cilastatin 0.5 g for the treatment of acute uncomplicated pyelonephritis and complicated urinary tract infections

International Journal of Antimicrobial Agents 19 (2002) 95 – 103 www.ischemo.org

Original article

Piperacillin 2 g/tazobactam 0.5 g is as effective as imipenem 0.5 g/cilastatin 0.5 g for the treatment of acute uncomplicated pyelonephritis and complicated urinary tract infections Kurt G. Naber a,*, Orlin Savov a, Hans C. Salmen b a

Clinic of Urology, St. Elisabeth Hospital, St. Elisabeth Strasse 23, D-94315 Straubing, Germany b Wyeth Pharma GmbH, D-48159 Muenster, Germany Received 23 July 2001; accepted 24 September 2001

Abstract This randomised, double-blind, multicentre trial compared piperacillin/tazobactam (2 g/0.5 g/q8h) and imipenem/cilastatin (0.5 g/0.5 g/q8h) as monotherapy in patients with acute pyelonephritis or complicated urinary tract infections. In total, 237 patients were randomised to receive either piperacillin/tazobactam (n= 161) or imipenem/cilastatin (n = 166). At the early follow-up ( =test-of-cure-visit) 5–9 days after antibiotic therapy, clinical success was noted in 122/147 (83.0%) piperacillin/tazobactam recipients compared with 123/154 (79.9%) imipenem/cilastatin recipients, thus proving that both treatments were equally effective. On a descriptive level, an advantage of piperacillin/tazobactam was demonstrated. Microbiological success at the early follow-up was 78/135 (57.8%) for piperacillin/tazobactam and 70/144 (48.6%) for imipenem/cilastatin. These results were confirmed by equivalent success rates on the last therapy day. Both drugs were generally well tolerated. © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Antibacterial; Acylamino-penicillin; Imipenem/cilastatin; Urinary tract infection; Pyelonephritis; Piperacillin/tazobactam

1. Introduction Urinary tract infections (UTIs) generate a large number of medical consultations. In hospital environments, they are responsible for 30 – 45% of all nosocomial infections [1,2]. Important predisposing factors which may favour the acquisition of bacterial UTIs include not only age and gender, but also complicating factors such as neurological disorders, vesico-ureteric reflux, kidney stones and residual bladder volume [3]. Pyelonephritis is an acute clinical syndrome associated with urinary tract infections [4,5]. The diagnosis is  This work was presented in part at the Eleventh Congress of Clinical Microbiology and Infectious Diseases, Istanbul, Turkey, April 1 – 4, 2001. * Corresponding author. Tel.: + 49-9421-710-1700; fax: +499421-710-270. E-mail address: [email protected] (K.G. Naber).

commonly based on bacteriological confirmation of a urinary tract infection associated with a systemic illness with fever and loin pain or tenderness. This syndrome occurs predominantly in women. A complicated disease is uncommon and has been reported in only :20% of patients [6,7]. Piperacillin is a semi-synthetic ureidopenicillin with a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria and with higher activity against Pseudomonas aeruginosa than other ureidopenicillins [8–14]. In order to prevent hydrolysis of piperacillin by bacterial b-lactamases, it was combined with the b-lactamase inhibitor tazobactam [15], which inhibits a broad spectrum of commonly occurring plasmid-mediated b-lactamases [16]. The combination of piperacillin and tazobactam is effective in vitro against a broad spectrum of bacteria, including Enterobacteriaceae, Pseudomonas spp., anaerobes and

0924-8579/02/$ - $20 © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 1 ) 0 0 4 8 1 - 2

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staphylococci [15,16]. Comparative and non-comparative clinical trials, with or without an aminoglycoside, have been carried out in patients with intra-abdominal infections [17–21], complicated urinary tract infections [12,22 –24], infections of the bones and joints [25,26], in the empirical treatment of febrile neutropenia [27–30] and in community-acquired or nosocomial pneumonia [31,32]. In all of the above trials, piperacillin– tazobactam showed comparable or better activity than the comparator treatment. The pathogens typically responsible for bacterial urinary tract infections fall within the antibacterial spectrum of piperacillin/tazobactam [12,33]. It was therefore justifiable to assume that this regimen would represent an effective therapeutic option for acute pyelonephritis and complicated urinary tract infections. This hypothesis was confirmed by a multinational, non-comparative trial, in which 217 patients with complicated urinary tract infections were treated with piperacillin 4 g/tazobactam 0.5 g. Success rates at the early follow-up evaluation 7 days after antibacterial treatment were 87.0% for clinical outcome and 83.2% for microbiological outcome [24]. The present clinical trial was conducted in order to demonstrate the clinical and microbiological efficacy of piperacillin 2 g/tazobactam 0.5 g in patients with acute uncomplicated pyelonephritis or complicated urinary tract infections under controlled conditions, according to the standards of good clinical practice (GCP). The study design was that of a non-inferiority trial in comparison with a positive standard [34– 37]. Imipenem 0.5 g/cilastatin 0.5 g was chosen as the comparator because it is regarded as standard treatment for the above indications. Additionally, it covers an antibacterial spectrum comparable with that of piperacillin/tazobactam.

