Journal of Antimicrobial Chemotherapy (1990) 25, 413-422

Cefodizime and cefotaxime in acute exacerbations of chronic bronchitis: a randomized doable-blind prospective study in 180 patients F. P. V. Maesen', B. L Darks6, J. J. A. M van den Bergh*, H. L. L. Gnbbelmans', J. C. E. Meek* and W. H. Geraedts*

In a double-blind prospective study, 180 patients admitted to hospital with acute purulent exacerbations of chronic bronchitis were treated for seven days with twice daily 1 g intramuscular injections of either cefodizime or cefotaxime. Sputum cultures performed before, during and immediately after treatment showed complete eradication of the infection in 89/90 given cefodizime and 86/90 receiving cefotaxime. Some symptomatic Pseudomonas aeruginosa superinfections occurred with each agent. During the follow-up week, recurrences or reinfections after apparent clearance occurred in IS patients given cefodizime and in 21 receiving cefotaxime. Pharmacokinetic studies in blood showed mean Cau values of 50-8 mg/1 for cefodizime and 36-5 mg/1 for cefotaxime, corresponding values in the sputum being 1-61 and 0-62 mg/1. Mean AUC values in both blood and sputum were 2f- to 3-fold higher for cefodizime. Some features suggested better performance by cefodizime than by cefotaxime, but the clinical results were not statistically significantly different

Introduction

Cefodizime (HR-221) is a recently developed aminothiazolyl cephalosporin (Jones et al., 1981; Limbert et al., 1984a, b). It differs structurally from cefotaxime only in the side chain at position 3 where it bears a mercapto-thiazolyl group, while cefotaxime has the naturally occurring acetyl-residue. The side chain is not only responsible for the antimicrobial activity and the kinetic properties of cefodizime (Klesel et al., 1984) but has also been claimed as being responsible for cefodizime's biological response modifying properties (Limbert et al., 1984a; Fietta et al., 1988; Vanholder et al., 1988). The molecule is free from haematological side effects associated with latamoxef, and does not influence plasma coagulation or platelet function (Andrassy et al., 1987). The result of the change in structure is that cefodizime is not metabolized and has a much longer elimination phase half-life than cefotaxime. These changes in kinetic properties also lead to peak concentrations in blood and sputum which are considerably higher than the corresponding values for cefotaxime (Maesen et al., 1980) after 1 or 2g intramuscular injections. In an earlier pilot study (Maesen el al., 1988) in 40 patients admitted to hospital because of respiratory infections, we had found excellent results in 65 to 74% of the cases with 1 or 2g drug doses given for ten days. However, we did see occasional problems when the infections were associated with /Mactamase producing Branhamella 413 0305-7453/90/030413 + 10 S02.00/0

© 1990 The British Society for Antimicrobial Oiemotherapy

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

Departments of'Respiratory Diseases and bMedical Microbiology, De Wever Ziekenhuis, 6401 CX Heerlen, The Netherlands

414

F. P. V. Maesen et d.

catarrhalis strains or when Pseudomonas aeruginosa was the infecting agent. Because of this we felt justified in undertaking a larger comparative double-blind randomized study against cefotaxime to ascertain whether the superior pharmacokinetic properties of cefodizime indeed led to improvement in the clinical results, especially with the B. catarrhalis infections. Materials and methods

Laboratory methods Bacteriological investigation of expectorated sputum was carried out according to the washing method of Mulder et al. (1952), more recently summarized by Da vies & Maesen (1983). After an urgent Gram stain of sputum had been examined, culture and susceptibility tests were carried out as in our previous studies. Sputum was examined on the day before treatment started and the culture was repeated on day 3, as well as one day after the end of treatment (day 8) and a week later on day 14. The susceptibilities of each cultured organism were assessed initially by disc-diffusion sensitivity tests but MICs were measured in batches at the end of the study by means of a standard agardilution method (Davies, Maesen & Brouwers, 1982) employing an inoculum of 5 x 104 organisms per inoculum point. Geometric mean MIC values were calculated by a programmable electric calculator (Hewlett Packard HP 97). All H. influenzae strains were biotyped (Kilians, 1985), in order to attempt to distinguish between relapses and reinfections. /Mactamase testing was performed with nitrocefin discs (Davies & Maesen, 1983). Haematological and biochemical safety screening was carried out on the same days as the cultures and the clinical progress of the patient was constantly monitored, a close watch being kept for any possible adverse drug effects. Kinetic studies Venous blood was obtained before and 1, 3, 5, 7,9 and 11 h after the first intramuscular injection on the first day of treatment. Furthermore, two-hour portions of expectorated sputum were collected up to 12 h after the first drug dose in order to measure the cefotaxime or cefodizime concentrations. For this reason, the bacteriological laboratory was given the code to the randomization list in order for the necessary standard solutions to be prepared and for the correct assay procedure to be followed. Cefotaxime concentrations were measured by an agar-well microbiological diffusion method

