Journal of Antimicrobial Chemotherapy (1992) 29, Suppl. A. 95-104
Cefpirome versus ceftaridime in the treatment of urinary tract infections Study Group*
Introduction
Cefpirome (HR 810) is a new, injectable, broad-spectrum cephalosporin. It differs from third-generation cephalosporins in its markedly improved activity against Gram-positive pathogens, especially methicillin-sensitive staphylococci, and its activity against Pseudomonas aeruginosa, which is similar to that of ceftazidime (Bauernfeind, 1983; Mackha & Braveny, 1983; Bertram, Bruckner & Young, 1984). Its phannacokinetics have been evaluated in healthy subjects and in patients with decreased renal function (Maass, Malerczyk & Verho, 1987; Malerczyk et al., 1987; Kavi et al., 1988; Lameire et al., 1991). It is not absorbed from the gastrointestinal tract and must be administered intravenously or intramuscularly. Binding to serum albumin is low. A peak serum concentration of about 100 mg/L is achieved after a 1 g intravenous injection over 5 mins. Elimination of cefpirome is renal and the half-life in the /?-phase is about 2 h in subjects with normal renal function. In subjects with renal impairment Correspondence to: S. Ragnar Norrby, Department of Infectious Diseases, University of Lund, Lund University Hospital, S-22185 Lund, Sweden. •Lin of participating investigators: Bernstein, Dictar, Laplume and Bare (Buenos Aires), Argentina; Frtck (Salzburg), Joost (Hall in Tirol), Madersbacher (Innsbruck), Porpazcy (Vienna), Wandschoeider (Graz), Austria; Kotlar (Havre), Chimeck (Brussels), Belgium; H&nninen (Turku), Sarnmalkorpi and Karessoja (Helsinki), Simula (Espoo), Finland; Humbert (Rouen), Tremolliere (Mantes La Jolie), Champ etier de Ribes (Levullois-Perret), Ducroix (Amiens), Luchu (St Etienne), France; Ecke (Magdeburg), Templin (Rostock), Muller (Cottbus), Frohlfch (Mechemich), Muschelknautz and Sell (Frankfurt), Moalem (Fulda), Muller-Mattheis (Dusseldorf), de Dycker (Essen-Altenessen), Schalkhauser (Dorfen), Sohn (Aachen), Germany; Dan (Holon), Israel; Berends (Curacao), Plasman (Ae Ruosendaal), The Netherlands; Brans (Oslo), Norway, Calais de Silva (Lisbon), Portugal; Norrby (Lund), Alestig (Gdteborg), Burman (Umea), Runehagen (Vaxjd), Wetland (Stockholm), Philipton (Stockholm), Sweden; Wdsby (Edinburgh), Bint (Newcastle), UK; Schonwakl (Zagreb), Yugoslavia. 95 0305-7453/92/29A095 + 10 $03.00/0
© 1992 The British Society for Antimicrobial Chemotherapy
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In an open, randomized multidinic trial, hospitalized patients with upper or complicated lower urinary tract infections requiring treatment with a parenteral antibiotic were randomized to receive 1 g doses of cefpirome (594 patients) or ceftazidime (303 patients) 12 hourly for at least five days. Cefpirome was considerably more active in vitro than ceftazidime against Gram-positive pathogens isolated from the urine samples. At the early follow-up, 2-15 days after treatment, clinical cure was achieved in 86% and 82% of the patients in the cefpirome and ceftazidime groups respectively. Elimination of the causative pathogen without recurrence or early reinfection was achieved in 87% of the patients in both groups. Drug related adverse events occurred in 8-9% of cefpirome treated patients and in 4-6% of those receiving ceftazidime. No specific type of adverse reaction accounted for this difference. Treatment was discontinued because of adverse events in 2-5% and 1-7% of the patients respectively. Cefpirome was found to be safe and at least as effective as ceftazidime for the treatment of urinary tract infections in hospitalized patients.
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the half-life of cefpirome gradually increases to reach a mean value of about 15 h in uraemic patients (Lameire et al., 1991). The present study compared the efficacy and safety of cefpirome with ceftazidime in patients with urinary tract infections requiring treatment with a parenteral antibiotic. Materials and methods
The design of the study was approved by the Research Ethics Committees at the participating centres. Consent was obtained from all patients. Study design
Patient selection Patients 18 years of age or older with symptomatic pyelonephritis (fever ^ 38°C and flank pain) or complicated, symptomatic, lower urinary tract infection (see below) were eligible for inclusion into the trial. Exclusion criteria were hypersensitivity to cephalosporins, previous type I reactions to penicillins, effective antibiotic treatment in the three days before study entry, neutropenia ( < 1 x 109 neutrophils/L), hypogammaglobulinaemia (IgG < 200 mg/dL), rapidly fatal concomitant diseases, seriously impaired liver function (serum transaminases or bilirubin > 3 times upper normal limit), renal failure (creatinine clearance < 30 mL/min estimated by the Cockroft formula), pregnancy, and lactation. Antibiotic treatment Cefpirome and ceftazidime were given in 1 g doses 12-hourly as short term infusions over 15-30 min or as bolus injections over 5 min for a minimum of five days. In patients with renal impairment (creatinine clearance 30-50 mL/min) the dose was reduced to 0-5 g 12-hourly. Trial drugs were supplied by Hoechst AG, Frankfurt/Main, Germany or by Roussel Uclaf, Paris, France. Laboratory samples Urine cultures (midstream or catheter) were obtained before treatment, on the 2nd or 3rd days during treatment, and 2-15 days and, if possible, 4-8 weeks after treatment. Blood cultures were taken before treatment and were repeated during treatment if they were positive and the patient remained rifebrile. Bacterial isolates were identified using standard techniques. Susceptibility to cefpirome and ceftazidime was determined using a disc diffusion test or MlC-determination. The resistance breakpoints were > 8 mg/L
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on April 2, 2015
The trial was a prospective, open, randomized, multiple-independent study with stratification at each centre. Randomization was 2:1 (cefpirome: ceftazidime) using sealed envelopes. Forty-five centres in 14 countries recruited a total of 926 patients. The number of patients recruited at each centre varied between 1 and 90. The sample size calculated to test the null hypothesis that the difference in bacteriological cure rate was not greater than 10% was 340 evaluable patients in the cefpirome group and 170 in the ceftazidime group with a type I error of 0-05 (two-sided), a type II error of 0-2 (statistical power of 80%) and an assumed cure rate of 80% in the ceftazidime group.