2. Methods

2.1. Study design and selection criteria Hospitalized patients (]18 years) were eligible to enter the study if they had pyuria (] 10 leukocytes per ml native urine or per high power field in urinary sediment) and bacteriuria (i.e. cfu/ml ] P, as defined in

Table 1). Specimens had to have been taken within 48 h before the start of study treatment. Principal exclusion criteria were prostatitis, presence of a catheter, ureteric splint or nephrostomia, which was not expected to be removed earlier than 2 days before the end of treatment; prior treatment with more than one dose of an antibacterial drug within 72 h before the start of the trial medication— except in the case of clinical failure and proven resistance to the compounds used; severe concomitant diseases; known or suspected sensitivity to penicillins, cephalosporins, other b-lactam antibiotics or b-lactamase inhibitors, or carbapenems. Acute uncomplicated pyelonephritis was characterised by fever \ 38 °C, pain in the upper urinary tract (pain in the flanks, percussion pain over the renal bed, pain in the back) and the absence of urological abnormalities. Complicated urinary tract infections were defined by the presence of complicating factors (Table 2) and by at least one of the following symptoms: fever \38 °C, pain in the upper urinary tract as specified above, pain in the lower urinary tract (perineal pain, urethralgia, pain in the vesical region) and micturition difficulties (dysuria, urgency, frequency). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments [38], the GCP guidelines [39], the German Drug Law §§ 40, 41 [40] and the European Guidelines for Evaluation of Antibacterial Drugs in urinary tract infections [41]. All patients were informed about the nature, importance and implications of the trial and were required to give written informed consent.

2.2. Randomisation, blinding and trial medication Patients were randomised in a 1:1 ratio, using computer-generated randomisation envelopes to receive either piperacillin/tazobactam or imipenem/cilastatin. The trial medication was administered as a 30-min infusion every 8 h. A treatment duration of not less than 5 and no more than 14 days was recommended. If the patient was febrile, at least four doses had to be given after resolution of the fever; and if the patient had an indwelling catheter, splint or nephrostomy, at least four doses had to be given after removal. Preparation of the antibiotic solution was carried out by a

Table 1 Limits of positive (cfu]P) and negative (cfuBN) counts of colony forming units (cfu) in urine depending on sex and technique of urine specimen collection Technique of urine specimen collection

Midstream urine Catheter specimen Suprapubic bladder puncture

Positive limit (P)

Negative limit (N)

Female (cfu/ml)

Male (cfu/ml)

Female (cfu/ml)

Male (cfu/ml)

105 104 102

104 104 102

103 103 B102

103 103 B102

K.G. Naber et al. / International Journal of Antimicrobial Agents 19 (2002) 95–103 Table 2 Demographic and anamnestic data Parameter

Piperacillin/tazo- Imipenem/cilastbactam (n =166) atin (n= 171)

Age (years; means 9 S.D. (range))

59.1 9 17.5 (18–92)

Sex Male Female Acute uncomplicated pyelonephritis Complicated urinary tract infection

98 (59.0%) 68 (41.0%)

95 (55.6%) 76 (44.4%)

22 (13.3%)

18 (10.5%)

144 (86.7%)

153 (89.5%)

Complicating factors (multiple ratings) Anatomical or functional 78 (54.2%) abnormalities Neurogenic bladder 6 (4.2%) disturbance Urological intervention in 79 (54.9%) the history Catheterisation, ureteric 69 (47.9%) splint, nephrostomy Course of the disease First episode Recurrent episode Clinical persistent UTI Risk factors

87 (56.9%) 7 (4.6%) 68 (44.4%) 68 (44.4%)

120 (72.3%) 43 (25.9%)

114 (66.7%) 54 (31.6%)

3 (1.8%) 96 (57.8%)

3 (1.8%) 97 (56.7%)

Main predisposing factors (multiple ratings) Cardiopulmonary disease 55 (33.1%) Neoplasia 33 (19.9%) Diabetes mellitus 29 (17.5%) Arterial occlusive disease 11 (6.6%) Concomitant medication

58.7 918.7 (18–88)

129 (77.7%)

55 29 27 16

(32.2%) (17.0%) (15.8%) (9.4%)

139 (81.3%)

neutral person, according to the randomisation schedule drawn up by each individual centre. This person was responsible for ensuring that blinded infusion solutions were always available for the trial patients.

