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Usefulness and problems of the urinary tract infection criteria for evaluating drug efficacy for complicated urinary tract infections
J Infect Chemother (2007) 13:279–284 DOI 10.1007/s10156-007-0549-0
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2007
REVIEW ARTICLE Soichi Arakawa · Kazushi Tanaka · Tetsuya Miura Katsumi Shigemura · Atsushi Takenaka · Takashi Matsui Sadao Kamidono · Yuzo Nakano · Masato Fujisawa
Usefulness and problems of the urinary tract infection criteria for evaluating drug efficacy for complicated urinary tract infections
Received: June 27, 2007
Abstract We aimed to reveal the usefulness of and problematic points with the Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (draft fourth edition) proposed by the UTI Subcommittee of the Clinical Evaluation Guidelines Committee, Japan Society of Chemotherapy, for evaluating antimicrobial agents for complicated urinary tract infections. We conducted a multicenter trial involving 159 patients with complicated urinary tract infections without indwelling urinary catheters. The antimicrobial agents used were cefcapene pivoxil and levofloxacin. “Early evaluation” took place the day after completion of 7 days of therapy; “late evaluation” took place 5–9 days after the end of treatment, and “followup evaluation” was done 4–6 weeks after treatment. In the early evaluation, overall clinical efficacy was judged as excellent in 52.9% of the patients, moderate in 26.1%, and poor in 21.0%, and the bacteriological response was judged as “eradicated” for 86.4% of the 198 bacterial strains isolated. Of 96 patients included in the “late evaluation” category in accordance with the draft fourth edition, the clinical outcome was judged as “cured” in 68.4% and the microbiological outcome was judged as “eradicated” in 59.4%. These rates may be low, because 25 patients in whom clinical efficacy was evaluated as “poor” at the end
S. Arakawa (*) · K. Tanaka · T. Miura · K. Shigemura · Y. Nakano · A. Takenaka · M. Fujisawa Division of Urology, Department of Organs Therapeutics, Faculty of Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan Tel. +81-78-382-6155; Fax +81-78-382-6169 e-mail: [email protected] S. Arakawa Surgical Division, Kobe University Hospital, Kobe, Japan S. Arakawa Department of Infection Control and Prevention, Kobe University Hospital, Kobe, Japan T. Matsui · S. Kamidono Department of Urology, Kobe Red Cross Hospital, Kobe, Japan
of treatment were separately classified as “failed” at the late evaluation. Of the 49 patients with an excellent clinical response at the end of treatment, symptoms were exacerbated in 18 at the follow-up evaluation. Overall, the draft fourth edition, with some modifications of the third edition criteria, such as the addition of a follow-up evaluation 7 days after the cessation of drug administration, has the potential to play a role in the international standards for evaluating antimicrobial drug efficacy for complicated urinary tract infections. Key words Antimicrobial agents · Complicated urinary tract infection · Criteria · Guidelines
Introduction To date, the clinical evaluation of antimicrobial agents used for treating urinary tract infections (UTIs) in Japan has been conducted in accordance with the Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (third edition; hereinafter referred to as the third edition), first published in 1985.1 To promote harmonization with guidelines from the Infectious Diseases Society of America2 and the United States Food and Drug Administration, as well as European guidelines;3 however, the third edition was revised. This revision process led to the development of the Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (draft fourth edition; hereinafter referred to as the draft fourth edition)4 in 1997. The major changes from the third to the draft fourth edition focus on patient selection criteria. The third edition does not ask about the presence or absence of symptoms, whereas the draft fourth edition mainly targets those with symptoms. These symptoms are based on the Infectious Diseases Society of America guidelines for complicated UTIs.5,6 Pyuria is also investigated differently. The third edition requires the use of centrifuged urine with an average
280
of five or more fields, whereas the draft fourth edition requires the use of uncentrifuged urine with quantitative measurement done with a counting chamber. The draft fourth edition also requires a higher bacterial count before drug administration in females than that required in the third edition. Moreover, although early evaluation of clinical efficacy in the draft fourth edition is done similarly to that in the third edition, at the end of treatment, the draft fourth edition includes the additional evaluation of patients with moderate and excellent clinical and microbiological outcomes in a late evaluation (5 to 9 days after treatment) and in a follow-up evaluation (4 to 6 weeks after treatment). Patients who are evaluated as having a “poor” outcome in the early evaluation were evaluated as having “failed” therapy in the late evaluation (Table 1). The present study was conducted to verify the usefulness of the draft fourth edition in the treatment of patients with complicated urinary tract infections (UTIs) without indwelling urinary catheters.
Cinical trial of antimicrobial treatment administered according to the complicated urinary tract infection criteria of the draft fourth edition Study methods Facilities This multicenter study was conducted by the Kobe UTI Committee, comprising staff from Kobe University and 12 related facilities. The study protocol was prepared in accordance with the criteria of the draft fourth edition. A subcommittee was formed within the Kobe UTI Committee to consider issues such as patient handling, early evaluation, late evaluation, and follow-up (test-of-cure) evaluation.