Ccfptrome n ceftaxtdfane In UTI
97
and > 16 mg/L or corresponding zone diameters in disc diffusion tests for cefpirome and ceftazidime respectively (Hoechst AG data on file). Routine biochemical and haematological investigations and urinalysis were performed before, during, and after treatment. Definitions
Statistics The results in the two groups were compared by Fisher's exact test and by calculation of 95% confidence intervals. Results The treatment groups were comparable with respect to age, sex, underlying diseases, and types of urinary tract infection (Table I). Four patients randomized to receive cefpirome were not given the drug and were excluded from evaluation. The reasons for exclusion from clinical and bacteriological evaluation were premature discontinuation of treatment for reasons other than treatment failure (cefpirome/ceftazidime; 50/16), isolation of a pathogen resistant to the allocated drug (14/19), absence of clinical symptoms plus erroneous urine sampling (9/3), wrong diagnosis at entry (11/5), concomitant antimicrobial treatment (6/0), and wrong dosage of trial drugs (1/1). Exclusions from assessment of bacteriological efficacy were due to failure to identify significant bacteriuria (46/24), inadequate post-treatment samples (64/29), and no sensitivity data (6/6). Most patients had complicated urinary tract infections (Table II). The median duration of treatment was seven days in both groups. All patients, except five in the cefpirome group and two in the ceftazidime group who had reduced renal function, received 1 g of trial drug 12-hourly. There was no significant difference between the two treatment groups (Table III) in terms of clinical response. Complicating factors were significantly more common in both groups (P = 0-05, Fisher's exact test) in patients who failed to respond. As shown in Table IV, resistance to cefpirome was significantly less common than to ceftazidime amongst pre-treatment, Gram-positive pathogens. No such difference was
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An evaluable patient was one who had been treated for > 5 days (or at least two days if treatment failed), had not missed more than one dose and had significant bacteriuria ( > 105 cfu/mL except for staphylococci for which bacteriuria was defined as ^ 10* cfu/mL) before treatment. In addition, for evaluation of bacteriological efficacy the causative pathogens(s) must have been susceptible to the assigned drug, appropriate urine cultures must have been obtained before, during, and after treatment, and the patient must not have received any antibiotics between the last dose of trial drug and the first follow-up urine sample. Clinical response at the end of treatment was classified as satisfactory (all symptoms disappeared), improved (symptoms improved but at least one persisting) or unsatisfactory. Bacteriological response was classified as satisfactory (causative pathogen not present in post-treatment culture and no new pathogen isolated) or unsatisfactory (persistence, relapse or early recurrence of the original pathogen or superinfection). Safety was analysed in all patients who received at least one dose.
Study Group
98
Table L Patient characteristics Treatment Characteristic
Ceftazidime
594 1:1-4 73 61
303 1:1-3 73 64
498(84)
252 (83)
387 (65)
200(66)
268 (69) 119(31) 190 (49) 197 (51) 195 (50) 105 (27) 87 (22)
131 (65) 69(35) 106 (53) 94(47) 95(47) 63 (31) 42 (21)
observed for Gram-negative isolates. Fourteen cefpirome patients and 19 ceftazidime patients received treatment despite resistant pre-treatment pathogens. These organisms were eradicated in all 11 bacteriologically evaluable cefpirome patients and in 11 of 15 bacteriologically evaluable ceftazidime patients (four patients had relapses due to Gram-positive isolates soon after completing treatment). Tables V and VI show the bacteriological responses 2-15 days after completion of treatment. There were more failures in the ceftazidime group, both for patients with Table n. Complicating factors in bacteriologically evaluable patients Treatment group and No. (%) of patients Complicating factor None Residual urine Prostatk hypertrophy Indwelling catheter Extrarenal obstruction of urine flow Urogcnital malformation Stones Prostatic carcinoma Hydronephrosis Bladder carcinoma Urogcnital surgery Renal cysts Neurogenic bladder Other
Cefpirome
Ceftazidime
174(45) 77(20) 79 (20) 47 (12) 40(10) 24 (6) 31 (8) 25 (6) 12 (3) 13 (3) 12 (3) 7 (2) 10 (3) 35 (9)
83 (41) 40(20) 30(15) 34(17) 21 (10) 24(12) 15 (7) 10 (5) 12 (6) 5 (2) 4 (2) 4 (2) 3 (1) 18 (9)
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No. of patients entered Male: female ratio Median age males (years) Median age females (years) No. of clinically evaluable patients (% of patients entered) No. of bacteriologically evaluable patients (% of patients entered) Type of infection Sporadic infections (%) Recurrent infections (%) Lower UTI (%) Upper UTI (%) Community acquired UTI (%) Hospital acquired UTI (%) Unknown aetiology (%)
Cefpirome
Cefpfrome w cefUzklime in UT1
99
Table UL Clinical response-evaluable patients Treatment group and No. (%) of patients Response
Cefpirome
Ceftazidime
Upper
Satisfactory Improved Unsatisfactory
244(900) 19 (7-0) 8 (3-0)
115(85-2) 14 (104) 6 (4-4)
Lower
Satisfactory Improved Unsatisfactory
186 (81-9) 33 (14-5) 8 (3-5)
92 (78-6) 21 (17-9) 4 (3-4)
Overall
Satisfactory Improved Unsatisfactory
430 (86-3) 52 (104) 16 (3-2)
207 (821) 35 (13-9) 10 (4-0)
Table IV. Sensitivity of pre-treatment isolates to test agents
Noi. (%) susceptible* to Cefpirome Ceftazidime Organism (No. of strains)
S
S. aureus (27) Staphylococci, coagulase negative (38) Streptococcus spp. (11) Enterococcus faecalis (39) Group D streptococci (51)
24