2.3. Assessments and criteria for withdrawal Control visits took place before initiation of treatment (‘pre-treatment’), daily up to the last day of treatment, immediately or 1– 2 days after the end of treatment (‘post-treatment’), 5 – 9 days after treatment (early follow-up, FU1) and 4– 6 weeks after treatment (late follow-up, FU2). At baseline, a case history was recorded which included demographic data, diagnoses, history of infection, previous and current medication and concomitant disorders. Study treatment, as well as other medication and possible side-effects, were documented. Clinical signs and symptoms (dysuria; urgency; frequency; pain in the lower urinary tract: perineal pain, urethralgia, pain in the vesical region; pain in the upper urinary tract: loin pain, percussion pain over the renal bed, pain in the back; body temperature; chills)

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were recorded on days 1–7, day 9 (91), day 12 (91) and on the last treatment day or the ‘post-treatment’ day and at both follow-up visits. Urinalysis including microbiology was performed at entry, on day 4 (91) and at the three control visits after termination of the study drug. Laboratory safety parameters were monitored during and after treatment. Patients were withdrawn from treatment in the case of serious adverse events or clinical failure with a need for alternative antibiotic therapy, a change to another antibacterial agent due to a new infection at another site in the body caused by pathogens resistant to the trial drugs, a significant worsening of laboratory results or following a decision by the patient or the investigator. According to the study protocol, a verdict of ‘clinical failure’ could not be reached before at least six doses of the trial medication had been given. Early withdrawals after less than six doses were excluded from the efficacy evaluation.

2.4. Study endpoints and statistical implications The clinical and microbiological response was rated according to respective European guidelines for anti-infective drugs for the treatment of urinary tract infections [37]. Clinical cure was defined as resolution of all signs and symptoms of the UTI without any further antibacterial treatment, improvement as residual symptoms present, but no pain in the upper urinary tract and no necessity for further antibacterial treatment, and failure as unsatisfactory clinical response or relapse. The microbiological response was rated on the basis of changes affecting the primary pathogens initially identified as having caused the UTI and any secondary organisms, such as contaminants or new pathogens causing a superinfection. In the case of primary pathogens the following definitions applied: elimination was defined as reduction from cfu]P to cfuB N, suppression as reduction from cfu]P to cfu= N and failure as cfu\ N, if the control was in question, or missing data due to clinical failure occurred. In the case of secondary organisms, the microbiological result was directly classified as absent if no secondary organisms were detectable, as colonisation if secondary organisms were present with cfuB P and superinfection if secondary organisms were present with cfu] P (Table 1). The microbiological response post-treatment, at early follow-up and at late follow-up was rated separately as a microbiological success in the case of elimination of the primary pathogen(s) and absence or colonisation by secondary organisms. All other results were graded as failures, including suppression, superinfection and reinfection. On the basis of success/failure, missing data were replaced according to Naber [42] following a carry-forward of the corresponding rating in the case of

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failure or carry-backward of the corresponding rating in any case.

3. Results

3.1. Patient distribution and baseline characteristics 2.5. Study endpoints and exploratory data analysis The primary study endpoints were the bacteriological success rate and the clinical success rate at early followup. Non-inferiority was tested one-sided using 10% as the equivalence limit at a one-sided significance level h = 0.025 [34,36]. The success rates post-treatment and at late follow-up were used as secondary study endpoints and evaluated as described above. Further efficacy variables, such as microbiological findings including species, sensitivity of species [43,44], specific urinary variables, clinical signs and symptoms and safety variables, were analysed descriptively in the context of exploratory data analysis.

2.6. Statistical methods and sample size calculation For analysis of homogeneity, the baseline characteristics of the treatment groups were compared by the t-test and Wilcoxon– Mann –Whitney-test for continuous variables and by the  2-test for categorical variables. The main outcome measurements were analysed on the basis of intention-to-treat for all patients for whom there was, as a minimum, information about efficacy after not less than six doses of the study medication (ITT population under a slightly modified definition as a ‘full analysis set’ according to ICH-E9guidelines [36]). With regard to microbiological findings, a modified intention-to-treat population was considered, consisting of all patients with proven infection at study outset and/or at least one evaluable microbiological control after treatment. The microbiological findings without major violations of the protocol were additionally analysed in a per-protocol set. Violations of the clinical or bacteriological inclusion criteria, early follow-up after B 5 days and discontinuation of treatment after B 15 doses, for non-medical reasons were considered as major violations of the protocol. Using the data sets defined above, tests for non-inferiority were performed according to the confidence interval inclusion method [36]. Exploratory group comparisons were carried out by standard methods (t-test, U-test,  2-test, Mantel– Haenszel  2-test). SAS [45] was used as the statistical software package. The sample size was calculated prospectively under the following conditions: success rate= 75%, h =0.05 one-sided, 1-i = 0.85, equivalence limit of 15%. The calculation yielded 2×123 individuals per group. The tightening of the study requirements [34,36] during the clinical performance with the conditions ‘h = 0.025 onesided, equivalence limit 10%’ was compensated by an increase in sample size to a total of 327 evaluable patients.

