Drugs 42 (Suppl. 3): 25-33, 1991 0012-666 7/91/0300-0025/$4.50/0 © Adis International Limited. All rights reserved. DRSUP3228a

Cefpodoxime Proxetil in Upper Respiratory Tract Infections E. Bergogne-Berezin Department of Microbiology, Bichat-Claude Bernard University Hospital, Paris, France

Summary

Cefpodoxime proxetil is a new third generation oral cephalosporin, which shows potent antibacterial activity against both Gram-positive and Gram-negative bacteria, and high stability in the presence of /3-lactamases. Low concentrations of cefpodoxime inhibit most respiratory pathogens, including Haemophilus injluenzae, Streptococcus pneumoniae, and Moraxella (Branhamella) catarrhalis. Cefpodoxime reaches concentrations of 0.24 ± 0.06 mgjkg in tonsils, 0.89 ± 0.80 mgjkg in lung parenchyma, and 0.91 ± 0.01 mgjkg in bronchial mucosa; these values exceed by far the minimum inhibitory concentrations (MICs) of cefpodoxime for respiratory pathogens. Preliminary clinical studies were carried out in 181 patients with upper respiratory tract infections: the results indicated an overall clinical response in 88.4% of patients; in 30% the clinical efficacy was excellent and in 58.5% it was good. Further studies showed clinical cure in 90.3% of patients with pharyngotonsillitis, and clinical efficacy (cure plus improvement) in 95% of those with acute sinusitis. Moreover, bacterial eradication was obtained in 78 to 96.7% of cases, most of which involved H. injluenzae, streptococci, or M. catarrhalis. Cefpodoxime appears to be an effective new antibacterial that can be recommended as a drug of first choice in the treatment of most upper respiratory tract infections.

Significant advances have been made in the last decade in expanding the spectrum and potency of new parenteral cephalosporins. Similarly, during the last few years there has been a trend towards the development of orally absorbable wide spectrum antibacterials, and several C-4-esterified cephalosporins have become available (Fujimoto et al. 1987). Among these is cefpodoxime proxetil (CS 807, RU 51807), an orally active ester ofcefpodoxime (R-3763, RU 51763), which is a new methoxyiminoaminothiazolyl cephalosporin (Bryskier et al. 1989). The in vitro activity of cefpodoxime has the main characteristics of the third generation cephalosporins, especially high stability in the presence of many ~-lactamases (Utsui et al. 1987). In vitro

studies (Chin & Neu 1988; Dabernat et al. 1990; Jones & Barry 1988) have shown that this compound has a potent antibacterial activity against both Gram-positive and Gram-negative bacteria, inhibiting at particularly low concentrations most respiratory pathogens such as Haemophilus influenzae, Streptococcus pneumoniae, streptococci, and Moraxella (Branhamella) catarrhalis. Pharmacokinetically, cefpodoxime proxetil behaves as an ester-type prodrug cephalosporin (Fujimoto et al. 1987; Wise 1990). When orally administered, it is absorbed from the small intestine, hydrolysed in the intestinal epithelial cells by esterases, and transferred into the blood stream in the form of free cefpodoxime, which possesses the antibacterial activity. The serum pharmacokinetics

26

Drugs 42 (Supp/. 3) 1991

Table I_ In vitro activity of cefpodoxime and 4 comparative orallHactam antibacterials against respiratory pathogens (after Dabernat et al. 1990 and Jones & Barry 1988) Organisms (no. of strains)

Minimum concentration inhibiting 50% and 90% of pathogens (MICso or MICgo) range

MICso

MICgO

Haemophllus Influenzae iJ-Laclamase negative (65) Cefpodoxime Cefaclor Cefuroxime Amoxicillin Amoxicillin/clavulanic acid

0.03-0.5 0.5-16 0.12-2.0 0.12-2.0 0.06-2.0

0.06 4.0 1.0 0.5 0.5

0.12 16 2.0 1.0 1.0

iJ-Lactamase positive (38) Cefpodoxime Cefaclor Cefuroxime Amoxicillin Amoxicillin/clavulanic acid