Total Gram-positives (166) % resistant strains E. coli (462) Citrobacter spp (13) K. pneumoniae (37) Klebsiella spp. (30) E. cloacae (24) Enterobacter spp. (8) Serratia marctscens (6) Proteus mirabilis (48) Proteus spp. (28) P. aeruginosa (57) Pseudomonas spp. (16) Other Gram-negatives (10) Total Gram-negatives (739) % resistant strains
R ND' S 1 2
17
31 7 0 9 0 2 28 10 1 44 6 1 136 24 6
18 8 8 2 53
14-4'
R ND 8 2
20 1 30 48 107
0 2 1 1 6
65-1
443 1 18 440 3 19 13 0 0 12 1 0 35 1 1 34 2 1 28 1 1 29 1 0 24 0 0 21 3 0 8 0 0 8 0 0 6 0 0 6 0 0 48 0 0 47 0 1 28 0 0 28 0 0 54 2 1 54 3 0 13 2 1 15 1 0 8 1 1 9 1 0 708 8 23 703 15 21 11 21
*S - sensitive; R - resistant; ND «• not done. *Point estimate for the 95% confidence interval for the difference between the groups ii 42-3%, 60-3%.
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Type of UTI
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Table V. Bacteriological response at first post-treatment follow-up (2-15 days after last dose) No. (%) in each treatment group Response
Type of UTI
Cefpirome
Ceftazidime
Satisfactory Unsatisfactory
169 (9(M) 18 (9-6)
82 (87-2) 12 (12-8)
Lower
Satisfactory Unsatisfactory
168 (88-4) 22(11-6)
92 (86-8) 14(13-2)
Overall
Satisfactory Unsatisfactory
337 (894) 40(10*)
174 (87-0) 26 (13-0)
pyelonephritis and lower urinary tract infections, but the differences were not significant. The lowest eradication rates were seen in patients with infections caused by P. aeruginosa. Amongst patients with an unsatisfactory bacteriological response to treatment, there were 19 reinfections in the cefpirome group and 14 in the ceftazidime group. More of the isolates causing reinfection were resistant to ceftazidime than to cefpirome, largely because there were more Gram-positive organisms in the ceftazidime group. High clinical and bacteriological cure rates were achieved with both antibiotics in a subset of patients with bacteriuria and proven septicaemia (Table VII). Of the patients with hospital acquired urinary tract infections 106 of 113 cefpirometreated patients (94%) and 56 of 61 ceftazidime-treated patients (92%) had a satisfactory clinical response to treatment. The bacteriological response in these patients was satisfactory in 90% and 86%, respectively. At the late follow-up, 4-8 weeks posttreatment, a satisfactory bacteriological response was observed in 61 patients (79%) in Table VL Bacteriological results by pre-treatment species No. isolates eradicated/total no. (%) in each treatment group Pre-treatment organism
Cefpirome
Ceftazidime
E. coli Klebsiella spp. Enterobacter spp. Proteus spp. P. aeruginosa Pseudomonas spp. Citrobacter spp. Other Gram-negatives Staphylococcus spp. Streptococcus spp.
214/220 (97-3) 24/29 (82-8) 15/15 (100) 40/42 (95-2) 20/31 (64-5) 6/7 (85-7) 5/5 (100) 4/4 (100) 27/30 (90-0) 40/48 (83-3)
124/127 (97-6) 13/13(100) 7/10 (7(M)) 19/19 (100) 9/13 (69-2) 6/6 (100) 2/2 (100) 12/12 (100) 11/11 (100) 4/5 (80-0)
Total
395/431 (91-6)
205/218 (94-9)
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Upper
Cefpirome n ceftaxknme in UTI
101
Table VIL Clinical and bacteriological response in patients with UTI and septicaemia No. (%) of patients in treatment group Response
Cefpirome
Ccftaririimc
Clinical
—satisfactory —improved —unsatisfactory
30 (9(h9) 2 (6-1) 1 (30)
16 (8(M)) 2(100) 2(10-0)
Bacteriological
—satisfactory —unsatisfactory
23 (88-5) 3(11-5)
10 (83-3) 2(16-7)
the cefpirome group and 26 patients (76%) in the ceftazidime group. Of the 19 pathogens isolated from the urine of patients with these laterecurrences(13 in patients allocated to cefpirome and six in patients allocated to ceftazidime), two were resistant to both cefpirome and ceftazidime and the remaining strains were sensitive to both antibiotics. Tables Vm and DC summarize the adverse events reported. More events were reported in the cefpirome group but there were no significant differences in the numbers of patients in whom treatment was discontinued due to adverse events. No tendency towards a higher incidence of adverse events in a particular organ system was observed with cefpirome. Ten patients in the cefpirome group (1-7%) had adverse events which were classified as severe by the investigators. Five of these events (three cases of thrombophlebitis and one each of convulsions and vomiting) were considered related to cefpirome treatment. Six ceftazidime patients (2-0%) experienced such events, all of which were considered unrelated or remotely related to treatment. Death during or within one month of the end of treatment was reported for six patients (1-0%) allocated to cefpirome and five patients (1-7%) randomized to ceftazidime. All deaths were considered unrelated to treatment with the trial drugs. All but one death (in a patient who died from pancreatic cancer) were attributed to concomitant cardiovascular disease and in no case was treatment failure considered a contributory factor. Ninety-nine laboratory adverse events were reported in 47 cefpirome patients (8%) and 33 in 17 ceftazidime patients (6%). Fifty-three laboratory events in cefpirome patients and 12 in ceftazidime patients were considered highly probably or probably related to treatment. Discussion This study has shown that cefpirome given in a dose of 1 g 12-hourly is at least as effective in achieving a clinical and bacteriological cure as ceftazidime in the same dosage for the treatment of urinary tract infections in hospitalized patients. This result confirms thefindingsof a smaller uncontrolled, phase II study with cefpirome (Norrby et at., 1988). Only 22% of the patients in the cefpirome group and 26% in the ceftazidime group had hospital acquired infections. This accounts for the relatively low numbers of multiply resistant, urinary tract pathogens such as Enterobacter spp., Pseudomonas spp.