In total, 23 sites participated in the study enrolling 337 patients to receive either piperacillin/tazobactam (n=166) or imipenem/cilastatin (n=171). The mean age of the patients was 59.1 years in the piperacillin/ tazobactam group and 58.7 years in the imipenem/cilastatin group. Male patients dominated with 59.0% in the piperacillin/tazobactam group and 55.6% in the imipenem/cilastatin group. In most patients, the infection was classified as a complicated urinary tract infection (piperacillin/tazobactam: 86.7%; imipenem/ cilastatin: 89.5%). The remaining patients suffered from acute uncomplicated pyelonephritis (Table 2). Differences between the trial groups with respect to demographic data, medical history and main baseline characteristics were not significant. There was a high degree of homogeneity in both trial groups with respect to all pre-treatment conditions (Table 3). The ITT population comprised 327 patients (161 on piperacillin/tazobactam and 166 on imipenem/cilastatin). Ten patients stopped treatment after less than six doses. No evaluable microbiological information was available for 19 patients on piperacillin/tazobactam and 16 on imipenem/cilastatin. Twenty-two patients in the remaining modified ITT population showed further major protocol violations. Therefore, the PP population comprised 270 patients (134 on piperacillin/tazobactam, 136 on imipenem/cilastatin). The sample size decreased in the course of the study due to non-medical reasons. The drop-out rates were 14/161 (8.7%; piperacillin/ tazobactam) and 13/167 (7.8%; imipenem/cilastatin) at early follow-up in the ITT population. These results were acceptable. Table 3 Clinical baseline characteristics Parameter

Piperacillin/tazobactam (n =166)

Imipenem/cilastatin (n = 171)

In acute uncomplicated pyelonephritis (n = 22, 18) Fever \38 °C 21 (95.5%) 18 (100.0%) Pain in the flanks 22 (100.0%) 18 (100.0%) Percussion pain over 21 (95.5%) 18 (100.0%) the renal bed Pain in the back 20 (90.9%) 18 (100.0%) In complicated urinary tract infection (n = 144, Fever \38 °C 65 (45.1%) Pain in the upper 59 (41.0%) urinary tract Pain in the lower 69 (47.9%) urinary tract Micturition difficulties 88 (61.1%)

153) 66 (43.1%) 59 (38.6%) 73 (47.7%) 87 (56.9%)

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Table 4 Clinical results in the ITT evaluation Clinical response

Post-treatment

Early follow-up

Late follow-up

Piperacillin/ tazobactam

Imipenem/ cilastatin

Piperacillin/ tazobactam

Imipenem/ cilastatin

Piperacillin/ tazobactam

Imipenem/ cilastatin

Cure Improved Failure Indeterminate*

136 20 5 –

144 17 5 –

109 13 25 14

104 19 31 12

74 1 40 46

79 – 39 48

Success (N) Failure (N)

156 5

161 5

122 25

123 31

75 40

79 39

65.2

66.9

Success (%)

96.9

Non-inferiority tests Test-standard (%) 95% confidence limits (%)

97.0

83.0

−0.1 −3.8 to −3.6

79.9 3.1 −5.7 to 11.9

−1.7 −13.9 to 10.5

* Lost-to-follow-up; not evaluated.

3.2. Clinical efficacy The overall clinical response rates at the test-of-curevisit were satisfactory with both agents: at early followup, clinical success rates were 83.0% in the piperacillin/tazobactam group and 79.9% in the imipenem/cilastatin group (Table 5). The difference between the two treatments was not statistically significant. The clinical, success rates of piperacillin/tazobactam yielded a significant non-inferiority of this regimen compared with imipenem/cilastatin. At a descriptive level, a tendency in favour of piperacillin/tazobactam was detectable. High post-treatment success rates of 96.9% (piperacillin/tazobactam) and 97.0% (imipenem/cilastatin) were observed. These results were therapeutically equivalent (Table 4). Similar results were obtained in the PP population. Non-inferiority of piperacillin/ tazobactam was shown with P B0.001. If indeterminate cases were rated as failures, the success rates were 58.8% (piperacillin/tazobactam) and 48.5% (imipenem/ cilastatin). Similar clinical success rates were seen for both entry diagnoses at early follow-up 5– 9 days after therapy. Neither the inclusion diagnosis nor its severity appeared to influence the level of efficacy of either agent (Table 5).

3.3. Bacteriological efficacy A bacteriological documentation was mandatory for each patient. Dominating pathogens were Escherichia coli, P. aeruginosa and Gram-positive cocci. All but one strain in each group were susceptible or intermediate to the study drug. At the early follow-up, microbiological response rates were 57.8% in the piperacillin/tazobac-

tam and 48.6% in the imipenem/cilastatin group (modified ITT). A definite tendency in favour of piperacillin/tazobactam yielded significant equivalence of the test drug compared with the standard. Post-treatment, the efficacy rates indicated a significant superiority of piperacillin/tazobactam over imipenem/cilastatin at a significance level of h= 0.025 (Table 6). Piperacillin/tazobactam was more efficient at eradicating E. coli, Enterobacter cloacae and P. aeruginosa and a better bacteriological response was documented (Table 7).