0.03-0.5 2.0-64 0.25-8.0 4.0-128 0.12-8.0

0.06 4.0 1.0 8.0 0.5

0.25 32 4.0 128 2.0

Ampicillin resistant. iJ-lactamase negative (5) Cefpodoxime Cefaclor Cefuroxime Amoxicillin Amoxicillin/clavulanic acid

0.12-1.0 8.0-64 1.0-16 2.0-32 2.0-16

0.25 32 2.0 16 8.0

1.0 64 8.0 32 16

Moraxella catarrhalls iJ-Lactamase negative (21) Cefpodoxime Cefaclor Cefuroxime Amoxicillin Amoxicillin/clavulanic acid

0.12-1.0 0.25-1.0 0.25-1.0 0.25-2.0 0.03-1.0

0.25 1.0 0.5 0.25 0.12

0.5 1.0 1.0 0.5 0.25

iJ-Lactamase positive (33) Cefpodoxime Cefaclor Cefuroxime Amoxicillin Amoxicillin/clavulanic acid

0.25-1.0 1.0-4.0 0.5-2.0 8.0-128 0.03-2.0

0.5 2.0 1.0 32 0.12

1.0 4.0 2.0 64 1.0

Streptococcus pneumonlae Penicillin susceptible (10) Cefpodoxime Cefaclor Cefuroxime Amoxicillin/clavulanic acid

" " " "

0.06 0.25-0.5 0.25 0.06

" 0.06 0.5 " 0.25 " 0.06

" 0.06 0.5 " 0.25 " 0.06

Penicillin resistant (10) Cefpodoxime Cefaclor Cefuroxime Amoxicillin/clavulanic acid

0.12-1.0 " 0.25-> 32 " 0.25-4.0 " 0.06-1.0

0.25 0.5 0.5 " 0.06

1.0 8.0 2.0 0.5

S_ pyogenes (21) Cefpodoxime Cefaclor Cefuroxime Amoxicillin Amoxicillin/clavulanic acid

" " " " "

" " " " "

" " " " "

Staphylococcus aureus Penicillin susceptible (25) Cefpodoxime Cefaclor Cefuroxime Amoxicillin/clavulanic acid

2.0-4.0 0.5-2.0 0.5-2.0 0.12-0.25

2.0 1.0 1.0 0.12

2.0 1.0 2.0 0.25

Penicillin resistant (25) Cefpodoxime Cefaclor Cefuroxime Amoxicillin/clavulanic acid

2.0-4.0 1.0-8.0 1.0-2.0 0.25

2.0 2.0 2.0 0.5

4.0 8.0 2.0 1.0

0.06 0.25-0.5 0.25 0.06-0.12 0.06

0.06 0.25 0.25 0.06 0.06

0.06 0.25 0.25 0.06 0.06

Cefpodoxime Proxetil in URTI

of cefpodoxime proxetil have been studied (Hughes et al. 1990; Tremblay et al. 1990), and tissue distribution, especially in the respiratory tissues and fluids, has been analysed (Couraud et al. 1990; Dumont et al. 1990; Gehanno et al. 1990a); these studies have shown that cefpodoxime reaches high tissue concentrations (up to I mg/kg or more, with a tissue to serum ratio of at least 50%) thanks to its low serum protein binding (18 to 23%) [Borin 1991]. Clinical trials with cefpodoxime proxetil in upper respiratory tract infections (URTI) have provided satisfactory clinical results and bacteriological eradication rates. The purpose of this review is to discuss the microbiological and pharmacological bases for the use of cefpodoxime proxetil in upper respiratory infections, as well as to report clinical studies of drug efficacy in treating various URTIs.