Table 1. Evaluation criteria for complicated urinary tract infections UTI criteria third edition Target infection Target Patient selection (1) Age/sex (2) Symptoms (3) Pyuria (Pyuria/test method) (4) Bacterial count
Urinary tract infection with underlying disease in the urinary tract 16 Years or older, male or female ≥5 Cells/hpf Average of five or more fields for centrifuged urine ≥104 Cells/ml (Both male and female midstream urine)
(5) Bacterial species
Duration of treatment
5 Days
Evaluation of clinical efficacy Evaluation schedule
End of treatment
End of treatment (early evaluation)
Subjects are patients evaluated as showing “excellent” or “moderate” clinical efficacy at early evaluation. (1) Clinical outcome (2) Microbiological outcome Subjects are patients evaluated as showing “eradication” microbiologically at late evaluation (1) Clinical outcome (2) Microbiological outcome
4–6 Weeks after treatment (follow-up evaluation)
cfu; colony forming units
20 Years or older, male or female Fever, dysuria, frequency, urgency, suprapubic pain, flank pain, chills, costovertebral angle (CVA) tenderness ≥10 WBCs/mm3 Quantitative measurement of uncentrifuged urine with a counting chamber ≥104 cfu/ml (Male midstream urine and female catheterized urine); ≥105 cfu/ml (female midstream urine) Patients excluded when only organisms such as Corynebacterium spp., Lactobacillus spp. or others not involved in the disease are isolated. Usually 5 days for parenteral and 7 days for orally active drugs
End of treatment, plus 5–9 days and 4–6 weeks after treatment (1) Effect on subjective symptoms (2) Effect on pyuria (3) Effect on bacteriuria (4) Overall clinical efficacy (5) Bacteriological response
5–9 Days after treatment (late evaluation)
Usefulness Judgment
UTI criteria draft fourth edition
Judgment on an analogue scale in view of clinical efficacy, adverse drug reactions, and other factors
281
Target infection and patient selection The subjects were patients with complicated UTIs and underlying diseases of the urinary tract, but without indwelling catheters, who visited member facilities of the Kobe UTI Committee from April 2000 to August 2002 with findings of bacterial UTI. All subjects were considered candidates for oral antimicrobial agents. They also met the criteria specified in the draft fourth edition; namely, aged 20 years or older; of either sex; symptoms of fever, dysuria, frequency, urgency, suprapubic pain, flank pain, chills, and costovertebral angle (CVA) tenderness; pyuria before treatment (≥10 WBCs/mm3); and a viable bacterial count before treatment of 104 cfu/ml or more (men, with midstream urine and women with catheterized urine) or 105 cfu/ml or more (women, with midstream urine). Patients were excluded if the identified bacterial species did not clearly contribute to the disease; for example, Corynebacterium, Lactobacillus, and others. No criteria were set for the kind or severity of the underlying disease. Prior to initiation of the study, the attending physician provided written information about the study to the patients and obtained their consent to participate. Drug dosage and administration The study was conducted using a two-group comparative design based on random allocation (envelope method). Subjects were provided with 100-mg tablets containing the cephem antibiotic cefcapene pivoxil hydrochloride, or the quinolone antimicrobial levofloxacin. All drugs were provided at the usual dose, and the subjects were instructed to take a single tablet after breakfast, lunch, and dinner for 7 days, as specified in the draft fourth edition for orally active drugs in complicated UTI. Evaluation of drug efficacy Clinical outcome was evaluated by the subcommittee and by the attending physician. For the subcommittee, three evaluations were made: (1) at the end of treatment (early evaluation), including overall clinical efficacy, effect on pyuria, effect on bacteriuria, and bacteriological response; (2) at 5–9 days after completion of treatment (late evaluation), in which patients in whom overall clinical efficacy was judged as excellent or moderate in the early evaluation were evaluated for clinical outcome and microbiological outcome, whereas those in whom clinical efficacy was judged as poor at the end of treatment were separately classified as “failed”; and (3) at 4–6 weeks after treatment (follow-up evaluation), in which patients whose clinical outcome in the late evaluation was judged as “bacteria eradicated” were evaluated for clinical outcome and microbiological outcome. The criteria “excellent”, “moderate” and “poor” were used for the effects of the drugs on the courses of bacteriuria and pyuria (Table 2). For evaluation by the attending physician, the clinical efficacy at the end of drug administration was classified as
excellent, moderate, fair, or poor according to changes in subjective symptoms, objective signs, and laboratory findings, with the judgment being made by the attending physician. Identification of bacteria isolated from urine Bacteria in urine were cultured for 24 h, using a dip-slide technique (Uricult E; Daiichi-Yakuhin, Tokyo, Japan) at each facility, to determine the bacterial count, and then the cultures were immediately sent to central analysis facilities for identification of the bacterial species.
Results Subjects A total of 159 patients were evaluated. Of these, 22 did not meet the selection criteria and 18 dropped out because of poor drug compliance, failure to visit the hospital after enrollment, or other reasons. The remaining 119 were enrolled for early evaluation, and included 61 patients who received cefcapene pivoxil hydrochloride and 58 patients who received levofloxacin. Patient profiles by sex, age, hospitalization status, diagnosis, underlying disease, UTI group (classified as monomicrobial or polymicrobial and as upper or lower UTIs1,4), infectious status, presence or absence of subjective symptoms before treatment, and isolated bacteria, showed no significant differences between groups. Patient and bacterial profiles Ninety-two patients had subjective symptoms at the start of treatment, whereas 27 did not. Subjective symptoms were absent in 2 of 3 inpatients and 25 of 116 outpatients. Absence of subjective symptoms was more common in men than in women (absent in 16 of the 59 men and 11 of the 60 women) and increased with age (absent in 2 of 16 patients aged 40–59 years; 17 of 76 aged 60–79 years; and 8 of 27 aged 80 years or older). In terms of disease, symptoms were absent in 26 of 115 patients with complicated cystitis and in 1 of 4 with complicated pyelonephritis; similarly, symptoms were
Table 2. Overall clinical efficacy Pyuria Cleared Bacteriuria
Decreased Unchanged Effect on bacteriuria
Eliminated Decreased Replaced Unchanged Effect on pyuria Excellent Moderate Poor
6 0 1 2 9 (7.6%)
63 1 7 8 79 (66.4%) 63 (52.9%) 31 (26.1%) 25 (21.0%)
16 85 (71.4%) 1 2 (1.7%) 2 10 (8.4%) 12 22 (18.5%) 31 (26.1%) 119 Overall clinical efficacy (excellent + moderate) 94 (79.0%)
282 Table 3. Bacteria isolated before treatment (by case) Type of infection Monomicrobial infection
Polymicrobial infection Total
Bacteria isolated before treatment Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus spp. (other than epidermidis) Subtotal Gram-negative bacteria Escherichia coli Klebsiella spp. Pseudomonas aeruginosa Citrobacter koseri Others Subtotal Subtotal
No. of patients
Table 4. Distribution of bacteria isolated before treatment (by strain) Bacteria isolated before treatment
6 4 4 14 27 4 3 3 4 41 55 64 119
absent in 10 of the 55 patients with monomicrobial infection and 17 of the 64 with polymicrobial infection. In regard to distribution of bacteria isolated before the initiation of drug administration, by case, nearly half of the 55 patients with monomicrobial infection showed Escherichia coli (Table 3). When distribution by strain was investigated, the most common bacterial species was E. coli (58 strains; 29.3%), followed by Enterococcus faecalis (48 strains; 24.2%), and Staphylococcus epidermidis (18 strains; 9.1%; Table 4). At early evaluation, 25 patients evaluated as having a poor response and 23 who had dropped out were excluded, and the remaining 71 were enrolled for the late evaluation. The 25 patients evaluated as having a “poor” response were then separately categorized as “failed” and added to the 71 patients in the late evaluation. For microbiological outcome, 14 patients were evaluated as “failed” at the late evaluation and 21 patients had dropped out. These patients were excluded, and the remaining 36 were enrolled for the followup evaluation. Clinical efficacy Early evaluation Table 2 shows the data on overall clinical efficacy and the effects on pyuria and bacteriuria in the 119 patients enrolled for the early evaluation. Overall clinical efficacy was rated as excellent in 63 patients (52.9%), moderate in 31 (26.1%), and poor in 25 (21.0%), giving an efficacy rate of 79.0% according to the criteria of the third and fourth editions. Evaluation of the 92 patients with subjective symptoms was excellent in 53 (57.6%), moderate in 25 (27.2%), and poor in 14 (15.2%), giving an efficacy rate of 84.8% according to the above criteria. In the 27 patients without subjective symptoms, the evaluation was excellent in 10 (37.0%), moderate in 6 (22.2%), and poor in 11 (40.7%), giving an efficacy rate of 59.3% according to the above criteria.
Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus aureus CNS Other Subtotal Gram-negative bacteria Escherichia coli Klebsiella pneumoniae Citrobacter spp. Klebsiella oxytoca Pseudomonas aeruginosa Enterobacter cloacae Serratia marcescens Proteus spp. Other Subtotal Total
No. of strains 48 18 8 7 14 95 58 10 6 5 5 4 4 4 7 103 198
Bacteriuria was evaluated as eliminated in 85 patients (71.4%), decreased in 2 (1.7%), replaced in 10 (8.4%), and unchanged in 22 (18.5%) of the 119 patients enrolled in the early evaluation, giving a rate of 73.1% for decreased or better according to the third and fourth edition criteria. When stratified by the presence or absence of subjective symptoms, bacteriuria was evaluated as eliminated in 69 (75.0%), decreased in 2 (2.2%), replaced in 8 (8.7%), and unchanged in 13 (14.1%) of the 92 patients with subjective symptoms, giving a rate of 77.2% for decreased or eliminated according to the above criteria. In the 27 patients without subjective symptoms, bacteriuria was evaluated as eliminated in 16 (59.3%), decreased in none (0%), replaced in 2 (7.4%), and unchanged in 9 (33.3%), giving a rate of 59.3% for decreased or eliminated according to the above criteria. With regard to pyuria, this sign was evaluated as cleared in 79 (66.4%), decreased in 9 patients (7.6%), and unchanged in 31 (26.1%), giving a rate of decreased or better of 73.9% for the 119 patients enrolled in the early evaluation, according to the fourth edition criteria. When stratified by the presence or absence of subjective symptoms, pyuria was evaluated as cleared in 67 patients (72.8%), decreased in 7 (7.6%), and unchanged in 18 (19.6%) of the 92 patients with subjective symptoms, giving a rate of decreased or higher of 80.4%. In the 27 patients without subjective symptoms, pyuria was evaluated as cleared in 12 (44.4%), decreased in 2 (7.4%), and unchanged in 13 (48.1%), giving a rate of decreased or higher of 51.9% according to the above criteria. Bacteriological response in the 119 patients in the early evaluation was rated as eradicated for 171 (86.4%) and persistent for 27 (13.6%) of the 198 strains isolated. When evaluated by the attending physician on the final day of drug administration, clinical efficacy was rated excellent in 58 patients (48.7%), moderate in 33 (27.7%), fair in 16 (13.4%), and poor in 12 (10.1%), giving an efficacy rate of 76.5% for the 119 patients.
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Late evaluation In the late evaluation, when the 25 patients in whom overall clinical efficacy was evaluated as “poor” in the early evaluation were excluded, and the remaining 71 were studied, the clinical outcome was rated as cured in 65 (91.5%) and failed in 6 (8.5%). When the above 25 patients in whom overall clinical efficacy was evaluated as “poor” were included in the failed group and a total of 96 patients were evaluated in the late evaluation, in accordance with the draft fourth edition, the clinical outcome was rated as cured in 65 (67.7%) and failed in 31 (32.3%). Patients who had no symptoms at either entry or evaluation were regarded as cured. The relationship between clinical outcomes at the early and late evaluations was studied in 96 patients. Of the 49 patients initially evaluated as having an excellent outcome, the late evaluation was cured in 46 (93.9%) and failure in 3 (6.1%). Of the 22 patients initially evaluated as having a moderate outcome, the late evaluation was cured in 19 (86.4%) and failure in 3 (13.6%). Of the 25 patients initially evaluated as having a poor outcome, the late evaluation was cured in none (0%) and failure in 25 (100%). When stratified by the presence or absence of subjective symptoms, the outcome was evaluated as cured in 52 (72.2%) and failure in 20 (27.8%) of the 72 patients with subjective symptoms and as cured in 13 (54.2%) and failure in 11 (45.8%) of the 24 patients without subjective symptoms. Microbiological outcome was rated as eradicated in 57 (80.3%) and failed in 14 (19.7%) of the 71 patients in the late evaluation. When the 25 patients evaluated as having a poor response in the early evaluation were counted as failed in accordance with the draft fourth edition criteria, giving a total of 96 patients for the late evaluation, the microbiological outcome was rated as eradicated in 57 (59.4%) and failed in 39 (40.6%). The relationship between microbiological outcome at the early and late evaluations was studied in 96 patients. Outcome was rated as eradicated in 39 (79.6%) and failed in 10 (20.4%) of the 49 patients evaluated as excellent in the early evaluation; eradicated in 18 (81.8%), and failed in 4 (18.2%) of the 22 evaluated as moderate in the early evaluation, and eradicated in none (0%) and failed in 25 (100%) of the 25 evaluated as poor in the early evaluation. When clinical outcome was stratified by the presence or absence of subjective symptoms, the evaluation was cured in 52 (72.2%) and failed in 20 (27.8%) of the 72 patients with subjective symptoms, and cured in 13 (54.2%) and failed in 11 (45.8%) of the 24 patients without subjective symptoms.