3.4. Tolerability and safety analysis Both agents were well tolerated. The incidence of adverse events was 28/138 (16.9%) in the piperacillin/ tazobactam group and 28/171 (16.4%) in the imipenem/ cilastatin group. Gastrointestinal symptoms, particularly diarrhoea and nausea, predominated in both groups (9.6 and 9.9%, respectively). A causal relationship to the trial medication was rated as at least possible with the following frequencies in 20/166 (12.1%) in the piperacillin/tazobactam arm and in 16/ 171 (9.4%) in the imipenem/cilastatin arm and were generally rated as mild or moderate (Table 8). Table 5 Clinical success rates for entry diagnoses at early follow-up Diagnosis

Piperacillin/ tazobactam

Imipenem/ cilastatin

Clinical success rate in total and percent Acute pyelonephritis Complicated urinary tract infection

13/16 (81.3%) 11/15 (73.3%) 109/131 (82.2%) 112/139 (80.6%)

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Table 6 Tests of non-inferiority of piperacillin/tazobactam versus imipenem/cilastatin with regard to microbiological success rates in the modified ITT population Visit

Post-treatment (%) Early follow-up (%) Late follow-up (%)

D

Success rates Piperacillin/tazobactam

Imipenem/cilastatin

96.4 57.8 49.1

89.3 48.6 48.6

95%-CI of D

7.1 9.2 0.5

Lower limit

Upper limit

1.2 −2.5 −12.2

13.0 20.9 13.8

D, difference ‘test-standard’; CI, confidence interval.

Four patients died during the trial. In none of these cases was a causative relationship to the trial medication documented by the investigators (causes of death— in the piperacillin/tazobactam group: suicide, advanced rectal carcinoma; and in the imipenem/cilastatin group: septic shock, advanced prostatic carcinoma and decompensated cardiac failure). Other severe adverse events were reported in two additional cases in the piperacillin/tazobactam group and five additional cases in the imipenem/cilastatin group; these events were also regarded as unrelated to the trial medication.

4. Discussion In order to cover a broad spectrum of pathogens from the start of treatment without specific knowledge of the causative pathogen, it is advisable to use highly potent antibiotics with activity against both Gram-positive and Gram-negative pathogens. The present trial could prove equal microbiological and clinical efficacy of piperacillin 2 g/tazobactam 0.5 g compared with imipenem 0.5 g/cilastatin 0.5 g in the treatment of acute pyelonephritis and complicated urinary tract infections. Since it is the clinical status that determines the need for rapid institution of antibacterial therapy, it was necessary to adopt the clinical success rate as the primary target parameter. The clinical response rates at early follow-up in the ITT population were 83.0% (piperacillin/tazobactam) and 79.9% (imipenem/cilastatin); non-inferiority was confirmed with P = 0.002. This provided impressive confirmation of the experience with piperacillin/tazobactam of a pilot study and also confirmed the relevance of the results by clearly demonstrating therapeutic equivalence to the established standard regimen [46]. In acute pyelonephritis and complicated urinary tract infections, an antibiotic treatment is usually started empirically. If symptoms are acute, it is particularly important to start an antibiotic treatment before the results of bacteriological tests are available. Mild infections can be treated with co-trimoxazole or amoxycillin. However, approximately one-third of all E. coli strains are resistant to ampicillin and amoxycillin [47], so that

parenteral therapy with cephalosporins, carbapenems or acylaminopenicillins is indicated, particularly in the case of complicating factors such as urological interventions or abnormalities in the urinary tract. Acylaminopenicillins, with their broad spectrum of activity, are increasingly being seen as the drugs of choice because of increasing resistance rates for enterococci to quinolones and cephalosporins and by enterobacteria to quinolones and carbapenems [46,48]. Young women have a predisposition to develop acute pyelonephritis. The most common pathogens are E. coli, Proteus mirabilis and Klebsiella pneumoniae, less commonly other enterobacteria or staphylococci. According to official recommendations, either a fluoroquinolone or an acylaminopenicillin/b-lactamase inhibitor combination, such as piperacillin/tazobactam, should be used for initial treatment, in order to combat the infection effectively and prevent damage to the renal parenchyma [48]. Table 7 Bacteriological eradication rates of pathogens isolated before treatment from evaluable patients Pathogen

Gram-negative E. coli Proteus mirabilis Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Others Gram-positive Enterococcus spp. Enterococcus faecalis Staphylococcus aureus Staphylococcus epi-group

Piperacillin/tazobacta Imipenem/cilastatin m

40/60 10/12 3/4 6/9

44/82 6/7 1/1 7/15

10/17

9/17

5/10

9/12

6/13 6/11 4/5

4/12 3/10 3/5

9/12

5/6

Others

–/–

3/3

Total eradication (%)

64.7

55.3

K.G. Naber et al. / International Journal of Antimicrobial Agents 19 (2002) 95–103 Table 8 Summary of drug related adverse events (AEs) Criteria

Piperacillin/ tazobactam

Imipenem/ cilastatin

Patients with drug related adverse events Drug related adverse events Diarrhoea Increased liver enzymes Headache/fatigue Hypertonia Hallucination/insomnia Dizziness Tachycardia Vulvovaginitis

20 (12.1%)

16 (9.4%)