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

All the patients studied had been admitted to hospital with bacteriologically confirmed acute purulent exacerbations of chronic bronchitis associated with Haemophilus influenzae, B. catarrhalis and/or Streptococcus pneitmoniae. They all gave informed consent to participate in the investigation. Pregnant women, patients who were allergic to penicillins or cephalosporins, and patients with abnormal liver or kidney function test results were excluded from the study, as were any who had received antimicrobial agents in the three days before admission to hospital. A randomization list was provided by the manufacturer of the drugs and the patients were assigned in strict numerical order to receive either 1 g or cefotaxime or 1 g or cefodizime twice daily for seven days by intramuscular injection. Patients were not permitted to enter more than once in the study. The hospital Medical Ethics Committee assessed the study protocol and gave permission for the investigation to take place.

Cefodizbne and cefotaxiroe in chronic bronchitis

415

Results In total, 186 patients were recruited into the study, all of whom were ill enough to require urgent admission to hospital. There were 152 males and 34 females. The demographic data on the 180 evaluable patients in the two groups are shown in Table I. Table L Comparative data on 180 evahiable patients receiving either cefodizime or cefotaxime

Total number no. males no. females Male patients: mean age (years) (range) mean body wt (kg) (range) no. receiving theophylline: intravenously orally not given theophylline Female patients: mean age (years) (range) mean body wt (kg) (range) no. receiving theophylline: intravenously orally not given theophylline

Cefodizime

Cefotaxime

90 72 18

90 74 16

671

664

33-87 years 70-3 45-93 kg

46-81 years 68-0 44-92 kg

29 35 8

31 38 5

55-1 25-72 years 68-6 55-87 kg

65-8 38-76 years 63-7 46-79 kg

9 8 1

5 10 1

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

(Maesen et al., 1980) in Iso-Scnsitest agar (Oxoid CM 471) although a different organism (Escherichia coli 1341, kindly supplied by Hoffmann-La Roche, Basel) was used as indicator strain. Because this assay procedure yielded rather difficult plots with the higher cefodizime standards, the serum concentrations of this drug had to be measured by a completely different agar-well diffusion method employing Str. pyogenes A77 (Hoechst Forschung, Frankfurt) as indicator organism in Mueller-Hinton agar containing 10% sheep blood (N. Klesel, personal communication). The indicator organism was grown for 18 h (not longer) in brain-heart infusion broth and 2 ml of this culture was added to each 200 ml quantity of the blood agar mixture at 45°C, prior to pouring into large square assay plates (Nunc N 1015). Holes 10 mm in diameter were punched in the seeded agar and the plates were loaded conventionally with the test and standard solutions. All standards for the serum assays were made up in sterile horse serum and ranged from 1 to 64 mg/1. The inoculated plates were incubated overnight in air. The sputum assays for cefodizime employed the conventional E. coli assay procedure, but the standards (also in horse serum) ranged only from 0-12 to 4 mg/1. Both serum assays were accurate within the range 1-60 mg/1, the sputum assays between 0-1 and 10 mg/1. The clinical results were evaluated on the days 11 and 17 and assessed according to our standard criteria (Davies et al., 1978) as 'excellent', 'good', 'moderate' or 'poor'.

416

F. P. V. Maesen et aL

Table II. MICs of cefodizime and cefotaxime Numbers of strains with these MICs (mg/1): 8 16 32 > 3 2 GM 0-5 1 2 4

O03 (H)6 0-125 0-25 Str. pneumoniae (64) cefodizime cefotaxime

35 53

22 6

2 2

3

H. influenzae (84) cefodizime cefotaxime

72 55

7 20

2 7

1

1

B. catarrhalis (/Mactamase pos. 82) 29 cefodizime 21 30 cefotaxime 10

9 11

6 9

4 12

B. catarrhalis (^-lactamase neg. 36) cefodizime 18 15 11 cefotaxime 21

2 2

1

3

— —

GM, Geometric mean MIC.