Follow-up evaluation In the 36 patients enrolled in the follow-up evaluation, clinical outcome was rated as cured in 31 (86.1%) and failed in 5 (13.9%). Evaluation of the relationship between clinical
outcomes at the early and follow-up evaluations gave an outcome of cured in 21 (87.5%) and failed in 3 (12.5%) of the 24 patients initially evaluated as excellent, and cured in 10 (83.3%) and failed in 2 (16.7%) of the 12 patients initially evaluated as moderate. When stratified by the presence or absence of subjective symptoms, the clinical outcome was evaluated as cured in 27 (84.4%) and failed in 5 (15.6%) of the 32 patients with subjective symptoms, and cured in all 4 (100%) of those without subjective symptoms. Microbiological outcome was evaluated as eradicated in 24 (66.7%) and failed in 12 (33.3%) of the 36 patients enrolled in the follow-up evaluation. The relationship between microbiological outcomes at the early and followup evaluations gave outcomes of eradicated in 17 (70.8%) and failure in 7 (29.2%) of the 24 patients initially evaluated as excellent; and eradicated in 7 (58.3%) and failure in 5 (41.7%) of the 12 initially evaluated as moderate. When stratified by the presence or absence of subjective symptoms, microbiological outcome was evaluated as cured in 21 (65.6%) and failed in 11 (34.4%) of the 32 patients with subjective symptoms, and cured in 3 (75.0%) and failed in 1 (25.0%) of the 4 patients without subjective symptoms. Regarding the relationship between the early and late evaluation results, although outcome was evaluated as cured in about 90% of patients evaluated as excellent and moderate in the early evaluation, about 20% of these patients showed resurgence of bacteriuria in the microbiological outcome. Table 5 shows the results for overall clinical efficacy at the early and late evaluations. Of the 49 patients evaluated as excellent in the early evaluation, 31 were subsequently rated excellent, 6 moderate, and 12 poor, indicating that symptoms were exacerbated in 18 patients (36.7%). According to the third edition criteria the 49 patients evaluated as excellent in the early evaluation would have been classified as showing good drug efficacy. Of 22 patients evaluated as moderate in the early evaluation, 4 were rated excellent, 11 moderate, and 7 poor, indicating that symptoms were improved in 4 (18.2%), but exacerbated in 7 (31.8%), again demonstrating potentially discrepant results according to the criteria of the two editions. All 12 patients evaluated as poor in the early evaluation were subsequently rated poor.
Table 5. Relationship between results for overall clinical efficacy at early and late evaluations Judgment
Early evaluation Excellent Moderate Poor Total
Late evaluation Excellent
Moderate
Poor
Total
31 4 0 35
6 11 0 17
12 7 12 31
49 22 12 83
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Problems with and future aspects of the urinary tract infection criteria in the draft fourth edition The clinical evaluation of antimicrobial agents used for treating UTIs in Japan has been based on the third edition, published in 1985. In the 1990s, however, the move to international harmonization of clinical evaluation led to a reassessment of these guidelines, culminating in the promulgation of the draft fourth edition in 1996. The most significant difference between the third and fourth editions is that while the former states that the UTI criteria are not “test-of-cure” but “evaluation of drug efficacy,” whereas the latter states that the UTI criteria are aimed at objective “evaluation of drug efficacy” for antimicrobial agents and “test-of-cure” of the disease. No clinical studies using the draft fourth edition have been published, although a number are ongoing. Here, we attempted to verify the usefulness of and identify problems with the draft fourth edition by assessing and observing both the efficacy of antimicrobial drugs in the treatment of complicated UTIs and the courses of the diseases after treatment. A number of interesting results were obtained. First, overall clinical efficacy in the early evaluation was rated as excellent in 52.9%, moderate in 26.1%, and poor in 21.0% of the patients, giving an efficacy rate of 79.0%. For the 96 patients enrolled in the late evaluation, clinical outcome was evaluated as cured in 65 (67.7%) and failed in 31 (32.3%; 6 patients plus 25 patients in whom clinical outcome was evaluated as poor in the early evaluation), while microbiological outcome was evaluated as eradicated in 57 (59.4%) and failed in 39 (40.6%; 14 patients plus 25, as above). Patients without symptoms at entry or at evaluation were evaluated as cured. Second, in the 36 patients in whom the microbiological outcome was rated as eradicated in the late evaluation, clinical outcome at the follow-up evaluation was rated as cured in 31 (86.1%) and failed in 5 (13.9%), whereas the microbiological outcome was rated as eradicated in 24 (66.7%) and failed in 12 (33.3%). These findings highlight the need for long-term follow-up in the evaluation of a drug’s efficacy. Finally, regarding the relationship between the early and follow-up evaluations, clinical outcome on follow-up was rated as cured in 17 (70.8%) of the 24 patients evaluated as having an excellent outcome in the early evaluation and in 7 (58.3%) of the 12 evaluated as moderate. Follow-up microbiological outcome was rated as eradicated in 17 (70.8%) and as failed in 7 (29.2%) of the 24 patients rated as having an excellent outcome in the early evaluation; and as eradicated in 7 (58.3%) and failed in 5 (41.7%) of the 12 patients evaluated as having a moderate outcome in the
early evaluation, indicating an increased frequency of the appearance of bacteriuria. The draft fourth edition was devised to achieve harmonization with United States and European guidelines and to allow comparison with the third edition. The results of the present study have revealed the need for modifications. Among these, one issue is that the draft fourth edition primarily targets patients with subjective symptoms, but is also applicable to patients without subjective symptoms. The results of the present study, however, show that these patients without subjective symptoms (asymptomatic bacteriuria) influenced the evaluation of efficacy and precluded the evaluation of clinical outcome, suggesting the need to review the treatment and evaluation of such patients. Further, the draft fourth edition defines early evaluation differently from the definition used in the United States and European guidelines, in that, in the draft fourth edition, some patients may be evaluated as having a poor outcome or as dropping out at early evaluation, whereas others evaluated as having a poor outcome in the early evaluation can be enrolled in the late evaluation. Again, this finding suggests that a need exists to review the handling of such patients. Overall, with some modifications, the draft fourth edition has the potential to play a role in the international standards for evaluating antimicrobial drug efficacy in the treatment of complicated urinary tract infections. Acknowledgments The authors acknowledge our colleagues who contributed to this review article.