22 13 3 3 – 1 1 – –

17 12 – 1 – 1 – 2 1

Complicated urinary tract infections, particularly following urological procedures, carry an increased risk of infection with multi-resistant Pseudomonas spp., Proteus spp., Serratia spp., Enterobacter spp., enterococci and staphylococci. According to recommendations, initial therapy should be started with parenteral antibiotics with an appropriate broad spectrum of activity. Here third-generation cephalosporins, fluoroquinolones with high urinary excretion, piperacillin/tazobactam or carbapenems are recommended [46,48]. The overall microbiological outcome was confirmed in the ITT group by bacteriological response rates of 57.8% (piperacillin/tazobactam) and 48.6% (imipenem/ cilastatin). In the PP population, the corresponding rates were 60.2 and 49.2%, respectively. In both evaluations, piperacillin/tazobactam was shown to be at least as effective as imipenem/cilastatin. On a descriptive level, higher eradication rates for piperacillin/tazobactam were observed. Lower microbiological response rates in both treatment arms were due to the fact that the present trial used a strict missing data handling which yielded higher rates of an assumed microbiological failure [42]. Additionally, a significant incidence of secondary organisms with a trend towards higher incidence in the imipenem/ cilastatin group was noted leading to lower success rates in the overall microbiological results. In the modified ITT group, these incidence rates were more evident in the imipenem/cilastatin arm resulting in a lower efficacy rate. The bacteriological success rates at early follow-up in the modified ITT population were 57.8% for piperacillin/tazobactam and 48.6% for imipenem/cilastatin (Table 6). These rates found good support in the PP group with corresponding rates of 68.8 and 63.6%, respectively. The observations were additionally confirmed by eradication rates relating to primary pathogens alone which were isolated before treatment. Here, eradication rates were 64.7% for piperacillin/tazobactam and 55.3% for imipenem/cilastatin (Table 7).

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Non-inferiority of piperacillin/tazobactam was also confirmed at the controls following termination of the treatment phase and at late follow-up after 4– 6 weeks. As with all the statistical tests, strict criteria were used here: h= 0.025 one-sided and an equivalence limit of 10%. With success rates close to 50%, one could certainly argue for a limit of 15%, which would have yielded a significant result at FU2 as well. However, strictest statistical conditions were realised in the present trial which thus differ methodologically from common practice in published reports, in which ‘equivalence’ is erroneously deduced from a non-significant test for difference. There were no significant differences in adverse events between the two groups. No serious adverse event with even a possible relationship towards the trial medication were seen in either the piperacillin/tazobactam or imipenem/cilastatin group (Table 8). The results of the trial confirmed the excellent clinical and bacteriological efficacy of piperacillin/tazobactam in the treatment of acute pyelonephritis and complicated urinary tract infections and demonstrated that this regimen was equally as effective as imipenem/ cilastatin.

Acknowledgements The authors gratefully acknowledge the participants of the study group listed below: UTI-Study Group: Hans-Joachim Peters, Urological Clinic, St. ElisabethHospital, 50935 Ko¨ ln, Germany. Ulf Tunn, Urological Clinic, Community Hospital, 63069 Offenbach, Germany. Axel Richter, Urological Clinic, Community Hospital, 04129 Leipzig, Germany. Peter Saschova, Urological Clinic, Hospital Berlin-Buch, 13122 Berlin, Germany. Ju¨ rgen Breul, Urological Clinic, Clinic Rechts der Isar, 81675 Mu¨ nchen, Germany. Peter Bru¨ hl, University Clinic, Urological Clinic, 53105, Bonn, Germany. Reinhard Fu¨ nfstu¨ ck, Nephrological Clinic, University Clinic, 07740 Jena, Germany. Klaus Ho¨ necke, Urological Clinic, Elisabeth Hospital, 49477 Ibbenbu¨ ren, Germany. Walter Houda, Department of Urology, Vogtland-Clinic, 08529 Plauen, Germany. Lutz-Ulrich Kelly, Department of Urology, Deaconess Hospital, 01099 Dresden, Germany. Vladimir Krcmery, National Cancer Institute, SK-83303 Bratislava, Slovak Republic. Martin Kriegmair, Clinic Großhadern, Urological Clinic, 81377 Munich, Germany. Burkhart Knorr, Department of Urology, Hospital Eisleben, 06295 Lutherstadt Eisleben, Germany. Endre Ludwig Hospital and S. Peterfy, Department of Urology, u.-i. Korhaz-Rendelo¨ intezet, Budapest, Hungary. Jens Jochen Rassweiler, Department of Urology, Municipal Hospital, 74074 Heilbronn, Germany. Udo Rebmann, Department of Urology, Anhaltische Deaconess Clinik

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Dessau, 06846, Dessau, Germany. Slavko Scho¨ nwald, University Hospital of Infectious Disease, 41000 Zagreb, Croatia. Peter Tenke, Department of Urology, Jahn Ferenc Delpesti Korhaz, Budapest, Hungary. Wolf-Ferdinand Wieland, Department of Urology, St. Josef-Hospital, 93053 Regensburg, Germany. Rainer Wittenberger, Department of Urology, Municipal Hospital, 91757 Treuchlingen, Germany.