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Unsatisfactory response based on positive post-treatment urine cultures.
102
Study Group TaWe V m . Adverse events Related adverse events* Ccfpirome
Ceftazidime
Cardiovascular system thrombophlebitis Lung Kidney/genitourinary system Abdomen/gastrointestinal tract diarrhoea Neurological/psychiatric nausea taste perversion headache convulsions paraesthesia vertigo dizziness insomnia Psychovegetative symptoms vomiting anorexia flushes constipation Allergic reactions rash Haematology Musculoskeletal system Infection Local reactions Other
15 14 0 0 10 8 13 4 3 2 1 1 1 1 0 6 3 2 1 0 11 11 1 0 2 7 1
3 3 0 0 4 4 1 1 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 0 1 4 1
Total No. of reactions
66
18
No. of patients with reactions % of randomized and treated No. of patients with related events % of randomized and treated
83 13-9 53' 8-9
29 9-5 14 4-6
•Several patienti had more than one adverse event 'Events classified by the investigators u highly probably or probably related to treatment given. 'Point estimate of the 95% confidence interval for differences between groups was 1-0%, 7-6%.
and Acinetobacter spp. Rather, Escherichia coli, enterococci, Klebsiella spp. and Proteus mirabilis were the commonest isolates. The superior activity of cefpirome against Gram-positive organisms was demonstrated by the higher incidence of resistance to ceftazidime amongst pre-treatment, Gram-positive isolates. Both drugs were equally active against the Gram-negative urinary pathogens. More adverse reactions were reported in cefpirome-treated patients than in those who received ceftazidime. However, with the exception of a higher incidence of thrombophlebitis, no pattern was detected in the type of adverse events reported, suggesting that there is no specific toxicity associated with cefpirome.
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Adverse event* by body system
Cefpirome n ceftazidime in UTI
103
Table DL Clinical and laboratory adverse events leading to discontinuation of treatment No. of patients in .each group Adverse event
Ceftazidime
0 2 5 2
1 2 0 0 0 0 1 1 0 0 1 1 0 0 0
24
15 (2-5)
5(1-7)
"Event considered unrelated to treatment *One reaction was Considered unrelated to treatment
In conclusion, this trial which included a large number of patients has shown that the overall efficacy of cefpirome and ceftazidime is comparable. Acknowledgement This study was supported by grants from Hoechst AG, Frankfurt, Germany and Roussel-Uclaf, Paris, France. References Bauernfeind, A. (1983). Susceptibility of Gram-positive aerobic cocci to the new cephalosporin HR 810. European Journal of Clinical Microbiology 2, 354-5. Bertram, M. A., Bruckner, D. A. & Young, L. S. (1984). In vitro activity of HR 810, a new cephalosporin. Antimicrobial Agents and Chemotherapy 26, 277-9. Kavi, J., Andrews, J. W., Ashby, J. P., Hillman, G. & Wise, R. (1988). Pharmacokinetics and tissue penetration of cefpirome, a new cephalosporin. Journal of Antimicrobial Chemotherapy 22, 911-6. Lameire, N., Malerczyk, V., Drees, B., Lehr, K. & Rosenkranz, B. (1991). Single-dose pharmacokinetics of cefpirome in patients with renal impairment. Clinical Pharmacology and Therapeutics, in press. Maass, L., Malerczyk, V. & Verho, M. (1987). Pharmacokinetics of cefpirome (HR 810), a new cephalosporin derivative administered intramuscularly and intravenously to healthy volunteers. Infection 15, 207-10.
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Thrombophlebitis Rash or urticaria Vomiting Peripheral vasodilation Diarrhoea Seizures Pain at injection site Fever Vertigo Myocardial infarction' Heart failure* Pulmonary embolism' Leukopenia Abnormal liver function test* Eosinophilia Total events related to treatment No. of patients in whom treatment was discontinued due to related adverse events (% of treated)
Cefpirome
104
Study Group
Mackha, K. & Braveny, I. (1983). In vitro activity of HR 810, a new broad spectrum cephalosporin. European Journal of Clinical Microbiology 2, 354-9. Malerczyk, V. , Maass, L., Vcrho, M., Hajdu, P., Klesel, N. & Rangoonwala, R. (1987). Single and multiple dose pharmacokinetics of intravenous cefpirome (HR 810), a novel cephalosporin derivative. Infection 15, 211-4. Norrby, S. R., Dotevall, L., Eriksson, M., Settergren, B. t Larsspn, P., Lundhohn, R. eial. (1988). Efficacy and safety of cefpirome (HR &\Q)., Journal of Antimicrobial Chemotherapy 22,
541-7.
