A. G. Hofstetter
Cefodizime Given Once Daily for the Treatment of Upper Urinary Tract Infections and Complicated Lower Urinary Tract Infections Summary: The efficacy of cefodizime (CDZ) in upper urinary tract infections (UUTI) and complicated lower urinary tract infections (LUTI) was assessed by analysis of the combined results of five clinical trials. Doses of CDZ lg i.m. daily, 1 x 2 g i.v. or i.m. and 2 x 2 g i.v. were investigated; comparative agents were cefuroxime 3 x 1.5 g and ceftizoxime 1 x 2 g. Median duration of treatment was seven days. A total of 544 patients, 61% of whom had UUTI, entered the studies. Four hundred twenty-two patients were evaluable clinically and 375 bacteriologically. The most frequent pathogen at baseline was Eschoichia coli, followed by Proteus mirabilis, Klebsiella spp. and Staphylococcus aureus. Both clinical and bacteriological cure rates were above 90% in all study groups. The dosage of 1 x 2 g C D Z is recommended for the treatment of UUTI and complicated LUTI. Znsammenfassung: Cefodizim einmal t?iglich bei der Behandlung yon lnfektionen des oberen Harntraktes und komplizierten Infektionen des unteren Harntraktes. Die kombinierte Analyse der Wirksamkeit von Cefodizim (CDZ) bei Infektionen der oberen Harnwege und komplizierten Infektionen der unteren Harnwege anhand von ffinf klinischen Pr/Jfungen umfal3te folgende Dosierungen: C D Z 1 g/d i.m., 1 x 2 g/d i.v. oder i.m. und 2 x 2 g/d i.v., Vergleichssubstanzen: Cefuroxim 3 x 1,5 g, Ceftizoxim 1 x 2 g. Die Behandlungsdauer betrug im Median sieben Tage. Fiinfhundertvierundvierzig Patienten wurden in die klinischen Pr/Jfungen aufgenommen, bei 61% davon bestand eine Infektion der oberen Harnwege. Vierhundertzweiundzwanzig Patienten waren klinisch auswertbar, 375 bakteriologisch. Die h~iufigsten Keime ware Escherichia coli, gefolgt von Proteus mirabilis, Klebsiella spp. und Staphylococcus aureus. Sowohl die klinischen als auch die bakteriologischen Heilungsquoten lagen in allen Dosisgruppen fiber 90%. Die empfohlene Dosis von C D Z bei Infektionen der oberen Harnwege und bei komplizierten Infektionen der unteren Harnwege betrfigt 1 x 2 g/d. Introduction
Cefodizime is a new third-generation cephalosporin with an antimicrobial spectrum including most pathogens relevant for infections of the urinary tract, such as Escherichia coli, Klebsiella spp., Proteus vulgaris, Proteus mirabilis, most other members of the Enterobacteriaceae, and methicillin-susceptible strains of Staphylococcus aureus [1-3]. Most strains of Enterobacter cloacae and S 18
Serratia marcescens are susceptible to cefodizime. Cefodizime achieves high concentrations in serum and various tissues after both intravenous and intramuscular injection [4,5]. It is excreted predominantly by the kidneys, with 80% of unchanged drug being recovered from urine . The terminal serum half-life is 4 h . These pharmacokinetic properties suggest that a once-daily dosage regimen is appropriate for the treatment of urinary tract infections. Cefodizime has been found efficacious for the treatment of lower urinary tract infections with minor complications when given as a single i.v. dose of 1 g or 2 g . The aim of this report is to review the efficacy of cefodizime in upper urinary tract infection and complicated lower urinary tract infection, in comparison to that of cefuroxime and ceftizoxime, by analysis of the combined results of five clinical trials. Patients and Methods
Analysis of the efficacy of cefodizime in upper urinary tract infection and complicated lower urinary tract infection was performed on the basis of pooled data from four comparative, randomized clinical trials and one open clinical study. All trials followed a standardized protocol. A regimen of cefodizime 2 g i.v. once daily was compared to cefuroxime 1.5 g i.v.t.i.d, or to ceftizoxime 2 g i.v. once daily. The same dosage of cefodizime (2 g once daily) was used in the open study, but the mode of administration was by either i.m. or i.v. injection. In two further studies, different dosages of cefodizime were compared with each other: 2 g i.v. once daily vs. 2 g i.v.b.i.d., and 1 g i.m. once daily vs. 0.5 g i.m.b.i.d. Hospitalized patients aged 16-80 years with a diagnosis of upper urinary tract infection and/or complicated lower urinary tract infection were admitted to the studies. The following exclusion criteria were applied: pregnancy, nursing, concomitant treatment with other antimicrobial substances, antibiotic pretreatment of the infection unless this had resulted in a therapeutic failure, history of hypersensitivity to cephalosporins, treatment with another investigational drug within eight weeks prior to the study, and treatment with probenecid or with drugs known to cause defined organ toxicity. Patients with serum creatinine above 2.5 mg/dl, those having impaired liver function or abnormal findings which might affect the interpretation of study results, and patients who were unable to give informed consent were also excluded. Urine bacteriology, including sensitivity testing of the pathogen against the study drugs, a complete blood count, prothrombin time, and liver and kidney function tests were performed at baseline and at the end of the study. If a resistant pathogen was cultured or if the clinical picture had deteriorated after a minimum treatment duration of three days, the study drugs were discontinued in favor of a more appropriate treatment, in most cases a combination with an aminoglycoside. Criteria for the evaluation of efficacy Prof. Dr. A. G. Hofstetter, Urologische Klinik, Klinikum Groghadern, Ludwig-Maximilians-Universit~it, Marchioninistr. 15, W-8000 Mtinchen 70.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, Mfinchen 1992
A. G. Hofstetter: Cefodizime in Urinary Tract Infections were the isolation of > lOs CFU of a single pathogen at baseline, susceptibility of that strain to the study drug, and a minimum treatment duration of five days, with the exception of a treatment failure after a minimum of three days. For the evaluation of bacteriological efficacy, an adequate post-treatment culture was mandatory, while the presence of symptoms typical for UTI at baseline was critical for the evaluation of clinical response. If symptoms h a d not disappeared completely, response was classified as "fair."
