R. A. Pauwels
Review of Effectiveness of Cefodizime in the Treatment of Lower Respiratory Tract Infections with Parenchymal Involvement Summary: The efficacy of cefodizime (CDZ) in lower respiratory tract infections (LRTI) with parenchymal involvement was assessed by the analysis of data from 919 patients who participated in four controlled, randomized studies and three open studies. Sputum bacteriology and a chest x-ray were performed at baseline and after therapy. A total of 778 patients were evaluable for clinical efficacy and 451 for bacteriological efficacy. The most frequent pathogen was Streptococcus pneumoniae, followed by Staphylococcus aureus, Klebsiella pneumoniae and Haemophilus influenzae. CDZ 1 g b.i.d., 2 g b.i.d, and 2 g once daily achieved clinical and bacteriological cure rates above 90%, which matched those observed with the comparators (cefuroxime 1.5 g t.i.d, and cefotaxime 2 g b.i.d.). No significant differences in clinical and bacteriological outcome were detected when the various CDZ dosage regimens were compared. 1 g CDZ b.i.d, is therefore recommended as the regimen of choice for the treatment of LRTI with parenchymal involvement, with CDZ 2 g once daily as an alternative. Zusammenfassung: Wirksamkeit von Cefodizim bei tiefen Atemwegsinfektionen mit Parenchymbeteiligung. Introduction Cefodizime is a new third-generation cephalosporin with an antimicrobial spectrum similar to that of cefotaxime. Susceptible pathogens include Streptococcus pneurnoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae and most members of the Enterobacteriaceae [1,2]. The susceptibility of Enterobacter cloacae and Serratia marcescens varies. Pseudornonas aeruginosa and Enterococcus faecalis are usually resistant [3]. In several in vivo experimental models of infection, cefodizime exhibited a protective action against infection with both in vitro cefodizime-sensitive and cefodizime-resistant organisms [4]. These findings have been attributed to a biological response modifying activity of the molecule
[5]. High and long-lasting concentrations of cefodizime in serum and tissue are achieved after both intravenous and intramuscular injection. Cefodizime has linear pharmacokinetics and is not metabolized; it is excreted predominantly via the kidneys [6,7]. Terminal elimination half-life of the antibiotic is 4 h, theoretically allowing a once or twice daily administration [8]. Cefodizime has mainly been investigated in upper and complicated lower urinary tract infections and in lower S 26
Die Wirksamkeit von Cefodizim (CDZ) bei der Behandlung von Infektionen der tiefen Atemwege mit Parenchymbeteiligung wurde anhand von vier kontrollierten, randomisierten und drei offenen klinischen Studien mit insgesamt 919 Patienten beurteilt. Zu Studienbeginn und -ende wurden Thoraxrrntgen und Sputumbakteriologie durchgeffihrt. 778 Patienten waren hinsichtlich der klinischen Wirksamkeit, 451 bezfiglich der bakteriologischen Wirksamkeit auswertbar. Die h/iufigsten Keime waren
Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae und Haemophilus influenzae. Sowohl mit CDZ 2 x 1 g/d als auch mit 2 x 2 g/d und l x2 g/d wurden klinische und bakteriologische Heilungsraten von fiber 90% erzielt, /ihnlich wie mit den Referenzsubstanzen, Cefuroxim 3 x 1,5 g/d und Cefotaxim 2 x 2 g/d. Zwischen den drei Dosierungsschemata von CDZ wurde kein statistisch signifikanter Unterschied festgestellt, daher wird gegenw/irtig die Dosis von CDZ 2 x 1 g/d zur Behandlung von Infektionen der tiefen Atemwege mit Parenchymbeteiligung empfohlen. Ein alternatives Behandlungsschema w/ire die einmal t/igliche Verabreichung von 2 g CDZ.
respiratory tract infections with and without parenchymal involvement [8-10]. The aim of the present study was to review the efficacy of cefodizime in lower respiratory tract infections with parenchymal involvement by the combined analysis of data from four controlled, randomized studies and three open clinical studies.
Patients and Methods Data from patients with signs of parenchymal involvement on chest x-ray from four controlled and three open clinical studies were pooled for analysis of the efficacy of cefodizime in lower respiratory tract infections. Doses of 1 g cefodizime b.i.d, and 2 g cefodizime b.i.d, have been used in a dose comparison study and in studies of each dose vs. cefuroxime 1.5 g t.i.d. Cefodizime 2 g b.i.d, was compared to cefotaxime 2 g b.i.d. The dose of cefodizime 1 g b.i.d, has also been investigated in an open study and that of 2 g cefodizime once daily was employed in two open studies. All studies followed a similar protocol. Hospitalized patients suffering from lower respiratory tract infection and parenchymal involvement demonstrated on chest x-ray were admitted to the studies. Exclusion criteria were an age below 16 years, pregnancy, nursing, a history of hypersensitivity to cephalospoProf. Dr. IL A. Pauwels, Department of Pneumology, Medical School, University of Gent, De Pintelaan 185, B-9000 Gent, Belgium.