References 1. Ohkoshi M. Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (third edition). Jpn J Antibiot 1987;40:2149–91. 2. Beam TR, Gilbert DN, Kunin CM. General guidelines for the clinical evaluation of anti-infective drug products. Infect Dis 1992;15: S5–32. 3. Naber KG, Bergman B, Bishop MC, Bjerklund-Johansen TE, Botto H, Lobel B, et al. FAU guidelines for the management of urinary and male genital tract infections. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). Eur Urol 2001;40:576–88. 4. UTI Subcommittee of the Clinical Evaluation Guidelines Committee, Japan Society of Chemotherapy. Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (draft fourth edition). Jpn J Antibiot 1997;50:533–78. 5. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America Guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40:643–54. 6. Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of the new anti-infective drugs for the treatment of urinary tract infection. Clin Infect Dis 1992;15 (Suppl 1):S216– 27.
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2007
REVIEW ARTICLE Soichi Arakawa · Kazushi Tanaka · Tetsuya Miura Katsumi Shigemura · Atsushi Takenaka · Takashi Matsui Sadao Kamidono · Yuzo Nakano · Masato Fujisawa
Usefulness and problems of the urinary tract infection criteria for evaluating drug efficacy for complicated urinary tract infections
Received: June 27, 2007
Abstract We aimed to reveal the usefulness of and problematic points with the Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (draft fourth edition) proposed by the UTI Subcommittee of the Clinical Evaluation Guidelines Committee, Japan Society of Chemotherapy, for evaluating antimicrobial agents for complicated urinary tract infections. We conducted a multicenter trial involving 159 patients with complicated urinary tract infections without indwelling urinary catheters. The antimicrobial agents used were cefcapene pivoxil and levofloxacin. “Early evaluation” took place the day after completion of 7 days of therapy; “late evaluation” took place 5–9 days after the end of treatment, and “followup evaluation” was done 4–6 weeks after treatment. In the early evaluation, overall clinical efficacy was judged as excellent in 52.9% of the patients, moderate in 26.1%, and poor in 21.0%, and the bacteriological response was judged as “eradicated” for 86.4% of the 198 bacterial strains isolated. Of 96 patients included in the “late evaluation” category in accordance with the draft fourth edition, the clinical outcome was judged as “cured” in 68.4% and the microbiological outcome was judged as “eradicated” in 59.4%. These rates may be low, because 25 patients in whom clinical efficacy was evaluated as “poor” at the end
S. Arakawa (*) · K. Tanaka · T. Miura · K. Shigemura · Y. Nakano · A. Takenaka · M. Fujisawa Division of Urology, Department of Organs Therapeutics, Faculty of Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan Tel. +81-78-382-6155; Fax +81-78-382-6169 e-mail: [email protected] S. Arakawa Surgical Division, Kobe University Hospital, Kobe, Japan S. Arakawa Department of Infection Control and Prevention, Kobe University Hospital, Kobe, Japan T. Matsui · S. Kamidono Department of Urology, Kobe Red Cross Hospital, Kobe, Japan
of treatment were separately classified as “failed” at the late evaluation. Of the 49 patients with an excellent clinical response at the end of treatment, symptoms were exacerbated in 18 at the follow-up evaluation. Overall, the draft fourth edition, with some modifications of the third edition criteria, such as the addition of a follow-up evaluation 7 days after the cessation of drug administration, has the potential to play a role in the international standards for evaluating antimicrobial drug efficacy for complicated urinary tract infections. Key words Antimicrobial agents · Complicated urinary tract infection · Criteria · Guidelines
Introduction To date, the clinical evaluation of antimicrobial agents used for treating urinary tract infections (UTIs) in Japan has been conducted in accordance with the Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (third edition; hereinafter referred to as the third edition), first published in 1985.1 To promote harmonization with guidelines from the Infectious Diseases Society of America2 and the United States Food and Drug Administration, as well as European guidelines;3 however, the third edition was revised. This revision process led to the development of the Criteria for evaluation of clinical efficacy of antimicrobial agents on urinary tract infection (draft fourth edition; hereinafter referred to as the draft fourth edition)4 in 1997. The major changes from the third to the draft fourth edition focus on patient selection criteria. The third edition does not ask about the presence or absence of symptoms, whereas the draft fourth edition mainly targets those with symptoms. These symptoms are based on the Infectious Diseases Society of America guidelines for complicated UTIs.5,6 Pyuria is also investigated differently. The third edition requires the use of centrifuged urine with an average
280
of five or more fields, whereas the draft fourth edition requires the use of uncentrifuged urine with quantitative measurement done with a counting chamber. The draft fourth edition also requires a higher bacterial count before drug administration in females than that required in the third edition. Moreover, although early evaluation of clinical efficacy in the draft fourth edition is done similarly to that in the third edition, at the end of treatment, the draft fourth edition includes the additional evaluation of patients with moderate and excellent clinical and microbiological outcomes in a late evaluation (5 to 9 days after treatment) and in a follow-up evaluation (4 to 6 weeks after treatment). Patients who are evaluated as having a “poor” outcome in the early evaluation were evaluated as having “failed” therapy in the late evaluation (Table 1). The present study was conducted to verify the usefulness of the draft fourth edition in the treatment of patients with complicated urinary tract infections (UTIs) without indwelling urinary catheters.
Cinical trial of antimicrobial treatment administered according to the complicated urinary tract infection criteria of the draft fourth edition Study methods Facilities This multicenter study was conducted by the Kobe UTI Committee, comprising staff from Kobe University and 12 related facilities. The study protocol was prepared in accordance with the criteria of the draft fourth edition. A subcommittee was formed within the Kobe UTI Committee to consider issues such as patient handling, early evaluation, late evaluation, and follow-up (test-of-cure) evaluation.