References [1] Stamm WE. Nosocomial urinary tract infections. In: Bennett JV, Brachmann PS, editors. Hospital infections. Boston: Little, Brown and Co, 1992:597 –610. [2] Haley RW. Surveillance of nosocomial infections. In: Bennett JV, Brachmann, editors. Hospital infections. Boston: Little, Brown and Co, 1992:79 –108. [3] Hatton J, Hughes M, Raymond CM. Management of bacterial urinary tract infections in adults. Ann Pharmacother 1994;28:1264 – 72. [4] Bailey RR, Lynn KL, Robson RA, et al. DMSA renal scans in adults with acute pyelonephritis. Clin Nephrol 1996;46:99 – 104. [5] Nicolle LE. Management of acute uncomplicated pyelonephritis, vol. 1. Basel: Karger, 1997:8 –13. [6] Bailey RR. Uncomplicated acute pyelonephritis. In: Bergan TE, editor. Urinary tract infections, vol. 1. Basel: Karger, 1993:14 – 8. [7] Johnson JR, Vincent LM, Wang K, et al. Renal ultrasonographic correlates of acute pyelonephritis. Clin Infect Dis 1992;14:15 – 22. [8] Perry MP, Markham A. Piperacillin/tazobactam— an updated review of its use in the treatment of bacterial infections. Drugs 1999;57:805 – 43. [9] Eliopoulos GM, Moellering RC. Azlocillin, mezlocillin, and piperacillin: new broad-spectrum penicillins. Ann Int Med 1982;97:755 – 60. [10] Fass RJ. Statistical comparison of the antibacterial activities of broad-spectrum penicillins against Gram-negative bacilli. Antimicrob Agents Chemother 1983;24:156 – 62. [11] Grimm H. Methodische Besonderheiten der Testung von Tazobactam/Piperacillin (Tazobac®). Fortschr Antimikrob Antineoplast Chemother 1992;11:1 –10. [12] Naber KG. Antibiotikatherapie von Patienten mit akuter Pyelonephritis und/oder komplizierten Harnwegsinfektionen mit Tazobactam/Piperacillin (Tazobac®): eine multizentrische Studie. Fortschr Antimikrob Antineoplast Chemother 1992;11:547 – 58. [13] Sanders WE, Sanders CC. Piperacillin/tazobactam: a critical review of the evolving clinical literature. Clin Infect Dis 1996;22:107 – 23. [14] Rosenstil NA, Grimm H. Piperacillin/tazobactam: antibiotic profile. Antiinf Drugs Chemother 1996;14:187 –99. [15] Acar JF, Goldstein FW, Kitzis D. Susceptibility survey of piperacillin alone and in the presence of tazobactam. J Antimicrob Ther Suppl A 1993;31:23 –8. [16] Bryson HM, Brogden RN. Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs 1994;47:506 –35. [17] Brismar B, Malmborg AS, Tunevall G, et al. Piperacillin – tazobactam versus imipenem –cilastatin for treatment of intraabdominal infections. Antimicrob Agents Chemother 1992;36:2766 – 73. [18] Gorbach SL. Piperacillin/tazobactam in the treatment of polymicrobial infections. Intens Care Med 1994;20:27 –34.