Infection 20 (1992) Suppl. 1 © MMV Medizin Veflag GmbH M/inchen, Miinchen 1992
R. A. Pauwels: Cefodizime in LRTI rins, and severe renal or hepatic impairment. Patients were excluded if they were treated with another antibiotic concomitantly to cefodizime, with an investigational drug within eight weeks prior to the study, with drugs possessing a defined organ toxicity or with probenecid. Antibiotic pretreatment was also a reason for exclusion, unless it had resulted in a treatment failure. A chest x-ray, together with measurement of complete blood counts, prothrombin time, and liver and kidney function tests were conducted at baseline and at the end of the study. Bacteriological culture from sputum or from bronchial secretions was performed at baseline and, if sputum was still available, at the end of therapy. If the clinical picture had aggravated after a minimum of three days of treatment, the study drug was discontinued in favor of a more appropriate therapy, usually a combined antibiotic treatment. Criteria for the evaluation of efficacy were symptoms indicative of lower respiratory tract infection, documentation o f parenchymal involvement on chest x-ray at baseline and a minimal treatment duration of five days. A clinical failure was considered evaluable after a minimum treatment duration of three days. If a patient died of infection, he was considered a clinical failure; if death was attributed to another reason, t h e patient was excluded from the evaluation of efficacy. Patients were only considered for evaluation of bacteriological response if they were evaluable clinically, if a pathogen had been cultured at baseline, and if that pathogen was shown to be sensitive to the study drugs. Bacteriological response was considered satisfactory if the infecting pathogen had been eradicated or if the patient had improved clinically to such a degree that no sputum was available for a post-treatment culture. Results
Patient Population Demography -
Nine hundred and nineteen patients with lower respiratory tract infections and parenchymal involvement entered the worldwide clinical trials with cefodizime, of whom 778 were evaluable for clinical efficacy and 451 for bacteriological efficacy. The combined patient numbers for each treatment regimen used are shown in Table 1. The most frequent reasons for non-evaluability were the absence of a chest x-ray at baseline and a dosage regimen Table 1: Dosage regimens investigated and numbers of patients in the clinical trials with cefodizime.
Cefodizime Cefodizime Cefodizime
2 g once daily 109 1 g b.Ld. 244 2 g b.i.d. 276
87 212 233
34 153 125
Cefuroxime Cefotaxime
1.5 g t~i.d. 2 g b.i.d.
172 118
151 95
114 25
Cefodizime
all regimens
629
532
312
Comparators
all regimens
290
246
139
100
80 so
[%l 40 20 0
-30 n=tO0
-40 n=74
° 50 n=87
I ITT~F~ B a c t e r i o l o g i c a l Underlying
-60 n=91 evaluability
respiratory
disorders
- 70 n=139
- 75 n=95
- 80 n=107 cure
> 80 yea n=85
m
Clinical
~]
Concomitant diseases
rate
I
I
III1[ IIIIIIII III
Figure 1: Age dependency of bacteriological evaluability, clinical cure rates, the incidence of underlying respiratory disorders and that of concomitant diseases. not in accordance with the study protocol. These patients excluded from the evaluation of efficacy did not differ from the evaluable patients in terms of age, sex distribution, underlying respiratory diseases, concomitant diseases or general condition. Sex distribution was similar in all studies, with 63% of all patients being men. Median age was 63 years in the cefodizime group and 63.5 years in the control groups. There was no difference in age between treatment groups in any of the individual studieS; however, age distribution varied from study to study. Median age was between 50 and 55 years in two open and the two controlled studies of cefodizime vs. cefuroxime, which together represented over half of the total patient population (508/911, 56%). Median age was 70 and 71 years in the dose comparison study and in the study vs. cefotaxime, respectively (38% of the patients). T h e patients participating in an open study with 2 g cefodizime once daily had a median age of 80 years. These differences in age should be taken into account when comparing rates of response to the dosage regimens, because there were relationships evident between the age of patients and the rate of bacteriological evaluability, the rate of underlying respiratory disorders and the presence of concomitant diseases (Figure 1). The clinical cure rates were also influenced by age, which is reflected in the apparently superior efficacy of the dosage regimen using 1 g b.i.d, of cefodizime and the differences in cure rates of cefuroxime and cefotaxime. Underlying respiratory disorders (mainly C O P D , emphysema and bronchiectasis; Table 2) were r e p o r t e d by between 40 and 46% of patients in the three cefodizime dose groups and in the cefotaxime group, whereas the incidence was 22.5% in the cefuroxime group. Concomitant diseases were reported in 57.3% of patients in the cefodizime group, in 77.9% of the cefotaxime group and in 34.4% of the cefuroxime group. About two-thirds of the overall patient population had cardiovascular diseases
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mfinchen, Miinchen 1992
S 27
R. A. Pauwels: Cefodizime in LRTI Table 2: Underlying respiratory disorders in clinical trials o f c e f o d i z i m e : percentage of patients in each treatment group presenting with the respective complication.
Respiratory disorders
42.9
30.5
Chronic bronchitis Emphysema Bronchiectasis Lung cancer Pneumothorax
22.4 19.2 5.6 2.6 1.5
13.8 12.2 1.2 2.8 0.8
9.4
4.5
Treatment with corticosteroids
(congestive heart failure, coronary heart disease, arterial hypertension, cardiac arrhythmia), whilst about a quarter of the cases had diabetes mellitus and a smaller proportion had impaired liver function. 2.6% of the patients had cancer of the respiratory tract and 5.2% had cancer of other organ systems. Median duration of treatment was ten days in all three cefodizime dosage groups and in the cefuroxime and cefotaxime groups. Demographics, underlying diseases and duration of treatment were comparable between groups in all of the controlled studies.