•
• •
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Cefpirome versus ceftaridime in the treatment of urinary tract infections Study Group*
Introduction
Cefpirome (HR 810) is a new, injectable, broad-spectrum cephalosporin. It differs from third-generation cephalosporins in its markedly improved activity against Gram-positive pathogens, especially methicillin-sensitive staphylococci, and its activity against Pseudomonas aeruginosa, which is similar to that of ceftazidime (Bauernfeind, 1983; Mackha & Braveny, 1983; Bertram, Bruckner & Young, 1984). Its phannacokinetics have been evaluated in healthy subjects and in patients with decreased renal function (Maass, Malerczyk & Verho, 1987; Malerczyk et al., 1987; Kavi et al., 1988; Lameire et al., 1991). It is not absorbed from the gastrointestinal tract and must be administered intravenously or intramuscularly. Binding to serum albumin is low. A peak serum concentration of about 100 mg/L is achieved after a 1 g intravenous injection over 5 mins. Elimination of cefpirome is renal and the half-life in the /?-phase is about 2 h in subjects with normal renal function. In subjects with renal impairment Correspondence to: S. Ragnar Norrby, Department of Infectious Diseases, University of Lund, Lund University Hospital, S-22185 Lund, Sweden. •Lin of participating investigators: Bernstein, Dictar, Laplume and Bare (Buenos Aires), Argentina; Frtck (Salzburg), Joost (Hall in Tirol), Madersbacher (Innsbruck), Porpazcy (Vienna), Wandschoeider (Graz), Austria; Kotlar (Havre), Chimeck (Brussels), Belgium; H&nninen (Turku), Sarnmalkorpi and Karessoja (Helsinki), Simula (Espoo), Finland; Humbert (Rouen), Tremolliere (Mantes La Jolie), Champ etier de Ribes (Levullois-Perret), Ducroix (Amiens), Luchu (St Etienne), France; Ecke (Magdeburg), Templin (Rostock), Muller (Cottbus), Frohlfch (Mechemich), Muschelknautz and Sell (Frankfurt), Moalem (Fulda), Muller-Mattheis (Dusseldorf), de Dycker (Essen-Altenessen), Schalkhauser (Dorfen), Sohn (Aachen), Germany; Dan (Holon), Israel; Berends (Curacao), Plasman (Ae Ruosendaal), The Netherlands; Brans (Oslo), Norway, Calais de Silva (Lisbon), Portugal; Norrby (Lund), Alestig (Gdteborg), Burman (Umea), Runehagen (Vaxjd), Wetland (Stockholm), Philipton (Stockholm), Sweden; Wdsby (Edinburgh), Bint (Newcastle), UK; Schonwakl (Zagreb), Yugoslavia. 95 0305-7453/92/29A095 + 10 $03.00/0
© 1992 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on April 2, 2015
In an open, randomized multidinic trial, hospitalized patients with upper or complicated lower urinary tract infections requiring treatment with a parenteral antibiotic were randomized to receive 1 g doses of cefpirome (594 patients) or ceftazidime (303 patients) 12 hourly for at least five days. Cefpirome was considerably more active in vitro than ceftazidime against Gram-positive pathogens isolated from the urine samples. At the early follow-up, 2-15 days after treatment, clinical cure was achieved in 86% and 82% of the patients in the cefpirome and ceftazidime groups respectively. Elimination of the causative pathogen without recurrence or early reinfection was achieved in 87% of the patients in both groups. Drug related adverse events occurred in 8-9% of cefpirome treated patients and in 4-6% of those receiving ceftazidime. No specific type of adverse reaction accounted for this difference. Treatment was discontinued because of adverse events in 2-5% and 1-7% of the patients respectively. Cefpirome was found to be safe and at least as effective as ceftazidime for the treatment of urinary tract infections in hospitalized patients.
96
Study Groop
the half-life of cefpirome gradually increases to reach a mean value of about 15 h in uraemic patients (Lameire et al., 1991). The present study compared the efficacy and safety of cefpirome with ceftazidime in patients with urinary tract infections requiring treatment with a parenteral antibiotic. Materials and methods
The design of the study was approved by the Research Ethics Committees at the participating centres. Consent was obtained from all patients. Study design
Patient selection Patients 18 years of age or older with symptomatic pyelonephritis (fever ^ 38°C and flank pain) or complicated, symptomatic, lower urinary tract infection (see below) were eligible for inclusion into the trial. Exclusion criteria were hypersensitivity to cephalosporins, previous type I reactions to penicillins, effective antibiotic treatment in the three days before study entry, neutropenia ( < 1 x 109 neutrophils/L), hypogammaglobulinaemia (IgG < 200 mg/dL), rapidly fatal concomitant diseases, seriously impaired liver function (serum transaminases or bilirubin > 3 times upper normal limit), renal failure (creatinine clearance < 30 mL/min estimated by the Cockroft formula), pregnancy, and lactation. Antibiotic treatment Cefpirome and ceftazidime were given in 1 g doses 12-hourly as short term infusions over 15-30 min or as bolus injections over 5 min for a minimum of five days. In patients with renal impairment (creatinine clearance 30-50 mL/min) the dose was reduced to 0-5 g 12-hourly. Trial drugs were supplied by Hoechst AG, Frankfurt/Main, Germany or by Roussel Uclaf, Paris, France. Laboratory samples Urine cultures (midstream or catheter) were obtained before treatment, on the 2nd or 3rd days during treatment, and 2-15 days and, if possible, 4-8 weeks after treatment. Blood cultures were taken before treatment and were repeated during treatment if they were positive and the patient remained rifebrile. Bacterial isolates were identified using standard techniques. Susceptibility to cefpirome and ceftazidime was determined using a disc diffusion test or MlC-determination. The resistance breakpoints were > 8 mg/L
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on April 2, 2015
The trial was a prospective, open, randomized, multiple-independent study with stratification at each centre. Randomization was 2:1 (cefpirome: ceftazidime) using sealed envelopes. Forty-five centres in 14 countries recruited a total of 926 patients. The number of patients recruited at each centre varied between 1 and 90. The sample size calculated to test the null hypothesis that the difference in bacteriological cure rate was not greater than 10% was 340 evaluable patients in the cefpirome group and 170 in the ceftazidime group with a type I error of 0-05 (two-sided), a type II error of 0-2 (statistical power of 80%) and an assumed cure rate of 80% in the ceftazidime group.