Results Table 1 shows the combined numbers of patients for each treatment regimen of cefodizime and of the comparators, cefuroxime and ceftizoxime. A total of 544 patients entered the studies, of which 422 were evaluable for clinical efficacy and 375 for bacteriological efficacy. The most frequent reasons for non-evaluability were the failure to isolate a pathogen at baseline or an insufficient duration of treatment. Analysis of the combined results of all studies revealed the following demographic characteristics: median age 63 years, 55.5% male. Sixty-one percent of patients had upper urinary tract infection. Complications of lower
Table 1: Dosage regimens investigated in the clinical trials with cefodizime, and numbers of patients included in the trials, evaluable for clinical efficacy and evaluable for bacteriological efficacy.
Table 3: Symptoms of urinary tract infection in the clinical trials with cefodizime: percentage of patients in each treatment group presenting with the respective symptom.
FrequentT Urgency Flank pain Suprapubic.pain Macrohematuria Rigors
1 g daily 2 g once daily 2 g b.i.d. 1.5 g t.i.d. 2 g once daily all regimens all regimens
92 259 40 70 83 391 153
72 202 21 64 63 295 127
71 170 21 62 51 262 113
Table 2: Complications of urinary tract infection in the clinical trials with cefodizime: percentage of patients in each treatment group presenting with the respective complication.
Surgery prior to infection Indwelling catheter Obstruction of urinary flow: Urethra Prostate Bladder Ureter/kidney Urinary concrement Renal impairment Diabetes mellitus
6 16 10 6 16 14 13
8 13 15 6 14 20 17
55 53 52 29 17 17
Table 4: Clinical trials of cefodizime in urinary tract infection: distribution of urinary pathogens isolated at baseline in the bacteriologically evaluable patients, given as percentage of pathogens within each treatment group.
Escherichia coli Proteus mirabilis Proteus spp. Klebst'ella pneumoniae Klebsiella spp. Staphylococcus aureus Staphylococcus epidermidis Staphylococcus spp. Pseudomonas aeruginosa Pseudomonas spp. Streptococcus spp. Enterococcus spp. Enterobacter cloacae Serratia spp. Citrobacter spp.
Other gram-negative rods Cefodizime Cefodizime Cefodizime Cefuroxime Ceftizoxime Cefodizime Comparators
62 53 5t 27 17 12
57.8 10.9 2.9 1.5 5.8 4.0 4.7 1.0 2.5 1.5 1.8 1.5 1.5 1.5 0.4 0.7
45.0 16.8 3.0 3.5 6.1 5.3 1.5 1.5 0.7 4.6 0.0 5.3 1.5 0.7 3.0 1.5
urinary tract infection are listed in Table 2; the most frequent were obstruction of urinary flow by anatomic abnormalities, or surgery prior to the development of urinary infection. The median duration of treatment was seven days in all studies. Demographic features of the treatment groups were comparable in all of the comparative studies. Altogether, 295 of 391 patients (75.4%) in the cefodizime groups and 127 of 153 (83%) in the control groups were evaluable clinically. The commonest symptoms were frequency, urgency and flank pain (Table 3). Clinical cure rates were similar in all study groups (Figure 1). A total of 275 organisms were isolated from 262 patients evaluable for bacteriological efficacy in the cefodizime group, while "131 pathogens were found in 113 bacteriologically evaluable patients in the control groups. Table 4 shows the distribution of isolates at baseline. Bacteriological cure rates were 92% for all dosage regimens of cefodizime and 91% for the comparators. Figure 2 shows the bacteriological cure rates for each individual dosage regimen.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1992
A. G. Hofstetter: Cefodizime in Urinary Tract Infections
10~ 10 o
Figure 1: Clinical cure rates observed with different dosage regimens of cefodizime and two cephalosporins used as comparators in controlled clinical trials.