Table 3: Results of clinical trials investigating cefodizime in lower respiratory tract infection: distribution of pathogens isolated at baseline in the bacteriologically evaluable patients (percent within each treatment group).
Streptococcuspneumoniae Streptococcus spp. Staphylococcus aureus Staphylococcus spp. Enterococcusfaecalis
147 27 45 7 4
(39.84%) (7.32 %) ( 12.20 % ) (1.90 %) (1.08 % )
3
(0.81%)
0
(0.00%)
Haemophilus influenzae Haemophilus spp.
22 10
(5.96 % ) (2.71%)
12 1
(7.84%) (0.65%)
Klebsiellapneumoniae Klebsiella spp. Escherichia coil Proteus spp. Morganellamorganii Serratia spp. Enterobacter spp. Citrobacterspp.
33 9 16 14 2 6 6 3
(8.94 %) (2.44 % ) (4.34 %) (3.79 %) (0.54 %) (1.63 %) (1.63 %) (0.81%)
11 3 11 6 0 4 3 4
(7.19%) (1.96%) (7.19%) (3.92%) (0.00%) (2.61%) (1.96%) (2.61%)
Pseudomonas aeruginosa Pseudomonas spp. Alcaligenesfaecalis Acinetobacter spp.
6 2 1 2
(1.63 %) (0.54 %) (0.27 %) (0.54 %)
4 1 0 1
(2.61%) (0.65%) (0.00%) (0;65%)
Bacteroides spp. Fusobacterium spp.
2 2
(0.54 %) (0.54 %)
0 0
(0.00%) (0.00%)
Neisseria spp;
72 ( 47.06%) 3 (1.96%) 12 (7.84%) 2 (1.31%) 3 (1.96% )
Bacteriological and Clinical Responses A total of 522 organisms were isolated from 451 bacteriologically evaluable patients at baseline. The usual community-acquired organisms, namely S. pneumoniae, S. aureus, H. influenzae and other gram-positive cocci, accounted for 70.3% of these 522 isolates. Gram-negative cocci were cultured in only 0.6%. Enterobacteriaceae were found in 25.1%, Pseudomonas spp. in 2.7% and lOO
771"77 8O
\\\\\\\\\\\\
6O
\\ \\\\ \\\\
tlt
ff f f#
40
=
20
(JLL# ~N
O
1 x2g
2xlg Cef, o d i z i m e
2x2g
3 x 1.5g
2 x 2g
Cefur-
Cefo-
oxime
taxime
Figure 2: Clinical cure rates (+_ 95% confidence intervals) observed with different dosage regimens of cefodizime and two cephalosporins used as comparators in the controlled clinical trials,
S 28
Acinetobacter spp. in 0.6%. Anaerobes (Bacteroides spp. and Fusobacterium spp.) were isolated in 0.7%. Table 3 shows the distribution of isolates among the treatment groups. All treatment regimens resulted in a favorable clinical outcome in more than 85% of the cases. The overall clinical cure rate with cefodizime was 93.05% and that of the comparators 90.24%. Cure rates and 95% confidence intervals for each dosage regimen are given in Figure 2. No significant differences were found between the regimens in any randomized, controlled study. Bacteriological cure rates (shown in Figure 3) were equally favorable. Again, no significant differences were found between groups in any controlled study. Bacteriological failures occurred in 8/312 patients (2.56%) in the cefodizime groups and were in one case each associated with a new infection caused by Citrobacter freundii, the persistence of S. aureus, P. aeruginosa (two cases), Pseudomonas spp., P. aeruginosa + E. faecalis, C. freundii and S. pneumoniae. The latter three patients were considered clinically cured a n d required no further antibiotic treatment; the patient in whom pneumococci persisted and who had been treated with 2 g cefodizime b.i.d, for seven days showed good clinical response and regression of the consolidation in chest x-ray, both at the end of therapy and ten days later.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, M/inchen 1992
R. A. Pauwels: Cefodizime in LRTI
100
~
80
~
60
. . . .