Ccfptrome n ceftaxtdfane In UTI
97
and > 16 mg/L or corresponding zone diameters in disc diffusion tests for cefpirome and ceftazidime respectively (Hoechst AG data on file). Routine biochemical and haematological investigations and urinalysis were performed before, during, and after treatment. Definitions
Statistics The results in the two groups were compared by Fisher's exact test and by calculation of 95% confidence intervals. Results The treatment groups were comparable with respect to age, sex, underlying diseases, and types of urinary tract infection (Table I). Four patients randomized to receive cefpirome were not given the drug and were excluded from evaluation. The reasons for exclusion from clinical and bacteriological evaluation were premature discontinuation of treatment for reasons other than treatment failure (cefpirome/ceftazidime; 50/16), isolation of a pathogen resistant to the allocated drug (14/19), absence of clinical symptoms plus erroneous urine sampling (9/3), wrong diagnosis at entry (11/5), concomitant antimicrobial treatment (6/0), and wrong dosage of trial drugs (1/1). Exclusions from assessment of bacteriological efficacy were due to failure to identify significant bacteriuria (46/24), inadequate post-treatment samples (64/29), and no sensitivity data (6/6). Most patients had complicated urinary tract infections (Table II). The median duration of treatment was seven days in both groups. All patients, except five in the cefpirome group and two in the ceftazidime group who had reduced renal function, received 1 g of trial drug 12-hourly. There was no significant difference between the two treatment groups (Table III) in terms of clinical response. Complicating factors were significantly more common in both groups (P = 0-05, Fisher's exact test) in patients who failed to respond. As shown in Table IV, resistance to cefpirome was significantly less common than to ceftazidime amongst pre-treatment, Gram-positive pathogens. No such difference was
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An evaluable patient was one who had been treated for > 5 days (or at least two days if treatment failed), had not missed more than one dose and had significant bacteriuria ( > 105 cfu/mL except for staphylococci for which bacteriuria was defined as ^ 10* cfu/mL) before treatment. In addition, for evaluation of bacteriological efficacy the causative pathogens(s) must have been susceptible to the assigned drug, appropriate urine cultures must have been obtained before, during, and after treatment, and the patient must not have received any antibiotics between the last dose of trial drug and the first follow-up urine sample. Clinical response at the end of treatment was classified as satisfactory (all symptoms disappeared), improved (symptoms improved but at least one persisting) or unsatisfactory. Bacteriological response was classified as satisfactory (causative pathogen not present in post-treatment culture and no new pathogen isolated) or unsatisfactory (persistence, relapse or early recurrence of the original pathogen or superinfection). Safety was analysed in all patients who received at least one dose.
Study Group
98
Table L Patient characteristics Treatment Characteristic
Ceftazidime
594 1:1-4 73 61
303 1:1-3 73 64
498(84)
252 (83)
387 (65)
200(66)
268 (69) 119(31) 190 (49) 197 (51) 195 (50) 105 (27) 87 (22)
131 (65) 69(35) 106 (53) 94(47) 95(47) 63 (31) 42 (21)
observed for Gram-negative isolates. Fourteen cefpirome patients and 19 ceftazidime patients received treatment despite resistant pre-treatment pathogens. These organisms were eradicated in all 11 bacteriologically evaluable cefpirome patients and in 11 of 15 bacteriologically evaluable ceftazidime patients (four patients had relapses due to Gram-positive isolates soon after completing treatment). Tables V and VI show the bacteriological responses 2-15 days after completion of treatment. There were more failures in the ceftazidime group, both for patients with Table n. Complicating factors in bacteriologically evaluable patients Treatment group and No. (%) of patients Complicating factor None Residual urine Prostatk hypertrophy Indwelling catheter Extrarenal obstruction of urine flow Urogcnital malformation Stones Prostatic carcinoma Hydronephrosis Bladder carcinoma Urogcnital surgery Renal cysts Neurogenic bladder Other
Cefpirome
Ceftazidime
174(45) 77(20) 79 (20) 47 (12) 40(10) 24 (6) 31 (8) 25 (6) 12 (3) 13 (3) 12 (3) 7 (2) 10 (3) 35 (9)
83 (41) 40(20) 30(15) 34(17) 21 (10) 24(12) 15 (7) 10 (5) 12 (6) 5 (2) 4 (2) 4 (2) 3 (1) 18 (9)
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No. of patients entered Male: female ratio Median age males (years) Median age females (years) No. of clinically evaluable patients (% of patients entered) No. of bacteriologically evaluable patients (% of patients entered) Type of infection Sporadic infections (%) Recurrent infections (%) Lower UTI (%) Upper UTI (%) Community acquired UTI (%) Hospital acquired UTI (%) Unknown aetiology (%)
Cefpirome
Cefpfrome w cefUzklime in UT1
99
Table UL Clinical response-evaluable patients Treatment group and No. (%) of patients Response
Cefpirome
Ceftazidime
Upper
Satisfactory Improved Unsatisfactory
244(900) 19 (7-0) 8 (3-0)
115(85-2) 14 (104) 6 (4-4)
Lower
Satisfactory Improved Unsatisfactory
186 (81-9) 33 (14-5) 8 (3-5)
92 (78-6) 21 (17-9) 4 (3-4)
Overall
Satisfactory Improved Unsatisfactory
430 (86-3) 52 (104) 16 (3-2)
207 (821) 35 (13-9) 10 (4-0)
Table IV. Sensitivity of pre-treatment isolates to test agents
Noi. (%) susceptible* to Cefpirome Ceftazidime Organism (No. of strains)
S
S. aureus (27) Staphylococci, coagulase negative (38) Streptococcus spp. (11) Enterococcus faecalis (39) Group D streptococci (51)
24