1. In Vitro Activity Against Respiratory Pathogens 1.1 Epidemiology Most community-acquired URTIs involve 4 predominant pathogens: H. injluenzae. S. pneumoniae. S. pyogenes and M. catarrhalis. Other species, such as Staphylococcus aureus and a few anaerobes (Peptostreptococcus spp., Fusobacterium necrophorum) are frequently implicated, especially in sinusitis (Jousimes-Somer et al. 1988; Finch 1990); groups A, C and G streptococci are predominantly responsible for acute pharyngitis, and ahaemolytic or nonhaemolytic streptococci are found in all types of URTI. 1.2 Gram-Negative Bacteria Several studies have compared the in vitro activity of cefpodoxime with that of other oral iJ-lactam antibacterials against Gram-negative species such as Haemophilus and M. catarrhalis (Dabernat et al. 1990; Jones & Barry 1988) [table I]. H. in" jluenzae was highly susceptible to cefpodoxime, with minimum inhibitory concentrations (MICs) ranging from 0.03 to 0.5 mg/L even for iJ-lacta-

27

rnase-producing strains. Against M. catarrhalis, either iJ-lactamase producing or non producing, the MICs of cefpodoxime were low and did not exceed 0.5 or 1.0 mg/L, whereas the MICs of other iJ-lactam antibacterials, except amoxicillin/clavulanic acid, were greatly increased for iJ-lactamase-producing strains. 1.3 Gram-Positive Cocci In general, Gram-positive cocci were highly susceptible to all iJ-lactam antibacterials tested. Staphylococci were moderately susceptible to the oral cephalosporins, including cefpodoxime, with MICs ranging from 0.5 to 4 mg/L. Penicillin-resistant pneumococci were slightly less susceptible to cefpodoxime than penicillin-susceptible strains, but the MICs of the other oral cephalosporins were much higher (,.; 0.25-> 32 mg/L for cefaclor) for these strains than the MIC of cefpodoxime (0.121.0 mg/L). For penicillin-resistant S. aureus. the range of MICs of cefpodoxime were unchanged (24 mg/L) compared with that for susceptible strains, whereas with the other drugs the MICs increased. S. pyogenes and other streptococci (data for the latter not shown in table I) were uniformly susceptible to all of the iJ-lactam antibacterials, but the lowest MICs were measured for cefpodoxime and amoxicillin (,.; 0.06 mg/L). 1.4 Bactericidal Activity As cited in several studies (Chin & Neu 1988; Jones & Barry 1988), cefpodoxime was generally bactericidal at a concentration equal or up to 2 times higher than the measured MICs. The effects of increasing the inoculum were limited to bacteria possessing chromosomally mediated iJ-lactamases, such as M. catarrhalis. with a 4-fold increase in MICs when the inoculum was increased from I X 104 to I X 10 7 colony forming units (CFU)/ml (Jones & Barry 1988). The apparent stability of cefpodoxime in the presence of iJ-lactamases, as suggested by the MIC tests, was confirmed in several studies (Chin & Neu 1988; Utsui et al. 1987). This indicates that cefpodoxime should be active

28

Drugs 42 (Suppl. 3) 1991

in vivo against i1-lactamase-producing strains of H. injluenzae, M. catarrhalis, and S. aureus, which are increasingly being isolated in UR TIs (Finch 1990).

2. Distribution of Cefpodoxime in Respiratory Tissues and Fluids Table II summarises the available data on distribution of cefpodoxime in respiratory tissues and fluids, after oral administration of cefpodoxime proxetil. Several in vivo models of tissue distribution have been used and have provided information on the ability of cefpodoxime to reach the potential sites of respiratory infections.

2.1 Skin Blister Fluid Model The skin blister fluid model, obtained by using air suction (Borin et al. 1990) or induced by means of cantharides impregnated plasters (O'Neill et al. 1990), has provided data suggestive of concentrations of cefpodoxime achieved in inflammatory exudates. In both models, the concentrations of cefpodoxime were high, being 70 to more than 100% of contemporaneous serum concentrations. The fluid concentration was not higher at steady-state (2.84 ± 0.88 mgjL) after multiple doses (5 days with 400mg every 12 hours) [Borin et al. 19901 than after a single 400mg dose (2.94 ± 0.71 mgjL). This indicates that cefpodoxime does not accumulate