_~ 4o o o
"~ 2o m m
o
1 x 2g
2 x lg Cefodizime
2 x 2g
3 x 1.5g
2 x 2g
Cefuroxime
Cefotaxime
Figure 3: Bacteriological cure rates (+ 95% confidence intervals) observed with different=dosage regimens of cefodizime and two cephalosporins used as comparators in the controlled clinical trials. In the cefuroxime group, bacteriological - and simultaneously clinical - failures occurred in 4/114 patients (3.51%): one case e a c h of persistence of Escherichia coli, Serratia marcescens and Pseudomonas spp., as well as a persistence of E. coli plus a new infection with Klebsiella pneurnoniae, were reported. In the cefotaxime group 2/25 (8%) bacteriological failures were recorded: persistence of Pseudomonas spp. and of S. aureus, in both cases accompanied by a new infection with E. faecalis. Discussion
Age differences and variations in the incidence of concomitant diseases proved to be important factors when assessing the results of these trials. A middle-aged patient population has been studied in trials with all three dosage regimens of cefodizime and with cefuroxime 1.5 g t.i.d. An elderly patient population was investigated in the dose comparison study of cefodizime l g b.i.d, and 2 g b.i.d, and in the study comparing cefodizime 2 g b.i.d, with cefotaxime 2 g b.i.d. The dose of cefodizime 2 g once daily was also employed in a study conducted mainly in geriatric patients. Concomitant diseases were more frequent in the elderly patient population than in the middle-aged one, and the same applied to underlying respiratory diseases. In view of the incidence of concomitant diseases and of underlying respiratory disorders, as well as that of hospital-acquired pathogens isolated at baseline, the cure
rate obtained with 2 g cefodizime b.i.d, should be compared with that of cefotaxime 2 g b.i.d., while the cure rate observed in the studies with 1 g cefodizime b.i.d, is appropriately contrasted with that of 1.5 g cefuroxime t.i.d. The two open studies with 2 g cefodizime once daily were conducted in severely ill middle-aged patients and in a geriatric population. Concomitant diseases were present in 55.2% of the patients and underlying respiratory disorders in 40.2%. The cure rates observed with this dosage regimen should thus be compared with those of both cefodizime 1 g b.i.d, and 2 g b.i.d. No statistically significant differences have been detected between the cure rates observed with the three different dose regimens of cefodizime. The dosages of cefodizime investigated were equally effective as those of the comparator cephalosporins, cefuroxime and cefotaxime, in the treatment of patients with lower respiratory tract infections and having signs of parenchymal involvement in chest x-ray. The majority of pathogens identified in these studies are usually community-acquired. As expected, the most frequent organism was S. pneumoniae, followed by S. aureus and H. influenzae. The incidence of Enterobacteriaceae, Pseudomonas spp. and other organisms frequently acquired in hospitals was 24.5% in the studies with a middle-aged population and 37% in those performed in elderly patients. No isolates of Moraxella catarrhalis and only three strains o f Neisseria spp. were cultured, probably because their pathogenicity in lower respiratory tract infections is considered equivocal by some of the participating laboratories. The pathogen may not have been selectively cultured and therefore the bacteriological findings may represent an underestimate of Moraxella. Among the rare bacteriological treatment failures with cefodizime, P. aeruginosa has been identified in 4/8 cases. This finding is not unexpected, as this species is known to be problematical for cephalosporin treatment. The dosage regimen of cefodizime 1 g b.i.d., which is supported by data from a good-sized patient population, proved highly effective and is currently recommended as the regimen of choice for cefodizime treatment of lower respiratory tract infections with parenchymal involvement in a hospital environment. However, based on patient comfort and the increasing recognition of cost-benefit factors in medical care, the single daily application of 2 g of cefodizime should be considered an alternative regimen.
References 1. Limbert, M., Klesel, N., Seeger, K., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. I. In vitro activity. J. Antibiot. 37 (1984) 1719-1726. 2. Scully, B. E., Jules, K., Nen, H. C.: In vitro activity and beta-laetamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin. Antimicrob. Agents Chemother. 23 (1983) 907-913.
3. Kasai, K., Tsuji, A., Miyazaki, S., Goto, S., Fujimoto, K., Masuyoshi, S., Arai, S.: In vitro antibacterial activity and [5- lactamase stability of cefodizime, a new cephalosporin antibiotic. Jpn. J. Antibiot. 37 (1984) 1294-1305. 4. Limbert, M., Bartlett, R., Dickneite, G., Klesel, N., Schorlemmer, H. U., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. IV. Influence on the immune system,
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1992
S 29
IL A. Pauwels: Cefodizime in L R T I
J. Antibiot. 37 (1984) 1719-1726. 5. Labro, M. T.: Cefodizime as a biological response modifier: a review of its in vivo, ex vivo and in vitro immunomodulatory properties. J. Antimicrob. Chemother. 26 ($3) (1990) 37--47. 6. Korting, H. C., Sehiifer-Kortiug, M., Maas, L., Klesel, N., Mutsehler, E.: Cefodizime in serum and skin blister fluid after single intravenous and intramuscular doses in healthy volunteers. Antimicrob. Agents Chemother. 31 (1987) 1822-1825. 7. Dagrosa, E. E., Hajdfi, P., Malerezyk, V., de Looze, S., Seeger, K., Griitsch, H.: Dose linearity and other pharmacokinetics of cefodizime after single-dose intravenous administration. Clin. Ther. 10 (1987) 18-31. 8. Maesen, F. P. V., Davies, B. I., van den Bergh, J. J. A. M., Gubbelmanns, H. L. L., Meek, J. C. E., Geraedts, W. H.: Cefodizime