Total Gram-positives (166) % resistant strains E. coli (462) Citrobacter spp (13) K. pneumoniae (37) Klebsiella spp. (30) E. cloacae (24) Enterobacter spp. (8) Serratia marctscens (6) Proteus mirabilis (48) Proteus spp. (28) P. aeruginosa (57) Pseudomonas spp. (16) Other Gram-negatives (10) Total Gram-negatives (739) % resistant strains
R ND' S 1 2
17
31 7 0 9 0 2 28 10 1 44 6 1 136 24 6
18 8 8 2 53
14-4'
R ND 8 2
20 1 30 48 107
0 2 1 1 6
65-1
443 1 18 440 3 19 13 0 0 12 1 0 35 1 1 34 2 1 28 1 1 29 1 0 24 0 0 21 3 0 8 0 0 8 0 0 6 0 0 6 0 0 48 0 0 47 0 1 28 0 0 28 0 0 54 2 1 54 3 0 13 2 1 15 1 0 8 1 1 9 1 0 708 8 23 703 15 21 11 21
*S - sensitive; R - resistant; ND «• not done. *Point estimate for the 95% confidence interval for the difference between the groups ii 42-3%, 60-3%.
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Type of UTI
100
Study Groop
Table V. Bacteriological response at first post-treatment follow-up (2-15 days after last dose) No. (%) in each treatment group Response
Type of UTI
Cefpirome
Ceftazidime
Satisfactory Unsatisfactory
169 (9(M) 18 (9-6)
82 (87-2) 12 (12-8)
Lower
Satisfactory Unsatisfactory
168 (88-4) 22(11-6)
92 (86-8) 14(13-2)
Overall
Satisfactory Unsatisfactory
337 (894) 40(10*)
174 (87-0) 26 (13-0)
pyelonephritis and lower urinary tract infections, but the differences were not significant. The lowest eradication rates were seen in patients with infections caused by P. aeruginosa. Amongst patients with an unsatisfactory bacteriological response to treatment, there were 19 reinfections in the cefpirome group and 14 in the ceftazidime group. More of the isolates causing reinfection were resistant to ceftazidime than to cefpirome, largely because there were more Gram-positive organisms in the ceftazidime group. High clinical and bacteriological cure rates were achieved with both antibiotics in a subset of patients with bacteriuria and proven septicaemia (Table VII). Of the patients with hospital acquired urinary tract infections 106 of 113 cefpirometreated patients (94%) and 56 of 61 ceftazidime-treated patients (92%) had a satisfactory clinical response to treatment. The bacteriological response in these patients was satisfactory in 90% and 86%, respectively. At the late follow-up, 4-8 weeks posttreatment, a satisfactory bacteriological response was observed in 61 patients (79%) in Table VL Bacteriological results by pre-treatment species No. isolates eradicated/total no. (%) in each treatment group Pre-treatment organism
Cefpirome
Ceftazidime
E. coli Klebsiella spp. Enterobacter spp. Proteus spp. P. aeruginosa Pseudomonas spp. Citrobacter spp. Other Gram-negatives Staphylococcus spp. Streptococcus spp.
214/220 (97-3) 24/29 (82-8) 15/15 (100) 40/42 (95-2) 20/31 (64-5) 6/7 (85-7) 5/5 (100) 4/4 (100) 27/30 (90-0) 40/48 (83-3)
124/127 (97-6) 13/13(100) 7/10 (7(M)) 19/19 (100) 9/13 (69-2) 6/6 (100) 2/2 (100) 12/12 (100) 11/11 (100) 4/5 (80-0)
Total
395/431 (91-6)
205/218 (94-9)
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Upper
Cefpirome n ceftaxknme in UTI
101
Table VIL Clinical and bacteriological response in patients with UTI and septicaemia No. (%) of patients in treatment group Response
Cefpirome
Ccftaririimc
Clinical
—satisfactory —improved —unsatisfactory
30 (9(h9) 2 (6-1) 1 (30)
16 (8(M)) 2(100) 2(10-0)
Bacteriological
—satisfactory —unsatisfactory
23 (88-5) 3(11-5)
10 (83-3) 2(16-7)
the cefpirome group and 26 patients (76%) in the ceftazidime group. Of the 19 pathogens isolated from the urine of patients with these laterecurrences(13 in patients allocated to cefpirome and six in patients allocated to ceftazidime), two were resistant to both cefpirome and ceftazidime and the remaining strains were sensitive to both antibiotics. Tables Vm and DC summarize the adverse events reported. More events were reported in the cefpirome group but there were no significant differences in the numbers of patients in whom treatment was discontinued due to adverse events. No tendency towards a higher incidence of adverse events in a particular organ system was observed with cefpirome. Ten patients in the cefpirome group (1-7%) had adverse events which were classified as severe by the investigators. Five of these events (three cases of thrombophlebitis and one each of convulsions and vomiting) were considered related to cefpirome treatment. Six ceftazidime patients (2-0%) experienced such events, all of which were considered unrelated or remotely related to treatment. Death during or within one month of the end of treatment was reported for six patients (1-0%) allocated to cefpirome and five patients (1-7%) randomized to ceftazidime. All deaths were considered unrelated to treatment with the trial drugs. All but one death (in a patient who died from pancreatic cancer) were attributed to concomitant cardiovascular disease and in no case was treatment failure considered a contributory factor. Ninety-nine laboratory adverse events were reported in 47 cefpirome patients (8%) and 33 in 17 ceftazidime patients (6%). Fifty-three laboratory events in cefpirome patients and 12 in ceftazidime patients were considered highly probably or probably related to treatment. Discussion This study has shown that cefpirome given in a dose of 1 g 12-hourly is at least as effective in achieving a clinical and bacteriological cure as ceftazidime in the same dosage for the treatment of urinary tract infections in hospitalized patients. This result confirms thefindingsof a smaller uncontrolled, phase II study with cefpirome (Norrby et at., 1988). Only 22% of the patients in the cefpirome group and 26% in the ceftazidime group had hospital acquired infections. This accounts for the relatively low numbers of multiply resistant, urinary tract pathogens such as Enterobacter spp., Pseudomonas spp.