- — _

— —

(M)5 (KM

2

1 — — — —

— —

(KM (KM

6 9

6 1

1 — — —

— —

0-11 0-13

— —

005 0O5

1 — =

P. aeruginosa (20) cefodizime cefotaxime

_

2

1

— 1

1

1 1

2

2

:

— —



:

:

2 4

3 5

12 6

32-0 16-6

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

More than 90% of the patients required concomitant theophylline, 74/180 intravenously (41-1%). There were no notable differences between the two treatment groups as far as the male patients were concerned, but the 18 females receiving cefodizime were slightly younger and heavier than the 16 given cefotaxime. Six patients discontinued treatment prematurely: of those receiving cefotaxime, one died from respiratory failure on the second treatment day and two had to be withdrawn from the study when the pre-treatment cultures were found to yield P. aeruginosa. In the cefodizime group, one patient had to be transferred to the intensive care unit for assisted respiration after three days, one was changed prematurely to doxycycline for reasons which are not clear, and another was transferred to a different hospital for an open heart operation during the follow-up period. These patients were replaced with others according to the extended randomization list, so that the final groups each consisted of 90 evaluable patients, with 72 males plus 18 females receiving cefodizime and 74 plus 16 being treated with cefotaxime. Table II gives an overview of the susceptibility of the bacteria cultured from the sputum to the two antibiotics investigated. Str.pneumoniae (64 strains) was highly susceptible to both cephalosporins, although cefotaxime was slightly more active. The geometric mean MIC values of the two antibiotics were identical for the 36 /Mactamase negative strains of B. catarrhalis (0-05 mg/1) and for the 84 H. influenzae strains (geometric means both 0-04 mg/1). The 82 /Mactamase producing strains of B. catarrhalis yielded geometric mean MIC values of 011 mg/1 for cefodizime and 0-13 mg/1 for cefotaxime. There were 20 isolates of P. aeruginosa cultured during the study, of which only three seemed to be susceptible to cefodizime (MICs 4 mg/1, or less) while five of the strains were susceptible to cefotaxime.

Cefodizhne and cefotaxhne in chronic bronchitis

417

Table HI. Sputum culture results before, during and after 7-day courses of ccfodizime or cefotaxime in 180 evaluable patients Study day: 8

14

1

11

3

Required other antibiotics Culture negative/no sputum

62

3(1-)

54(41-)

23 15 10 (6-) 4 (4-)

2

— — — — 1 1

7 (40

1(10

1 — — 4 1

8(4")

4 1 —

3(20

4 3 2

-

1 173

2 170

5 137

Cleared bacteriologically: 73/90 cefodizime patients (811%) 64/90 cefotaxime patients (711%) •ft-1jtctamnnr. producing strains of B. eatarrhalU.

Table i n presents the sputum culture results in the 180 evaluable patients. There were no major differences in the distribution of the infecting organisms over the two treatment groups and on days 3 and 8 the sputum cultures were negative in the great majority of patients. However, occasional symptomatic P. aeruginosa superinfections were seen in both treatment groups. There were five infections with /Mactamase producing strains of H. influenzae. All were eliminated but one other patient had a symptomatic reinfection with such a strain on day 14. In total, 55 of the 75 pretreatment B. catanhalis isolates were /Mactamase producers (73-3%) in contrast to seven out of 12 strains cultured after treatment (58-3%). As shown in Table IV, the numbers of patients with persistently positive or recurring positive cultures after initial Table IV. Bacteriological evaluations on day 14

Elimination Recurrence after initial elimination Persistence Reinfections after initial elimination Superinfection during therapy

Evaluable cefodizime patients (90)

Evaluable cefotaxime patients (90)

73 4 1 11 1

64 9 1 12 3

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

H. influenzae B. catanhalis Sir. pneumoniae Str. pneumoniae + H. influenzae B. catanhalis + H. influenzae B. catarrhalis+Str. pneumoniae P. aeruginosa Streptococcus spp. Staphylococcus aureus Str. pneumoniae+ B. catanhalis + H. influenzae Str. pneumoniae+H. influenzae + Neisseria meningitidis various other organisms

F. P. V. Maesen et al

418

Table V. Phannacokinetic results Cefodizime in = 90)

Cefotaxime (n = 90)

Serum results range

36-5 mg/1 (±18-1) 11 to 100 mg/1 119 h (h9 mg/1 (±0-6) 1-9 h 104-0 mg/l.h (±621) 38 to 514 mg/l.h 14 patients (15-5%)

