days seemed to be more appropriate. A review of worldwide clinical trials and data from our own experience indicate that norfloxacin is highly
References 1 Bergeron MG, Thabet M, Ray R, et al: Norfloxacin penetration into human renal and prostatic tissues. Antimicrob Agents Chemother 1985;28:349-350. 2 Bologna M, Vaggi L, Tornei E: La norfloxacina nella terapia delle infezioni del tratto urinario. Eur J Chemother Antibiot 1983:3:37-47. 3 Charlton CAC, Crowther A, Davies JC, et al: Three-day and ten-day chemotherapy of urinary tract infections in general prac tice. Br Med J 1976;i:124—126. 4 Consoli C, Ranno S: La norfloxacina nel trattamento delle infe zioni urinarie. Ter Essenz Clin 1984;1:47-49. 5 Deaney WB, Vogel R. Vandemburg MJ, et al: Norfloxacin in acute urinary tract infections. Practitioner 1984;228(1387):11 1117. 6 Downs J, Andriole VT, Ryan JL: In vitro activity of MK-0366 against clinical urinary pathogens including gentamicin resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1982; 21:670-672. 7 Fair WR, Crane DB. Peterson LJ, et al: Three-day treatment of urinary tract infections. J Urol 1980;123:717-721. 8 Giuliani FP, Quagliarini P, Giuliani G: La norfloxacina nel trat tamento delle infezioni delle vie urinarie. Rassegna Urol Nefrol 1986;24:1-5. 9 Goldoni S, Paradiso Galatioto G, Manieri C, et al: Valutazione clinica della norfloxacina nel trattamento delle infezioni urinarie non complicate. Prog Med Roma 1984;40:285-288. 10 Haase D, Urias B, Harding G, et al: Comparative in vitro activ ity of norfloxacin against urinary tract pathogens. Eur J Clin Microbiol 1983;2:235-241. 1 1 Hooper DC. Wolfson JS: The fluoroquinolones: Pharmacology, clinical uses, and toxicity in humans. Antimicrob Agents Che mother 1985;28:616-721. 12 Hooper DC, Wolfson JS, Souza KS, et al: Genetic and biochem ical characterization of norfloxacin resistance in Escherichia coli. Antimicrob Agents Chemother 1986;29:639-644. 13 Khan MY, Gruninger RP, Nelson SM, et al: Comparative in vitro activity of norfloxacin (MK-0366) and ten oral antimicro bial agents against urinary bacterial isolates. Antimicrob Agents Chemother 1982;21:848-851. 14 Kirby CP: Treatment of simple urinary tract infections in gen eral practice with a 3-day course of norfloxacin. J Antimicrob Chemother 1984; 13(suppl B): 107-112. 15 Marble DA, Bosso JA: Norfloxacin: A quinolone antibiotic. Drug Intell Clin Pharm 1986;20:261-266. 16 Miano L. Goldoni S, Racheli T: Valutazione clinica comparativa dell’efficacia di un derivato dclfacido nalidixico (MK-366) e del cotrimoxazolo nel trattamento delle infezioni urinarie basse non complicate. Boll Atti SUCMI 1980;16:213-216. 1 7 Paoletti PP, Rimondi C, Tenti S, et al: Studio sulla attività' della Norfloxacina nelle infezioni del tratto urinario inferiore. Ter Essenz Clin 1986;4:173-174. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:49:37 PM
Assessable patients Total side effects reported Individual side effects Nausea Vomiting Loss of appetite Diarrhea Headache Dizziness Skin reactions
effective in the treatment of lower uncomplicated UTI, was generally well tolerated, and offers important advan tages over other existing available regimens.
Miano/Goldoni/Tubaro/Paradiso Galatioto/Gandolfi
23 Watt B, Chait I, Kelsey MC, et al: Norfloxacin vs. co-trimoxazole in the treatment of uncomplicated urinary tract infections. A multi-center trial. J Antimicrob Chemother 1984; 13 (suppl B): 89-94. 24 Wolfson JS, Hooper DC: The fluoroquinolones: Structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 1985;28:581-586.
Prof. L. Miano Chair of Urology Department of Urology ‘G. Mazzini’ General Hospital 1-64100 Teramo (Italy)
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18 Reeves DS, Lacey RW, Hummery RV, et al: Treatment of acute urinary infection by norfloxacin or nalidixic acid/citrate: A mul ti-center comparative study. J Antimicrob Chemother 1984; 13(suppl B):99— 105. 19 Sabbaj J, Hoagland VL, Cook T: Norfloxacin versus cotrimoxazole in the treatment of recurrent urinary tract infections in men. Scand J Infect Dis 1986;48(suppl):48-53. 20 Schaeffer AJ, Sisney GA: Efficacy of norfloxacin in urinary tract infections: Biological effects on vaginal and fecal flora. J Urol 1985;133:628-630. 21 Stein GE, Hummaw W, Goldstein EJC: A multi-center compar ative trial of three-day norfloxacin vs. ten-day sulfamethoxazole and trimethoprim for the treatment of uncomplicated urinary tract infections. Arch Intern Med 1987;147:1760-1762. 22 Swanson BN, Boppana VK, Vlasses PH, et al: Norfloxacin dis position after sequentially increasing oral doses. Antimicrob Agents Chemother 1983;23:284-288.