S 30
and cefotaxime in acute exacerbations of chronic bronchitis: a randomized double-blind prospective study in 180 patients. J. Antimicrob. Chemother. 25 (t990) 413-522. 9. Boelaert, J., Lambrecht, E., Van Couter, A., Temmeran, B., Dagrosa, E., Gordts, B., Van Landuvt, H. W.: Cefodizime versus cefuroxime for acute lower respiratory tract infections in geriatric patients. In: Program and abstracts of the 15th International Congress of Chemotherapy, Istanbul 1987, Abstract 1333. 10. Manciei, G., and the Cefodizime Study Group: Efficacy and tolerance of cefodizime in elderly patients with lower respiratory tract and urinary tract infections. In: Program and abstracts of the International Congress for Infectious Diseases, Montreal 1990, Abstract 656.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
Review of Effectiveness of Cefodizime in the Treatment of Lower Respiratory Tract Infections with Parenchymal Involvement Summary: The efficacy of cefodizime (CDZ) in lower respiratory tract infections (LRTI) with parenchymal involvement was assessed by the analysis of data from 919 patients who participated in four controlled, randomized studies and three open studies. Sputum bacteriology and a chest x-ray were performed at baseline and after therapy. A total of 778 patients were evaluable for clinical efficacy and 451 for bacteriological efficacy. The most frequent pathogen was Streptococcus pneumoniae, followed by Staphylococcus aureus, Klebsiella pneumoniae and Haemophilus influenzae. CDZ 1 g b.i.d., 2 g b.i.d, and 2 g once daily achieved clinical and bacteriological cure rates above 90%, which matched those observed with the comparators (cefuroxime 1.5 g t.i.d, and cefotaxime 2 g b.i.d.). No significant differences in clinical and bacteriological outcome were detected when the various CDZ dosage regimens were compared. 1 g CDZ b.i.d, is therefore recommended as the regimen of choice for the treatment of LRTI with parenchymal involvement, with CDZ 2 g once daily as an alternative. Zusammenfassung: Wirksamkeit von Cefodizim bei tiefen Atemwegsinfektionen mit Parenchymbeteiligung. Introduction Cefodizime is a new third-generation cephalosporin with an antimicrobial spectrum similar to that of cefotaxime. Susceptible pathogens include Streptococcus pneurnoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae and most members of the Enterobacteriaceae [1,2]. The susceptibility of Enterobacter cloacae and Serratia marcescens varies. Pseudornonas aeruginosa and Enterococcus faecalis are usually resistant [3]. In several in vivo experimental models of infection, cefodizime exhibited a protective action against infection with both in vitro cefodizime-sensitive and cefodizime-resistant organisms [4]. These findings have been attributed to a biological response modifying activity of the molecule
[5]. High and long-lasting concentrations of cefodizime in serum and tissue are achieved after both intravenous and intramuscular injection. Cefodizime has linear pharmacokinetics and is not metabolized; it is excreted predominantly via the kidneys [6,7]. Terminal elimination half-life of the antibiotic is 4 h, theoretically allowing a once or twice daily administration [8]. Cefodizime has mainly been investigated in upper and complicated lower urinary tract infections and in lower S 26
Die Wirksamkeit von Cefodizim (CDZ) bei der Behandlung von Infektionen der tiefen Atemwege mit Parenchymbeteiligung wurde anhand von vier kontrollierten, randomisierten und drei offenen klinischen Studien mit insgesamt 919 Patienten beurteilt. Zu Studienbeginn und -ende wurden Thoraxrrntgen und Sputumbakteriologie durchgeffihrt. 778 Patienten waren hinsichtlich der klinischen Wirksamkeit, 451 bezfiglich der bakteriologischen Wirksamkeit auswertbar. Die h/iufigsten Keime waren
Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae und Haemophilus influenzae. Sowohl mit CDZ 2 x 1 g/d als auch mit 2 x 2 g/d und l x2 g/d wurden klinische und bakteriologische Heilungsraten von fiber 90% erzielt, /ihnlich wie mit den Referenzsubstanzen, Cefuroxim 3 x 1,5 g/d und Cefotaxim 2 x 2 g/d. Zwischen den drei Dosierungsschemata von CDZ wurde kein statistisch signifikanter Unterschied festgestellt, daher wird gegenw/irtig die Dosis von CDZ 2 x 1 g/d zur Behandlung von Infektionen der tiefen Atemwege mit Parenchymbeteiligung empfohlen. Ein alternatives Behandlungsschema w/ire die einmal t/igliche Verabreichung von 2 g CDZ.
respiratory tract infections with and without parenchymal involvement [8-10]. The aim of the present study was to review the efficacy of cefodizime in lower respiratory tract infections with parenchymal involvement by the combined analysis of data from four controlled, randomized studies and three open clinical studies.
Patients and Methods Data from patients with signs of parenchymal involvement on chest x-ray from four controlled and three open clinical studies were pooled for analysis of the efficacy of cefodizime in lower respiratory tract infections. Doses of 1 g cefodizime b.i.d, and 2 g cefodizime b.i.d, have been used in a dose comparison study and in studies of each dose vs. cefuroxime 1.5 g t.i.d. Cefodizime 2 g b.i.d, was compared to cefotaxime 2 g b.i.d. The dose of cefodizime 1 g b.i.d, has also been investigated in an open study and that of 2 g cefodizime once daily was employed in two open studies. All studies followed a similar protocol. Hospitalized patients suffering from lower respiratory tract infection and parenchymal involvement demonstrated on chest x-ray were admitted to the studies. Exclusion criteria were an age below 16 years, pregnancy, nursing, a history of hypersensitivity to cephalospoProf. Dr. IL A. Pauwels, Department of Pneumology, Medical School, University of Gent, De Pintelaan 185, B-9000 Gent, Belgium.