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Unsatisfactory response based on positive post-treatment urine cultures.
102
Study Group TaWe V m . Adverse events Related adverse events* Ccfpirome
Ceftazidime
Cardiovascular system thrombophlebitis Lung Kidney/genitourinary system Abdomen/gastrointestinal tract diarrhoea Neurological/psychiatric nausea taste perversion headache convulsions paraesthesia vertigo dizziness insomnia Psychovegetative symptoms vomiting anorexia flushes constipation Allergic reactions rash Haematology Musculoskeletal system Infection Local reactions Other
15 14 0 0 10 8 13 4 3 2 1 1 1 1 0 6 3 2 1 0 11 11 1 0 2 7 1
3 3 0 0 4 4 1 1 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 0 1 4 1
Total No. of reactions
66
18
No. of patients with reactions % of randomized and treated No. of patients with related events % of randomized and treated
83 13-9 53' 8-9
29 9-5 14 4-6
•Several patienti had more than one adverse event 'Events classified by the investigators u highly probably or probably related to treatment given. 'Point estimate of the 95% confidence interval for differences between groups was 1-0%, 7-6%.
and Acinetobacter spp. Rather, Escherichia coli, enterococci, Klebsiella spp. and Proteus mirabilis were the commonest isolates. The superior activity of cefpirome against Gram-positive organisms was demonstrated by the higher incidence of resistance to ceftazidime amongst pre-treatment, Gram-positive isolates. Both drugs were equally active against the Gram-negative urinary pathogens. More adverse reactions were reported in cefpirome-treated patients than in those who received ceftazidime. However, with the exception of a higher incidence of thrombophlebitis, no pattern was detected in the type of adverse events reported, suggesting that there is no specific toxicity associated with cefpirome.
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Adverse event* by body system
Cefpirome n ceftazidime in UTI
103
Table DL Clinical and laboratory adverse events leading to discontinuation of treatment No. of patients in .each group Adverse event
Ceftazidime
0 2 5 2
1 2 0 0 0 0 1 1 0 0 1 1 0 0 0
24
15 (2-5)
5(1-7)
"Event considered unrelated to treatment *One reaction was Considered unrelated to treatment
In conclusion, this trial which included a large number of patients has shown that the overall efficacy of cefpirome and ceftazidime is comparable. Acknowledgement This study was supported by grants from Hoechst AG, Frankfurt, Germany and Roussel-Uclaf, Paris, France. References Bauernfeind, A. (1983). Susceptibility of Gram-positive aerobic cocci to the new cephalosporin HR 810. European Journal of Clinical Microbiology 2, 354-5. Bertram, M. A., Bruckner, D. A. & Young, L. S. (1984). In vitro activity of HR 810, a new cephalosporin. Antimicrobial Agents and Chemotherapy 26, 277-9. Kavi, J., Andrews, J. W., Ashby, J. P., Hillman, G. & Wise, R. (1988). Pharmacokinetics and tissue penetration of cefpirome, a new cephalosporin. Journal of Antimicrobial Chemotherapy 22, 911-6. Lameire, N., Malerczyk, V., Drees, B., Lehr, K. & Rosenkranz, B. (1991). Single-dose pharmacokinetics of cefpirome in patients with renal impairment. Clinical Pharmacology and Therapeutics, in press. Maass, L., Malerczyk, V. & Verho, M. (1987). Pharmacokinetics of cefpirome (HR 810), a new cephalosporin derivative administered intramuscularly and intravenously to healthy volunteers. Infection 15, 207-10.
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Thrombophlebitis Rash or urticaria Vomiting Peripheral vasodilation Diarrhoea Seizures Pain at injection site Fever Vertigo Myocardial infarction' Heart failure* Pulmonary embolism' Leukopenia Abnormal liver function test* Eosinophilia Total events related to treatment No. of patients in whom treatment was discontinued due to related adverse events (% of treated)
Cefpirome
104
Study Group
Mackha, K. & Braveny, I. (1983). In vitro activity of HR 810, a new broad spectrum cephalosporin. European Journal of Clinical Microbiology 2, 354-9. Malerczyk, V. , Maass, L., Vcrho, M., Hajdu, P., Klesel, N. & Rangoonwala, R. (1987). Single and multiple dose pharmacokinetics of intravenous cefpirome (HR 810), a novel cephalosporin derivative. Infection 15, 211-4. Norrby, S. R., Dotevall, L., Eriksson, M., Settergren, B. t Larsspn, P., Lundhohn, R. eial. (1988). Efficacy and safety of cefpirome (HR &\Q)., Journal of Antimicrobial Chemotherapy 22,
541-7.
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