Table II. Concentrations of cefpodoxime in the respiratory tissues and fluids after oral administration of cefpodoxime proxetil Tissue or fluid

Dose (mg)

Serum or plasma concentrations (mg/L)9

Sampling time (h)

Concentrations in tissue or fluid (mg/kg or mg/L)9

Ratio (%)a,9

6

Inflammatory fluid

2.1 ± 0.4

3.5

1.7 ± 0.7

103 ± 14.3c

16

Inflammatory fluid

260 b (s) 400 (m)

4.20 ± 0.95

3.5

2.84 ± 0.88

71.2 ± 9.1

Dumont et al. (1990)

18

Pleural fluid

260b (s)

2.73 ± 0.34 2.72 ± 0.32 0.77 ± 0.14

3 6 12

0.62 ± 0.19 1.84 ± 0.33 0.78 ± 0.10

24 ± 0.7 67 ± 0.8 107 ± 0.8

Baldwin et al. (1990)

16

Bronchial mucosa

200 (s)

1.92 ± 0.13

1-7

0.91 ± 0.Q1

47

Couraud et al. (1990)

18

Lung parenchyma

260 b (s)

1.05 ± 0.39 0.91 ± 0.21 0.36 ± 0.03

3 6 12

0.63 ± 0.16 0.52 ± 0.09 0.19 ± 0.02

78 ± 25 70 ± 17 53 ± 0.4

Personal unpublished data

12

Lung parenchyma

260b (s)

1.05 ± 0.74 1.87 ± 1.76

3 6

0.89 ± 0.80 0.84 ± 0.61

84.7 53.7

Personal unpublished data

12

ELF

260 b (s)

1.25 ± 0.82 1.40 ± 1.25

3 6

0.22 ± 0.13 0.12 ± 0.14

10.8 6.05

Gehanno et al. (1990a)

17

Tonsillar tissue

130d (s)

1.25 ± 0.23 0.39 ± 0.06 ND

3 6 12

0.24 ± 0.06 0.09 ± 0.01 ND

22 24

Reference

O'Neill et al. (1990) Borin et al. (1990)

No. of pts

a Most ratios represent the ratios of tissue or fluid to contemporaneous serum concentrations. b Equivalent to 200mg of cefpodoxime. c AUC! : AUCp ratio (%) [f = fluid; p = plasma]. d Equivalent to 100mg of cefpodoxime. e Values are given as mean ± SD. Abbreviations: s = single dose; m = multiple dose; ND = none detected; ELF = alveolar epithelial lining fluid.

29

Cefpodoxime Proxetil in URTI

when multiple doses are given. However, a dosedependent effect was shown between the 200 and 400mg dose (table II) [Borin et al. 1990]. The extent of penetration of cefpodoxime into inflammatory fluid is consistent with its low protein binding (40%). 2.2 Pleural Fluid In pleural fluid, which behaves as an 'interstitial reservoir' (Lode et al. 1980), the concentrations of cefpodoxime reached a maximum value of 1.84 ± 0.33 mg/L after a single 260mg dose of cefpodoxime proxetil (Dumont et al. 1990). The penetration of the drug into pleural fluid was relatively slow, peaking at 6 hours after the dose; this is in agreement with previous studies with cephalosporins (Lode et al. 1980). 12 hours after the dose, a mean concentration of 0.78 ± 0.10 mg/L was still present in pleural fluid . In this study, the high albumin content in the pleural fluid of the 18 patients (22.8 ± 26.5 mg/L) indicated the presence of inflammatory conditions. However, there was no correlation between the concentration of cefpodoxime and that of albumin, a reflection of the low protein binding of the drug (Dumont et al. 1990). 2.3 Lung Parenchyma In respiratory tissues, such as lung parenchyma, the concentrations of cefpodoxime were lower and did not exceed I mg/kg (table II). Two studies have provided data on the penetration of lung parenchyma by cefpodoxime (Couraud et al. 1990; personal unpublished data); they were both carried out in patients undergoing thoracotomy for suspected pulmonary neoplasia, and the highest concentrations measured in both studies were convergent, being 0.63 ± 0.16 mg/kg in the former and 0.89 ± 0.80 mg/kg in the latter, 3 hours after the oral administration of a single 260mg dose of cefpodoxime proxetil. The percentage penetration ratios were 78 and 84.7%, respectively. In the personal unpublished study, in addition to lung tissue concentrations, the concentrations of cefpodoxime achieved in the alveolar epithelial Iin-