Infection 20 (1992) Suppl. 1 © MMV Medizin Veflag GmbH M/inchen, Miinchen 1992
R. A. Pauwels: Cefodizime in LRTI rins, and severe renal or hepatic impairment. Patients were excluded if they were treated with another antibiotic concomitantly to cefodizime, with an investigational drug within eight weeks prior to the study, with drugs possessing a defined organ toxicity or with probenecid. Antibiotic pretreatment was also a reason for exclusion, unless it had resulted in a treatment failure. A chest x-ray, together with measurement of complete blood counts, prothrombin time, and liver and kidney function tests were conducted at baseline and at the end of the study. Bacteriological culture from sputum or from bronchial secretions was performed at baseline and, if sputum was still available, at the end of therapy. If the clinical picture had aggravated after a minimum of three days of treatment, the study drug was discontinued in favor of a more appropriate therapy, usually a combined antibiotic treatment. Criteria for the evaluation of efficacy were symptoms indicative of lower respiratory tract infection, documentation o f parenchymal involvement on chest x-ray at baseline and a minimal treatment duration of five days. A clinical failure was considered evaluable after a minimum treatment duration of three days. If a patient died of infection, he was considered a clinical failure; if death was attributed to another reason, t h e patient was excluded from the evaluation of efficacy. Patients were only considered for evaluation of bacteriological response if they were evaluable clinically, if a pathogen had been cultured at baseline, and if that pathogen was shown to be sensitive to the study drugs. Bacteriological response was considered satisfactory if the infecting pathogen had been eradicated or if the patient had improved clinically to such a degree that no sputum was available for a post-treatment culture. Results
Patient Population Demography -
Nine hundred and nineteen patients with lower respiratory tract infections and parenchymal involvement entered the worldwide clinical trials with cefodizime, of whom 778 were evaluable for clinical efficacy and 451 for bacteriological efficacy. The combined patient numbers for each treatment regimen used are shown in Table 1. The most frequent reasons for non-evaluability were the absence of a chest x-ray at baseline and a dosage regimen Table 1: Dosage regimens investigated and numbers of patients in the clinical trials with cefodizime.
Cefodizime Cefodizime Cefodizime
2 g once daily 109 1 g b.Ld. 244 2 g b.i.d. 276
87 212 233
34 153 125
Cefuroxime Cefotaxime
1.5 g t~i.d. 2 g b.i.d.
172 118
151 95
114 25
Cefodizime
all regimens
629
532
312
Comparators
all regimens
290
246
139
100
80 so
[%l 40 20 0
-30 n=tO0
-40 n=74
° 50 n=87
I ITT~F~ B a c t e r i o l o g i c a l Underlying
-60 n=91 evaluability
respiratory
disorders
- 70 n=139
- 75 n=95
- 80 n=107 cure
> 80 yea n=85
m
Clinical
~]
Concomitant diseases
rate
I
I
III1[ IIIIIIII III
Figure 1: Age dependency of bacteriological evaluability, clinical cure rates, the incidence of underlying respiratory disorders and that of concomitant diseases. not in accordance with the study protocol. These patients excluded from the evaluation of efficacy did not differ from the evaluable patients in terms of age, sex distribution, underlying respiratory diseases, concomitant diseases or general condition. Sex distribution was similar in all studies, with 63% of all patients being men. Median age was 63 years in the cefodizime group and 63.5 years in the control groups. There was no difference in age between treatment groups in any of the individual studieS; however, age distribution varied from study to study. Median age was between 50 and 55 years in two open and the two controlled studies of cefodizime vs. cefuroxime, which together represented over half of the total patient population (508/911, 56%). Median age was 70 and 71 years in the dose comparison study and in the study vs. cefotaxime, respectively (38% of the patients). T h e patients participating in an open study with 2 g cefodizime once daily had a median age of 80 years. These differences in age should be taken into account when comparing rates of response to the dosage regimens, because there were relationships evident between the age of patients and the rate of bacteriological evaluability, the rate of underlying respiratory disorders and the presence of concomitant diseases (Figure 1). The clinical cure rates were also influenced by age, which is reflected in the apparently superior efficacy of the dosage regimen using 1 g b.i.d, of cefodizime and the differences in cure rates of cefuroxime and cefotaxime. Underlying respiratory disorders (mainly C O P D , emphysema and bronchiectasis; Table 2) were r e p o r t e d by between 40 and 46% of patients in the three cefodizime dose groups and in the cefotaxime group, whereas the incidence was 22.5% in the cefuroxime group. Concomitant diseases were reported in 57.3% of patients in the cefodizime group, in 77.9% of the cefotaxime group and in 34.4% of the cefuroxime group. About two-thirds of the overall patient population had cardiovascular diseases
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mfinchen, Miinchen 1992
S 27
R. A. Pauwels: Cefodizime in LRTI Table 2: Underlying respiratory disorders in clinical trials o f c e f o d i z i m e : percentage of patients in each treatment group presenting with the respective complication.
Respiratory disorders
42.9
30.5
Chronic bronchitis Emphysema Bronchiectasis Lung cancer Pneumothorax
22.4 19.2 5.6 2.6 1.5
13.8 12.2 1.2 2.8 0.8
9.4
4.5
Treatment with corticosteroids
(congestive heart failure, coronary heart disease, arterial hypertension, cardiac arrhythmia), whilst about a quarter of the cases had diabetes mellitus and a smaller proportion had impaired liver function. 2.6% of the patients had cancer of the respiratory tract and 5.2% had cancer of other organ systems. Median duration of treatment was ten days in all three cefodizime dosage groups and in the cefuroxime and cefotaxime groups. Demographics, underlying diseases and duration of treatment were comparable between groups in all of the controlled studies.