[19] Niinikoski J, Havia T, Alhava E, et al. Piperacillin/tazobactam versus imipenem/cilastatin in the treatment of intra-abdominal infections. Surg Gynecol Obs 1993;176:255 – 61. [20] Nord CE. The treatment of severe intra-abdominal infections: the role of piperacillin/tazobactam. Intens Care Med 1994;20:35 – 8. [21] Polk HC, Fink MP, Laverdiere M, et al. Prospective randomized study of piperacillin/tazobactam therapy of surgically treated intra-abdominal infection. Am J Surg 1993;59:598 – 605. [22] Nowe´ P. Piperacillin/tazobactam in complicated urinary tract infections. Intens Care Med 1994;20:39 – 42. [23] Bornkessel B. Antibiotikatherapie bei urologischen Infektionen. Klinikarzt 1999;28:16 – 8. [24] Sifuentes-Osornio. Piperacillin/tazobactam in the treatment of hospitalized patients with urinary tract infections: an open noncomparative and multicentered trial. J Chemother 1996;8:122 –9. [25] Incavo SJ, Ronchetti PJ, Choi JH, Wu H, So¨ rgel F. Penetration of piperacillin/tazobactam into cancellous and cortical bone tissues. Antiinf Agents Chemother 1994;38:905 – 7. [26] Tassler H. Therapie von Knochen- und Gelenkinfektionen mit Tazobactam/Piperacillin (Tazobac®). Fortschr Antimikr Antineopl Chemoth 1992;11:525 – 34. [27] Marie JP. Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin as empiric therapy for fever in severely ill neutropenic patients. Supp Care Cancer 1999;7:89 –94. [28] Hess U. Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients. Supp Care Cancer 1998;6:402 – 9. [29] Del Favero A. Double-blind, randomized clinical trial comparing monotherapy with piperacillin-tazobactam vs. piperacillintazobactam plus amikacin as empiric therapy for febrile neutropenic cancer patients. Abstract 1092, Thirty-Ninth ICAAC, San Francisco, 1999. [30] Glasmacher A. A randomized comparison of piperacillintazobactam versus ceftriaxone and gentamicin in 172 severely neutropenic patients with hematologic malignancies. Abstract 1090, Thirty-Ninth ICAAC, San Francisco, 1999. [31] Jaccard C, Troillet S, Harbarth G, et al. Prospective randomized comparison of imipenem/cilastatin vs. piperacillin/tazobactam in nosocomial pneumonia or peritonitis. Antimicrob Agents Chemother 1998;42:2966 – 72. [32] Joshi M, Bernstein J, Solomkin J, Wester B, Kuye O. Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin for the treatment of patients with nosocomial respiratory tract infections. J Antimicrob Chemother 1999;43:389 – 97. [33] Naber KG, Grimm H, Witte W. Erregerempfindlichkeit gegen Tazobactam/Piperacillin bei komplizierten und/oder im Krankenhaus erworbenen Harnwegsinfektionen. Fortschr Antimikrob Antineoplast Chemother 1993;11:33 – 7. [34] EMEA-Guideline. Note for guidance on evaluation of new antibacterial medicinal products (CPMP/EWP/558/95). [35] Smith C, Burley C, Ireson M, et al. Clinical trials of antibacterial agents: a practical guide to design and analysis. Antimicrob Chemother 1998;41:467 – 80. [36] ICH-Guideline. Statistical principles for clinical trials (ICH E9, final signed off, 5 February, 1998). [37] Rubin RH, Shapiro ED, Andriole VT, Davis RQ, Stamm WE. General guidelines for the evaluation of new anti-infective drugs for the treatment of urinary tract infections. Taufkirchen, Germany: The European Society of Clinical Microbiology and Infectious Diseases, 1993:294 – 310. [38] Declaration of Helsinki. Edition Somerset West, Republic of South Africa, October, 1996. [39] EG-GCP-Guideline. Gute klinische Praxis (GCP) fu¨ r die klinische Pru¨ fung von Arzneimitteln in der europa¨ ischen Gemein-

K.G. Naber et al. / International Journal of Antimicrobial Agents 19 (2002) 95–103

[40]

[41]

[42]

[43]

schaft. In: Klinische Arzneimittelpru¨ fungen in der EU. Aulendorf: Editio-Cantor-Verlag, 1995:40 –66. Bundesminister fu¨ r Jugend, Familie, Frauen und Gesundheit. Gesetz u¨ ber den Verkehr mit Arzneimitteln. In: Gesetz u¨ ber den Verkehr mit Arzneimitteln (AMG). Aulendorf: Editio-Cantor-Verlag, 1994. Finch R. General guidelines for the evaluation of new anti-infective drugs for the treatment of urinary tract infections. In: Beam TR, editor. European guidelines for the clinical evaluation of anti-infective drug product, 1993:101 –11 Part E. Naber KG. Experience with the new guidelines on evaluation of new anti-infective drugs for the treatment of urinary tract infections. Int J Antimicrob Agents 1999;11:189 –96. DIN: Deutsches Institut fu¨ r Normung e.V. Methoden zur Empfindlichkeitspru¨ fung von bakteriellen Krankheitserregern (außer Mykobakterien) gegen Chemotherapeutika. b. DIN 58940, Teil 3. Agar-Diffusionstest. Beuth-Verlag, Berlin, 1998 bzw. a. DIN 58940, Teil 6. Bestimmung der minimalen Hemmkonzentration nach der Agar-Verdu¨ nnungsmethode. c. DIN 58940, Teil 4, Beiblatt 1. Liste der Grenzwerte und Tagesdosierungen von Chemotherapeutika sowie Bewertung

[44]

[45] [46] [47]

[48]

103

der minimalen Hemmkonzentration (MHK). Beuth-Verlag, Berlin, 1998. NCCLS, National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disc susceptibility tests. 4th ed. Approved Standards, NCCLS Document M2-A4. Villanova, PA: NCCLS, 1990 bzw. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 2nd ed. Approved standard, NCCLS Document M7-A2. Villanova, PA: NCCLS, 1998/National Committee for Clinical Laboratory Standards: Methods for antimicrobial susceptibility testing of anaerobic bacteria. 2nd ed. NCCLS Document M11A2. Villanova, PA: NCCLS, 1998. SAS/STAT®. SAS Institute Inc. Cary, NC, USA, 1990. Bo¨ hm S. Antibiotikatherapie bei urologischen Infektionen. Klinikarzt 1999;25:16 – 9. Kresken M, Hafner D. Drug resistance among clinical isolates of frequently encountered species in central Europe during 1975 – 1995. Infection 1999;27(Suppl 2):1 – 8. Vogel F. Parenterale Antibiotika bei Erwachsenen: urogenitale Infektionen. Chemother J 1999;8:25 – 7.