ing fluid (ELF) were determined in the same patients by using bronchoalveolar lavage (BAL). The concentrations of cefpodoxime in ELF were measured and calculated according to a previously described procedure (Chastre et al. 1987). The ELF concentrations did not exceed the mean value of 0.22 ± 0.13 mg/L, which was achieved 3 hours after the dose. Large interindividual variations were noted, and were certainly related to the dilutional effect of the BAL and possibly to notable interindividual variations in the plasma concentrations, as observed frequently with orally administered drugs. 2.4 Bronchial Mucosa In bronchial mucosa (Baldwin et al. 1990), the concentrations of cefpodoxime were measured by using a previously described sampling technique for bronchial tissue (Marlin et al. 1981). Bronchoscopic biopsies were taken during fibreoptic bronchoscopy carried out for diagnostic purposes in 16 patients who had received a single dose of 200mg of cefpodoxime. The mean value in bronchial mucosa was 0.91 ± 0.01 mg/kg. However, significant concentrations were reached as early as I hour after the dose, indicating a rapid penetration of cefpodoxime into bronchial mucosa. 2.5 Tonsils The concentrations of cefpodoxime achieved in tonsillar tissue were measured in samples collected from 17 patients undergoing tonsillectomy (Gehan no et al. I 990a). Although the single dose administered to the patients was low (130mg of cefpodoxime proxetil, equivalent to 100mg of cefpodoxime), a mean concentration of 0.24 ± 0.06 mg/kg was found 4 hours after the dose, which was 22% of the contemporaneous serum concentration. Detectable concentrations (0.09 ± 0.01 mg/kg) were still present 7 hours postdose, but not at 12 hours (table II).

Drugs 42 (Suppl. 3) 1991

30

3. Clinical Experience with Cefpodoxime Proxetil in Upper Respiratory Tract Infections

ication was higher with cefpodoxime proxetil than with the comparators. 3.2 Acute Sinusitis

The in vitro and pharmacokinetic studies reported above suggest the potential efficacy of cefpodoxime proxetil in the treatment of respiratory tract infections. In UR TI, the results of preliminary clinical investigations were promising. Among 181 patients with URTI treated with cefpodoxime 200mg twice daily, the overall clinical efficacy was 88.4%; in 30% the results were excellent and in 58.5% they were good; in only 7.1 and 4.4% was the clinical efficacy fair and poor, respectively (Nakao et at. 1987). Further clinical studies were prospective, comparative and randomised and are summarised in table III. 3.1 Pharyngitis/Pharyngotonsillitis Three studies including a total of 548 adult patients were designed for comparison of cefpodoxime proxetil with cefuroxime axetil (Portier et at. 1990a), phenoxymethylpenicillin (penicillin V) [Portier et at. 1990a), and amoxicillin (Portier et at. I 990b). A fourth evaluation involved a multicentre study (Raso et at. 1990) with 62 patients. In all 4 studies the oral dose of cefpodoxime proxetil was 100mg twice daily. The comparators were administered at the usual dosage: 250mg twice daily for cefuroxime axetil, 600mg (or I million IU) 3 times daily for penicillin V, and 500mg 3 times daily for amoxicillin. The duration of treatment was 5 to 10 days. The predominant pathogens were S. pyogenes, groups C and G streptococci, and H. injluenzae (which ranked second in frequency). In one study, 12 strains of S. pneumoniae were also isolated (Raso et at. 1990). The clinical cure rates ranged from 90 to 100%, and the bacterial eradication rates with cefpodoxime proxetil ranged from 78 to 96.7% (table III). The percentage of bacterial eradication obtained with cefpodoxime proxetil did not vary with the duration of treatment (5 or 10 days). Except for one study (Portier et at. 1990a), the bacterial erad-