Table 3: Results of clinical trials investigating cefodizime in lower respiratory tract infection: distribution of pathogens isolated at baseline in the bacteriologically evaluable patients (percent within each treatment group).
Streptococcuspneumoniae Streptococcus spp. Staphylococcus aureus Staphylococcus spp. Enterococcusfaecalis
147 27 45 7 4
(39.84%) (7.32 %) ( 12.20 % ) (1.90 %) (1.08 % )
3
(0.81%)
0
(0.00%)
Haemophilus influenzae Haemophilus spp.
22 10
(5.96 % ) (2.71%)
12 1
(7.84%) (0.65%)
Klebsiellapneumoniae Klebsiella spp. Escherichia coil Proteus spp. Morganellamorganii Serratia spp. Enterobacter spp. Citrobacterspp.
33 9 16 14 2 6 6 3
(8.94 %) (2.44 % ) (4.34 %) (3.79 %) (0.54 %) (1.63 %) (1.63 %) (0.81%)
11 3 11 6 0 4 3 4
(7.19%) (1.96%) (7.19%) (3.92%) (0.00%) (2.61%) (1.96%) (2.61%)
Pseudomonas aeruginosa Pseudomonas spp. Alcaligenesfaecalis Acinetobacter spp.
6 2 1 2
(1.63 %) (0.54 %) (0.27 %) (0.54 %)
4 1 0 1
(2.61%) (0.65%) (0.00%) (0;65%)
Bacteroides spp. Fusobacterium spp.
2 2
(0.54 %) (0.54 %)
0 0
(0.00%) (0.00%)
Neisseria spp;
72 ( 47.06%) 3 (1.96%) 12 (7.84%) 2 (1.31%) 3 (1.96% )
Bacteriological and Clinical Responses A total of 522 organisms were isolated from 451 bacteriologically evaluable patients at baseline. The usual community-acquired organisms, namely S. pneumoniae, S. aureus, H. influenzae and other gram-positive cocci, accounted for 70.3% of these 522 isolates. Gram-negative cocci were cultured in only 0.6%. Enterobacteriaceae were found in 25.1%, Pseudomonas spp. in 2.7% and lOO
771"77 8O
\\\\\\\\\\\\
6O
\\ \\\\ \\\\
tlt
ff f f#
40
=
20
(JLL# ~N
O
1 x2g
2xlg Cef, o d i z i m e
2x2g
3 x 1.5g
2 x 2g
Cefur-
Cefo-
oxime
taxime
Figure 2: Clinical cure rates (+_ 95% confidence intervals) observed with different dosage regimens of cefodizime and two cephalosporins used as comparators in the controlled clinical trials,
S 28
Acinetobacter spp. in 0.6%. Anaerobes (Bacteroides spp. and Fusobacterium spp.) were isolated in 0.7%. Table 3 shows the distribution of isolates among the treatment groups. All treatment regimens resulted in a favorable clinical outcome in more than 85% of the cases. The overall clinical cure rate with cefodizime was 93.05% and that of the comparators 90.24%. Cure rates and 95% confidence intervals for each dosage regimen are given in Figure 2. No significant differences were found between the regimens in any randomized, controlled study. Bacteriological cure rates (shown in Figure 3) were equally favorable. Again, no significant differences were found between groups in any controlled study. Bacteriological failures occurred in 8/312 patients (2.56%) in the cefodizime groups and were in one case each associated with a new infection caused by Citrobacter freundii, the persistence of S. aureus, P. aeruginosa (two cases), Pseudomonas spp., P. aeruginosa + E. faecalis, C. freundii and S. pneumoniae. The latter three patients were considered clinically cured a n d required no further antibiotic treatment; the patient in whom pneumococci persisted and who had been treated with 2 g cefodizime b.i.d, for seven days showed good clinical response and regression of the consolidation in chest x-ray, both at the end of therapy and ten days later.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, M/inchen 1992
R. A. Pauwels: Cefodizime in LRTI
100
~
80
~
60
. . . .