Kidney [Pg/g ]
* Prostate : BPH, c a n c e r
Figure 3: Median tissue concentrations of cefodizime in kidney and prostate at different time points after injection of 2 g i.v. (adapted from ) and concentrations of cefodizime in fractional urine after administration of 1 g i. v. (adapted from ).
with somewhat more than half of the patients being male. About 60% suffered from upper urinary tract infection, in many cases with complicating factors, while the remainder ~, 6o had complicated lower urinary tract infection, usually obstruction of urinary flow or postoperative UTI. The g~ most frequent pathogen was E. coli, followed by Proteus spp., Klebsiella spp. and S. aureus. ":" 20 The dosage regimen of 1 x 2 g cefodizime, and even that of o 1 g daily, achieved cure rates of over 90%, which '~ 0 l g daily lx2g 2x2g 3x1.5g lx2g corresponds to the results observed with the comparator Cefodizime CefurCeftiantibiotics cefuroxime and ceftizoxime. oxime zoxime The pathogen most frequently associated with the rare Figure 2: Bacteriological cure rates observed with different instances of treatment failure with cefodizime was E. dosage regimens of eefodizime and two cephalosporins used faecalis. Pseudomonas and E. faecalis were found to be as comparators in controlled clinical trials. associated with therapeutic failures in the control groups and are known to pose problems in cephalosporin In the cefodizime group 98.5% of all pathogens isolated at treatment, so these findings are not unexpected . baseline were eradicated. The most frequent reason for In conclusion, cefodizime given as a Single daily injection bacteriological failure was a new infection with was highly effective for the treatment of upper urinary Enterococcusfaecalis (eight cases). Other pathogens rarely tract infections and complicated lower urinary tract associated with treatment failures were Pseudomonasspp. infections. The dosage regimen of 2 g cefodizime once and E. cloacae. daily is supported by data from a good-sized patient Unsatisfactory bacteriological results in the cefuroxime population and is presently recommended as the basic group were mainly associated with Pseudomonas aeruginosa and, in the ceftizoxime group, with regimen. However, pharmacokinetic data and good efficacy in 71 patients treated to date make the dosage Pseudomonas spp. and Enterococcus faecalis. regimen of cefodizime 1 g daily an alternative candidate for serious consideration in view of continuous efforts to Discussion optimize the cost/benefit ratio. Concentrations of cefodizime in prostate and kidney were found to be well above the microbiological breakpoints for clinically important pathogens 12 h post injection, while References levels in urine were higher, even after 24 h [4,5] (Figure 3). Cefodizime therefore appears to be a useful injectable 1. Knothe, H., Shah, P. M.: In vitro activity of eefodizime. Infection 20 (1992) (Suppl. I) S 3-S 8. antibiotic for the treatment of urinary tract infections, 2. Naber, K. G., Bauernfeind, A., Dieflein, G., Wittenberger, 1~: Urinary suitable for once-daily administration. pathogens and bacterial sensitivity in hospitalized urological patients The patient population treated in the studies reviewed based upon clinical aspects. Scand. J. Urol. Nephrol. 104 (1987) (Suppl. 0) 47-57. here was characterized by a median age above 60 years, 80
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
A. G. Hofstetter: Cefodizime in Urinary Tract Infections 3. Scully, B. E., Jules, K., Neu, H. C.: In vitro activity and 15-1actamase stability of cefodizime, an aminothiazolyl iminomethoxy eephalosporin. Antimicrob. Agents Chemother. 23 (1983) 907-913. 4. Korting, H. C., Sch~ifer-Korting, M., Maas, L., Klesel, N., Mntschler, E.: Cefodizime in serum and skin blister fluid after single intravenous and intramuscular doses in healthy volunteers. Antimicrob. Agents Chemother. 31 (1987) 1822-1825. 5. Hofstetter, A., Knipper, A., Dagrosa, E. E., Klesel, N.: Concentration of cefodizime (HR 221), a new cephalosporin, in urological tissues. In: lshigami, J. (ed.): Recent advances in chemotherapy, antimicrobial
section 2. University of Tokyo Press, Tokyo 1985, pp. 93%940. 6. Dagrosa, E. E., Hajdfi, P., Malerezyk, V., de Looze, S., Seeger, K., Gr6tseh, H.: Dose linearity and other pharmacokinetics of cefodizime after single-dose intravenous administration. Clin. Ther. 10 (1987) 18-31. 7. Asbach, H. W.: A randomized, dose comparison study of cefodizime in the treatment of lower urinary tract infections in women. Infection 19 (1991) 85-87. 8. Simon, C., Stille, W.: Antibiotikatherapie in Klinik und Praxis. Schattauer, Stuttgart-New York 1989, pp. 92-97.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, M(inchen 1992