Sputum results range T mean 11 h concentration mean 0-11 h AUC Penetration to sputum from blood Peak: peak ratios AUC: AUC ratios

1-61 mg/1 (±2-4) 0 to 19-0 mg/1 4-64 h 0-77 mg/1 (±0-83) 10-74 mg/l.h (±1604) 3-2% 3-9%

0-62 mg/1 (±11) 0 to 8-2 mg/1 4-48 h 0-13 mg/1 (±0-26) 3-40 mg/l.h (±7-13) 1-7% 3-3%

improvement weTe slightly higher in the cefotaxime group. However, statistical examination showed no significant differences in bacteriological clearance rates between the two groups (P = 0162). The comparative pharmacokinetic results (Table V) showed that the mean peak concentration (C^J in the serum after intramuscular administration of 1 g of cefodizime was considerably higher than that after 1 g of cefotazime, even though the peak concentration was reached rather later. Figure 1 shows the serum concentration-time curves for the two drugs. The average serum concentration of cefodizime after 11 h was 91 mg/1 (±8-6) compared with 0-9 mg/1 (±0-6) after a similar dose of cefotaxime. The areas under the 0-11 h concentration-time curves (AUC values) were 2\ times greater with cefodizime than with cefotaxime. Moreover, 93-3% of the patients receiving cefodizime yielded serum AUC values greater than 150 mg/l.h compared with only 14 such patients (15-5%) in the cefotaxime group. These higher and more longlasting serum concentrations of cefodizime were also related to a higher sputum C ^ (threefold greater), with a seven-fold higher concentration in the sputum 11 h after the first drug administration. The results of the clinical evaluation are presented in Table VI. Both drugs produced good results immediately after the end of treatment although the results with cefodizime were especially good, with 98-8% of patients showing 'excellent' scores. One week after the end of therapy this percentage fell to 77-7, mainly due to the numbers of symptomatic reinfections with different organisms which had then taken place. These clinical results agreed with the bacteriological evaluation and showed a trend towards better results after cefodizime. However, the differences were not statistically significant (P = 0368 for the results on day 8 and P = 0393 for those on day 14).

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

r^11 h concentration mean mean T,f mean 0-11 h AUC range number with AUC > 150

50-8 mg/1 (±21-8) 17 to 110 mg/1 1-66 h 9-1 mg/1 (±8-6) 3-9 h 277-2 mgb/l.h (±132-4) 131 to 858 mg/l.h 84 patients (93-3%)

Cefodizime and cefotaxime in chronic bronchitis

419

4

5

6

7

8

9

10

12

rimt (h) ofttr first intromutculor dot* ( I g )

Figure 1. Mean concentration-time curves in serum after O. 1 g cefodizime; • , 1 g cefotaxime. Vertical bars icpretent standard deviations for each measurement point.

Unwanted drug reactions were only observed in one patient who was accidentally included twice in the investigation and received one course of each of the study agents. The first time he developed a slight rash on day 2 with cefodizime but the drug did not need to be discontinued. However, during the following course of cefotaxime five months later he developed such a serious allergic skin reaction that the drug had to be stopped on the third day. Nevertheless, the antibiotic treatment was successful. The other patients presented no problems whatsoever with regard to drug tolerance. Discussion The results of this double-blind prospective study of two preparations with almost identical antibacterial properties but slightly different chemical structures suggested that the differences might produce some improvement in the clinical findings. The pharmacokinetic results demonstrated clearly how important it is for an antimicrobial Table VI. Clinical results with intramuscular cefodizime and cefotaxime in 180 fully cvaluable patients Results on day 8 cefodizime cefotaxime Excellent Good Moderate Poor/bad Percentage excellent:

Results on day 14 cefodizime cefotaxime

89 —

86

1 90

3 1 90

70 3 12 5 90

98-8

95-6

77-7

64 4 17 5 90 711

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

(O

420

F. P. V. Maesen et aL

Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on May 21, 2015

agent to be present in as high concentration as possible in the blood in order to achieve the most advantageous tissue or sputum concentrations. A high blood concentration over a long period generally leads to higher concentrations in the sputum. This is particularly important if the penetration percentage from blood to sputum is only 2 or 3% which is generally the

Cefodizime and cefotaxime in acute exacerbations of chronic bronchitis: a randomized double-blind prospective study in 180 patients.

In a double-blind prospective study, 180 patients admitted to hospital with acute purulent exacerbations of chronic bronchitis were treated for seven ...
516KB Sizes 0 Downloads 0 Views