_~ 4o o o
"~ 2o m m
o
1 x 2g
2 x lg Cefodizime
2 x 2g
3 x 1.5g
2 x 2g
Cefuroxime
Cefotaxime
Figure 3: Bacteriological cure rates (+ 95% confidence intervals) observed with different=dosage regimens of cefodizime and two cephalosporins used as comparators in the controlled clinical trials. In the cefuroxime group, bacteriological - and simultaneously clinical - failures occurred in 4/114 patients (3.51%): one case e a c h of persistence of Escherichia coli, Serratia marcescens and Pseudomonas spp., as well as a persistence of E. coli plus a new infection with Klebsiella pneurnoniae, were reported. In the cefotaxime group 2/25 (8%) bacteriological failures were recorded: persistence of Pseudomonas spp. and of S. aureus, in both cases accompanied by a new infection with E. faecalis. Discussion
Age differences and variations in the incidence of concomitant diseases proved to be important factors when assessing the results of these trials. A middle-aged patient population has been studied in trials with all three dosage regimens of cefodizime and with cefuroxime 1.5 g t.i.d. An elderly patient population was investigated in the dose comparison study of cefodizime l g b.i.d, and 2 g b.i.d, and in the study comparing cefodizime 2 g b.i.d, with cefotaxime 2 g b.i.d. The dose of cefodizime 2 g once daily was also employed in a study conducted mainly in geriatric patients. Concomitant diseases were more frequent in the elderly patient population than in the middle-aged one, and the same applied to underlying respiratory diseases. In view of the incidence of concomitant diseases and of underlying respiratory disorders, as well as that of hospital-acquired pathogens isolated at baseline, the cure
rate obtained with 2 g cefodizime b.i.d, should be compared with that of cefotaxime 2 g b.i.d., while the cure rate observed in the studies with 1 g cefodizime b.i.d, is appropriately contrasted with that of 1.5 g cefuroxime t.i.d. The two open studies with 2 g cefodizime once daily were conducted in severely ill middle-aged patients and in a geriatric population. Concomitant diseases were present in 55.2% of the patients and underlying respiratory disorders in 40.2%. The cure rates observed with this dosage regimen should thus be compared with those of both cefodizime 1 g b.i.d, and 2 g b.i.d. No statistically significant differences have been detected between the cure rates observed with the three different dose regimens of cefodizime. The dosages of cefodizime investigated were equally effective as those of the comparator cephalosporins, cefuroxime and cefotaxime, in the treatment of patients with lower respiratory tract infections and having signs of parenchymal involvement in chest x-ray. The majority of pathogens identified in these studies are usually community-acquired. As expected, the most frequent organism was S. pneumoniae, followed by S. aureus and H. influenzae. The incidence of Enterobacteriaceae, Pseudomonas spp. and other organisms frequently acquired in hospitals was 24.5% in the studies with a middle-aged population and 37% in those performed in elderly patients. No isolates of Moraxella catarrhalis and only three strains o f Neisseria spp. were cultured, probably because their pathogenicity in lower respiratory tract infections is considered equivocal by some of the participating laboratories. The pathogen may not have been selectively cultured and therefore the bacteriological findings may represent an underestimate of Moraxella. Among the rare bacteriological treatment failures with cefodizime, P. aeruginosa has been identified in 4/8 cases. This finding is not unexpected, as this species is known to be problematical for cephalosporin treatment. The dosage regimen of cefodizime 1 g b.i.d., which is supported by data from a good-sized patient population, proved highly effective and is currently recommended as the regimen of choice for cefodizime treatment of lower respiratory tract infections with parenchymal involvement in a hospital environment. However, based on patient comfort and the increasing recognition of cost-benefit factors in medical care, the single daily application of 2 g of cefodizime should be considered an alternative regimen.
References 1. Limbert, M., Klesel, N., Seeger, K., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. I. In vitro activity. J. Antibiot. 37 (1984) 1719-1726. 2. Scully, B. E., Jules, K., Nen, H. C.: In vitro activity and beta-laetamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin. Antimicrob. Agents Chemother. 23 (1983) 907-913.
3. Kasai, K., Tsuji, A., Miyazaki, S., Goto, S., Fujimoto, K., Masuyoshi, S., Arai, S.: In vitro antibacterial activity and [5- lactamase stability of cefodizime, a new cephalosporin antibiotic. Jpn. J. Antibiot. 37 (1984) 1294-1305. 4. Limbert, M., Bartlett, R., Dickneite, G., Klesel, N., Schorlemmer, H. U., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. IV. Influence on the immune system,
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1992
S 29
IL A. Pauwels: Cefodizime in L R T I
J. Antibiot. 37 (1984) 1719-1726. 5. Labro, M. T.: Cefodizime as a biological response modifier: a review of its in vivo, ex vivo and in vitro immunomodulatory properties. J. Antimicrob. Chemother. 26 ($3) (1990) 37--47. 6. Korting, H. C., Sehiifer-Kortiug, M., Maas, L., Klesel, N., Mutsehler, E.: Cefodizime in serum and skin blister fluid after single intravenous and intramuscular doses in healthy volunteers. Antimicrob. Agents Chemother. 31 (1987) 1822-1825. 7. Dagrosa, E. E., Hajdfi, P., Malerezyk, V., de Looze, S., Seeger, K., Griitsch, H.: Dose linearity and other pharmacokinetics of cefodizime after single-dose intravenous administration. Clin. Ther. 10 (1987) 18-31. 8. Maesen, F. P. V., Davies, B. I., van den Bergh, J. J. A. M., Gubbelmanns, H. L. L., Meek, J. C. E., Geraedts, W. H.: Cefodizime
S 30
and cefotaxime in acute exacerbations of chronic bronchitis: a randomized double-blind prospective study in 180 patients. J. Antimicrob. Chemother. 25 (t990) 413-522. 9. Boelaert, J., Lambrecht, E., Van Couter, A., Temmeran, B., Dagrosa, E., Gordts, B., Van Landuvt, H. W.: Cefodizime versus cefuroxime for acute lower respiratory tract infections in geriatric patients. In: Program and abstracts of the 15th International Congress of Chemotherapy, Istanbul 1987, Abstract 1333. 10. Manciei, G., and the Cefodizime Study Group: Efficacy and tolerance of cefodizime in elderly patients with lower respiratory tract and urinary tract infections. In: Program and abstracts of the International Congress for Infectious Diseases, Montreal 1990, Abstract 656.
Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