Table 1. Evaluation criteria for complicated urinary tract infections UTI criteria third edition Target infection Target Patient selection (1) Age/sex (2) Symptoms (3) Pyuria (Pyuria/test method) (4) Bacterial count
Urinary tract infection with underlying disease in the urinary tract 16 Years or older, male or female ≥5 Cells/hpf Average of five or more fields for centrifuged urine ≥104 Cells/ml (Both male and female midstream urine)
(5) Bacterial species
Duration of treatment
5 Days
Evaluation of clinical efficacy Evaluation schedule
End of treatment
End of treatment (early evaluation)
Subjects are patients evaluated as showing “excellent” or “moderate” clinical efficacy at early evaluation. (1) Clinical outcome (2) Microbiological outcome Subjects are patients evaluated as showing “eradication” microbiologically at late evaluation (1) Clinical outcome (2) Microbiological outcome
4–6 Weeks after treatment (follow-up evaluation)
cfu; colony forming units
20 Years or older, male or female Fever, dysuria, frequency, urgency, suprapubic pain, flank pain, chills, costovertebral angle (CVA) tenderness ≥10 WBCs/mm3 Quantitative measurement of uncentrifuged urine with a counting chamber ≥104 cfu/ml (Male midstream urine and female catheterized urine); ≥105 cfu/ml (female midstream urine) Patients excluded when only organisms such as Corynebacterium spp., Lactobacillus spp. or others not involved in the disease are isolated. Usually 5 days for parenteral and 7 days for orally active drugs
End of treatment, plus 5–9 days and 4–6 weeks after treatment (1) Effect on subjective symptoms (2) Effect on pyuria (3) Effect on bacteriuria (4) Overall clinical efficacy (5) Bacteriological response
5–9 Days after treatment (late evaluation)
Usefulness Judgment
UTI criteria draft fourth edition
Judgment on an analogue scale in view of clinical efficacy, adverse drug reactions, and other factors
281
Target infection and patient selection The subjects were patients with complicated UTIs and underlying diseases of the urinary tract, but without indwelling catheters, who visited member facilities of the Kobe UTI Committee from April 2000 to August 2002 with findings of bacterial UTI. All subjects were considered candidates for oral antimicrobial agents. They also met the criteria specified in the draft fourth edition; namely, aged 20 years or older; of either sex; symptoms of fever, dysuria, frequency, urgency, suprapubic pain, flank pain, chills, and costovertebral angle (CVA) tenderness; pyuria before treatment (≥10 WBCs/mm3); and a viable bacterial count before treatment of 104 cfu/ml or more (men, with midstream urine and women with catheterized urine) or 105 cfu/ml or more (women, with midstream urine). Patients were excluded if the identified bacterial species did not clearly contribute to the disease; for example, Corynebacterium, Lactobacillus, and others. No criteria were set for the kind or severity of the underlying disease. Prior to initiation of the study, the attending physician provided written information about the study to the patients and obtained their consent to participate. Drug dosage and administration The study was conducted using a two-group comparative design based on random allocation (envelope method). Subjects were provided with 100-mg tablets containing the cephem antibiotic cefcapene pivoxil hydrochloride, or the quinolone antimicrobial levofloxacin. All drugs were provided at the usual dose, and the subjects were instructed to take a single tablet after breakfast, lunch, and dinner for 7 days, as specified in the draft fourth edition for orally active drugs in complicated UTI. Evaluation of drug efficacy Clinical outcome was evaluated by the subcommittee and by the attending physician. For the subcommittee, three evaluations were made: (1) at the end of treatment (early evaluation), including overall clinical efficacy, effect on pyuria, effect on bacteriuria, and bacteriological response; (2) at 5–9 days after completion of treatment (late evaluation), in which patients in whom overall clinical efficacy was judged as excellent or moderate in the early evaluation were evaluated for clinical outcome and microbiological outcome, whereas those in whom clinical efficacy was judged as poor at the end of treatment were separately classified as “failed”; and (3) at 4–6 weeks after treatment (follow-up evaluation), in which patients whose clinical outcome in the late evaluation was judged as “bacteria eradicated” were evaluated for clinical outcome and microbiological outcome. The criteria “excellent”, “moderate” and “poor” were used for the effects of the drugs on the courses of bacteriuria and pyuria (Table 2). For evaluation by the attending physician, the clinical efficacy at the end of drug administration was classified as
excellent, moderate, fair, or poor according to changes in subjective symptoms, objective signs, and laboratory findings, with the judgment being made by the attending physician. Identification of bacteria isolated from urine Bacteria in urine were cultured for 24 h, using a dip-slide technique (Uricult E; Daiichi-Yakuhin, Tokyo, Japan) at each facility, to determine the bacterial count, and then the cultures were immediately sent to central analysis facilities for identification of the bacterial species.
Results Subjects A total of 159 patients were evaluated. Of these, 22 did not meet the selection criteria and 18 dropped out because of poor drug compliance, failure to visit the hospital after enrollment, or other reasons. The remaining 119 were enrolled for early evaluation, and included 61 patients who received cefcapene pivoxil hydrochloride and 58 patients who received levofloxacin. Patient profiles by sex, age, hospitalization status, diagnosis, underlying disease, UTI group (classified as monomicrobial or polymicrobial and as upper or lower UTIs1,4), infectious status, presence or absence of subjective symptoms before treatment, and isolated bacteria, showed no significant differences between groups. Patient and bacterial profiles Ninety-two patients had subjective symptoms at the start of treatment, whereas 27 did not. Subjective symptoms were absent in 2 of 3 inpatients and 25 of 116 outpatients. Absence of subjective symptoms was more common in men than in women (absent in 16 of the 59 men and 11 of the 60 women) and increased with age (absent in 2 of 16 patients aged 40–59 years; 17 of 76 aged 60–79 years; and 8 of 27 aged 80 years or older). In terms of disease, symptoms were absent in 26 of 115 patients with complicated cystitis and in 1 of 4 with complicated pyelonephritis; similarly, symptoms were
Table 2. Overall clinical efficacy Pyuria Cleared Bacteriuria
Decreased Unchanged Effect on bacteriuria
Eliminated Decreased Replaced Unchanged Effect on pyuria Excellent Moderate Poor
6 0 1 2 9 (7.6%)
63 1 7 8 79 (66.4%) 63 (52.9%) 31 (26.1%) 25 (21.0%)
16 85 (71.4%) 1 2 (1.7%) 2 10 (8.4%) 12 22 (18.5%) 31 (26.1%) 119 Overall clinical efficacy (excellent + moderate) 94 (79.0%)
282 Table 3. Bacteria isolated before treatment (by case) Type of infection Monomicrobial infection
Polymicrobial infection Total
Bacteria isolated before treatment Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus spp. (other than epidermidis) Subtotal Gram-negative bacteria Escherichia coli Klebsiella spp. Pseudomonas aeruginosa Citrobacter koseri Others Subtotal Subtotal
No. of patients
Table 4. Distribution of bacteria isolated before treatment (by strain) Bacteria isolated before treatment
6 4 4 14 27 4 3 3 4 41 55 64 119
absent in 10 of the 55 patients with monomicrobial infection and 17 of the 64 with polymicrobial infection. In regard to distribution of bacteria isolated before the initiation of drug administration, by case, nearly half of the 55 patients with monomicrobial infection showed Escherichia coli (Table 3). When distribution by strain was investigated, the most common bacterial species was E. coli (58 strains; 29.3%), followed by Enterococcus faecalis (48 strains; 24.2%), and Staphylococcus epidermidis (18 strains; 9.1%; Table 4). At early evaluation, 25 patients evaluated as having a poor response and 23 who had dropped out were excluded, and the remaining 71 were enrolled for the late evaluation. The 25 patients evaluated as having a “poor” response were then separately categorized as “failed” and added to the 71 patients in the late evaluation. For microbiological outcome, 14 patients were evaluated as “failed” at the late evaluation and 21 patients had dropped out. These patients were excluded, and the remaining 36 were enrolled for the followup evaluation. Clinical efficacy Early evaluation Table 2 shows the data on overall clinical efficacy and the effects on pyuria and bacteriuria in the 119 patients enrolled for the early evaluation. Overall clinical efficacy was rated as excellent in 63 patients (52.9%), moderate in 31 (26.1%), and poor in 25 (21.0%), giving an efficacy rate of 79.0% according to the criteria of the third and fourth editions. Evaluation of the 92 patients with subjective symptoms was excellent in 53 (57.6%), moderate in 25 (27.2%), and poor in 14 (15.2%), giving an efficacy rate of 84.8% according to the above criteria. In the 27 patients without subjective symptoms, the evaluation was excellent in 10 (37.0%), moderate in 6 (22.2%), and poor in 11 (40.7%), giving an efficacy rate of 59.3% according to the above criteria.
Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus aureus CNS Other Subtotal Gram-negative bacteria Escherichia coli Klebsiella pneumoniae Citrobacter spp. Klebsiella oxytoca Pseudomonas aeruginosa Enterobacter cloacae Serratia marcescens Proteus spp. Other Subtotal Total
No. of strains 48 18 8 7 14 95 58 10 6 5 5 4 4 4 7 103 198
Bacteriuria was evaluated as eliminated in 85 patients (71.4%), decreased in 2 (1.7%), replaced in 10 (8.4%), and unchanged in 22 (18.5%) of the 119 patients enrolled in the early evaluation, giving a rate of 73.1% for decreased or better according to the third and fourth edition criteria. When stratified by the presence or absence of subjective symptoms, bacteriuria was evaluated as eliminated in 69 (75.0%), decreased in 2 (2.2%), replaced in 8 (8.7%), and unchanged in 13 (14.1%) of the 92 patients with subjective symptoms, giving a rate of 77.2% for decreased or eliminated according to the above criteria. In the 27 patients without subjective symptoms, bacteriuria was evaluated as eliminated in 16 (59.3%), decreased in none (0%), replaced in 2 (7.4%), and unchanged in 9 (33.3%), giving a rate of 59.3% for decreased or eliminated according to the above criteria. With regard to pyuria, this sign was evaluated as cleared in 79 (66.4%), decreased in 9 patients (7.6%), and unchanged in 31 (26.1%), giving a rate of decreased or better of 73.9% for the 119 patients enrolled in the early evaluation, according to the fourth edition criteria. When stratified by the presence or absence of subjective symptoms, pyuria was evaluated as cleared in 67 patients (72.8%), decreased in 7 (7.6%), and unchanged in 18 (19.6%) of the 92 patients with subjective symptoms, giving a rate of decreased or higher of 80.4%. In the 27 patients without subjective symptoms, pyuria was evaluated as cleared in 12 (44.4%), decreased in 2 (7.4%), and unchanged in 13 (48.1%), giving a rate of decreased or higher of 51.9% according to the above criteria. Bacteriological response in the 119 patients in the early evaluation was rated as eradicated for 171 (86.4%) and persistent for 27 (13.6%) of the 198 strains isolated. When evaluated by the attending physician on the final day of drug administration, clinical efficacy was rated excellent in 58 patients (48.7%), moderate in 33 (27.7%), fair in 16 (13.4%), and poor in 12 (10.1%), giving an efficacy rate of 76.5% for the 119 patients.
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Late evaluation In the late evaluation, when the 25 patients in whom overall clinical efficacy was evaluated as “poor” in the early evaluation were excluded, and the remaining 71 were studied, the clinical outcome was rated as cured in 65 (91.5%) and failed in 6 (8.5%). When the above 25 patients in whom overall clinical efficacy was evaluated as “poor” were included in the failed group and a total of 96 patients were evaluated in the late evaluation, in accordance with the draft fourth edition, the clinical outcome was rated as cured in 65 (67.7%) and failed in 31 (32.3%). Patients who had no symptoms at either entry or evaluation were regarded as cured. The relationship between clinical outcomes at the early and late evaluations was studied in 96 patients. Of the 49 patients initially evaluated as having an excellent outcome, the late evaluation was cured in 46 (93.9%) and failure in 3 (6.1%). Of the 22 patients initially evaluated as having a moderate outcome, the late evaluation was cured in 19 (86.4%) and failure in 3 (13.6%). Of the 25 patients initially evaluated as having a poor outcome, the late evaluation was cured in none (0%) and failure in 25 (100%). When stratified by the presence or absence of subjective symptoms, the outcome was evaluated as cured in 52 (72.2%) and failure in 20 (27.8%) of the 72 patients with subjective symptoms and as cured in 13 (54.2%) and failure in 11 (45.8%) of the 24 patients without subjective symptoms. Microbiological outcome was rated as eradicated in 57 (80.3%) and failed in 14 (19.7%) of the 71 patients in the late evaluation. When the 25 patients evaluated as having a poor response in the early evaluation were counted as failed in accordance with the draft fourth edition criteria, giving a total of 96 patients for the late evaluation, the microbiological outcome was rated as eradicated in 57 (59.4%) and failed in 39 (40.6%). The relationship between microbiological outcome at the early and late evaluations was studied in 96 patients. Outcome was rated as eradicated in 39 (79.6%) and failed in 10 (20.4%) of the 49 patients evaluated as excellent in the early evaluation; eradicated in 18 (81.8%), and failed in 4 (18.2%) of the 22 evaluated as moderate in the early evaluation, and eradicated in none (0%) and failed in 25 (100%) of the 25 evaluated as poor in the early evaluation. When clinical outcome was stratified by the presence or absence of subjective symptoms, the evaluation was cured in 52 (72.2%) and failed in 20 (27.8%) of the 72 patients with subjective symptoms, and cured in 13 (54.2%) and failed in 11 (45.8%) of the 24 patients without subjective symptoms.