In a comparative study involving 258 patients, cefpodoxime proxetil was more effective than cefaclor, resulting in a complete clinical cure in 83.6% of patients, compared with 67.5% with cefaclor, and overall clinical efficacy rates (cure plus improvement) of 95% and 93%, respectively (Gehanno et at. 1990b; table III). It was concluded that cefpodoxime proxetil 200mg twice daily may be somewhat more effective than cefaclor 500mg 3 times daily in the treatment of acute sinusitis in adults. Of the 205 pathogens isolated, the predominant species were H. injluenzae (35.1 %), S. pneumoniae (15.1%), M. catarrhalis (12.7%) and S. aureus (12.2%). None of these were resistant in vitro to cefpodoxime, whereas 2 strains of H. injluenzae, one of M. catarrhalis, and one of S. aureus were resistant to cefaclor. Failure to eradicate H. injluenzae occurred in 5 patients receiving cefaclor, whereas H. injluenzae were eradicated from all patients in the cefpodoxime group. 3.3 Tolerability In the various clinical investigations of cefpodoxime proxetil in URTI, tolerability was good. In studies in pharyngotonsillitis no side effects were reported in an initial trial of cefpodoxime proxetil versus cefuroxime axetil (Portier et at. 1990a). In a second investigation of cefpodoxime proxetil versus phenoxymethylpenicillin, the same authors observed 2 cases of diarrhoea and one of urticaria. Similarly, in another study in pharyngotonsillitis, a limited number of adverse events included one case of diarrhoea, one of loose stools, and one of urticaria (Dansey et at. 1990). In a multicentre study, the adverse reactions were limited to 2 cases of diarrhoea and 3 of gastralgia; all reactions were mild and did not result in discontinuation of treatment (Raso et at. 1990). In treating acute sinusitis, 9 adverse effects were observed in the cefpodoxime proxetil group (vs 8 in the cefaclor group) and dis-

133 125

62

159

161

78

Abbreviations: bid = twice daily; tid = 3 times daily; NS = not stated.

200mg bid 500mg tid

100mg bid

500mg tid

Amoxicillin

Cefpodoxime proxetil (multicentre)

100mg bid

Cefpodoxime proxetil

600mg tid

Phenoxymethylpenicillin

84

33

250mg bid

100mg bid

33

100mg bid

Cefpodoxime proxetil

Gehanno et al. Cefpodoxime proxetil (1990b) Cefacior Cefaclor

Acute sinusitis

Raso et al. (1990)

Portier et al. (1990b)

Portier et al. (1990a)

Pharyngitis/pharyngotonsillitis Portier et al. Cefpodoxime proxetil (1990a) Cefuroxime axetil

No. of patients

10 10

7.6

10

10

10

5

5

5

Duration of treatment (days)

41 .3 ± 13.4 42.1 ± 15.1

38

NS

NS

27.1 27.1 ± 9.8

30 ± 12.4

31.6 ± 16.3

28.8 ± 11 .2

Mean age ± SO (years)

!!

83.6 (95) 67.5 (93)

90.3 (98.3)

93.9

95.1

96.7

100 100

100

100

% clinical cure (cure + improvement)

83.7

95.5

94.2

96.7

89

78

Bacterial eradication (%)) (%

72 H. influenzae 49 streptococci 26 M. catarrhalis 25 Staphylococcus aureus

94.8 91.3

94.6 16 streptococci 12 S. pneumoniae 12 H. influenzae 7 Moraxella catarrhalis 7 Klebsiella pneumoniae

49 streptococci 4 H. influenzae

5 H. H. influenzae

55 streptococci

80% Streptococcus pyogenes

8 Haemophilus influenzae

32 streptococci

Pathogens

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Cefpodoxime proxetil in upper respiratory tract infections.

Cefpodoxime proxetil is a new third generation oral cephalosporin, which shows potent antibacterial activity against both Gram-positive and Gram-negat...
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