Follow-up evaluation In the 36 patients enrolled in the follow-up evaluation, clinical outcome was rated as cured in 31 (86.1%) and failed in 5 (13.9%). Evaluation of the relationship between clinical
outcomes at the early and follow-up evaluations gave an outcome of cured in 21 (87.5%) and failed in 3 (12.5%) of the 24 patients initially evaluated as excellent, and cured in 10 (83.3%) and failed in 2 (16.7%) of the 12 patients initially evaluated as moderate. When stratified by the presence or absence of subjective symptoms, the clinical outcome was evaluated as cured in 27 (84.4%) and failed in 5 (15.6%) of the 32 patients with subjective symptoms, and cured in all 4 (100%) of those without subjective symptoms. Microbiological outcome was evaluated as eradicated in 24 (66.7%) and failed in 12 (33.3%) of the 36 patients enrolled in the follow-up evaluation. The relationship between microbiological outcomes at the early and followup evaluations gave outcomes of eradicated in 17 (70.8%) and failure in 7 (29.2%) of the 24 patients initially evaluated as excellent; and eradicated in 7 (58.3%) and failure in 5 (41.7%) of the 12 initially evaluated as moderate. When stratified by the presence or absence of subjective symptoms, microbiological outcome was evaluated as cured in 21 (65.6%) and failed in 11 (34.4%) of the 32 patients with subjective symptoms, and cured in 3 (75.0%) and failed in 1 (25.0%) of the 4 patients without subjective symptoms. Regarding the relationship between the early and late evaluation results, although outcome was evaluated as cured in about 90% of patients evaluated as excellent and moderate in the early evaluation, about 20% of these patients showed resurgence of bacteriuria in the microbiological outcome. Table 5 shows the results for overall clinical efficacy at the early and late evaluations. Of the 49 patients evaluated as excellent in the early evaluation, 31 were subsequently rated excellent, 6 moderate, and 12 poor, indicating that symptoms were exacerbated in 18 patients (36.7%). According to the third edition criteria the 49 patients evaluated as excellent in the early evaluation would have been classified as showing good drug efficacy. Of 22 patients evaluated as moderate in the early evaluation, 4 were rated excellent, 11 moderate, and 7 poor, indicating that symptoms were improved in 4 (18.2%), but exacerbated in 7 (31.8%), again demonstrating potentially discrepant results according to the criteria of the two editions. All 12 patients evaluated as poor in the early evaluation were subsequently rated poor.
Table 5. Relationship between results for overall clinical efficacy at early and late evaluations Judgment
Early evaluation Excellent Moderate Poor Total
Late evaluation Excellent
Moderate
Poor
Total
31 4 0 35
6 11 0 17
12 7 12 31
49 22 12 83
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Problems with and future aspects of the urinary tract infection criteria in the draft fourth edition The clinical evaluation of antimicrobial agents used for treating UTIs in Japan has been based on the third edition, published in 1985. In the 1990s, however, the move to international harmonization of clinical evaluation led to a reassessment of these guidelines, culminating in the promulgation of the draft fourth edition in 1996. The most significant difference between the third and fourth editions is that while the former states that the UTI criteria are not “test-of-cure” but “evaluation of drug efficacy,” whereas the latter states that the UTI criteria are aimed at objective “evaluation of drug efficacy” for antimicrobial agents and “test-of-cure” of the disease. No clinical studies using the draft fourth edition have been published, although a number are ongoing. Here, we attempted to verify the usefulness of and identify problems with the draft fourth edition by assessing and observing both the efficacy of antimicrobial drugs in the treatment of complicated UTIs and the courses of the diseases after treatment. A number of interesting results were obtained. First, overall clinical efficacy in the early evaluation was rated as excellent in 52.9%, moderate in 26.1%, and poor in 21.0% of the patients, giving an efficacy rate of 79.0%. For the 96 patients enrolled in the late evaluation, clinical outcome was evaluated as cured in 65 (67.7%) and failed in 31 (32.3%; 6 patients plus 25 patients in whom clinical outcome was evaluated as poor in the early evaluation), while microbiological outcome was evaluated as eradicated in 57 (59.4%) and failed in 39 (40.6%; 14 patients plus 25, as above). Patients without symptoms at entry or at evaluation were evaluated as cured. Second, in the 36 patients in whom the microbiological outcome was rated as eradicated in the late evaluation, clinical outcome at the follow-up evaluation was rated as cured in 31 (86.1%) and failed in 5 (13.9%), whereas the microbiological outcome was rated as eradicated in 24 (66.7%) and failed in 12 (33.3%). These findings highlight the need for long-term follow-up in the evaluation of a drug’s efficacy. Finally, regarding the relationship between the early and follow-up evaluations, clinical outcome on follow-up was rated as cured in 17 (70.8%) of the 24 patients evaluated as having an excellent outcome in the early evaluation and in 7 (58.3%) of the 12 evaluated as moderate. Follow-up microbiological outcome was rated as eradicated in 17 (70.8%) and as failed in 7 (29.2%) of the 24 patients rated as having an excellent outcome in the early evaluation; and as eradicated in 7 (58.3%) and failed in 5 (41.7%) of the 12 patients evaluated as having a moderate outcome in the
early evaluation, indicating an increased frequency of the appearance of bacteriuria. The draft fourth edition was devised to achieve harmonization with United States and European guidelines and to allow comparison with the third edition. The results of the present study have revealed the need for modifications. Among these, one issue is that the draft fourth edition primarily targets patients with subjective symptoms, but is also applicable to patients without subjective symptoms. The results of the present study, however, show that these patients without subjective symptoms (asymptomatic bacteriuria) influenced the evaluation of efficacy and precluded the evaluation of clinical outcome, suggesting the need to review the treatment and evaluation of such patients. Further, the draft fourth edition defines early evaluation differently from the definition used in the United States and European guidelines, in that, in the draft fourth edition, some patients may be evaluated as having a poor outcome or as dropping out at early evaluation, whereas others evaluated as having a poor outcome in the early evaluation can be enrolled in the late evaluation. Again, this finding suggests that a need exists to review the handling of such patients. Overall, with some modifications, the draft fourth edition has the potential to play a role in the international standards for evaluating antimicrobial drug efficacy in the treatment of complicated urinary tract infections. Acknowledgments The authors acknowledge our colleagues who contributed to this review article.
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