Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. E, 1-6
In-vitro activity of cefpodoxime against pathogens responsible for community-acquired respiratory tract infections H. Dabernaf, J. L. AvriP and Y. Boussouganr 'Laboratoire de Microbiologie, Centre Hospitalier Universitaire Purpan, Toulouse; Laboratoire de Bactiriologie, Centre Hospitalier Universitaire Pontchaillou, Rennes; c Laboratoire de Bacte'riologie, Hopital Louis Mourier, Colombes, France
b
Introduction
Cefpodoxime (R-3746, RU51746) is a methoxyimino aminothiazolyl cephalosporin available as an orally active ester prodrug, cefpodoxime proxetil (CS 807, RU 51807). It exhibits the main characteristics of the new cephalosporins, a broad spectrum of antibacterial activity and resistance to hydrolysis by many /Mactamases (Utsui, Inoue & Mitsuhashi, 1987; Jones & Barry, 1988). In this study the in-vitro activity of cefpodoxime was compared with that of other oral antimicrobial agents against pathogens isolated from patients with respiratory tract infections. Materials and methods
Bacterial strains The strains studied were clinical isolates belonging to the species, Haemophilus influenzae, Branhamella catarrhalis, Streptococcus pneumoniae, and other streptococci isolated from patients with respiratory tract infections. A total of 347 strains were examined. Antibiotics and media The /Mactam antibiotics evaluated were: cefpodoxime sodium (RU 51746) (Roussel UCLAF); amoxycillin (Beecham Laboratories); co-amoxiclav (Beecham Laboratories); 1 0305-7453/90/26E00I +06 102.00/0
© 1990 The firitish Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
The in-vitro activity of cefpodoxime, the active component of the ester prodrug, cefpodoxime proxetil, was compared with that of other antibiotics. The susceptibility of bacterial isolates from patients with respiratory tract infections was determined by an agar dilution method. The MlQoS of cefpodozime for ampitillinsensitive and /Mactamase-producing strains of Haemophilus influenzae were 0-12 and 0-25 mg/1, respectively; the MIC^s for ampicillin-resistant non-/Mactamaseproducing strains was 1 mg/1. Time-kill curves of cefpodoxime against ampicillinsensitive and ampicillin-resistant /Mactamase producing strains showed a timedependent bactericidal activity. The MIC^s for ampicillin-sensitive and ampicillinresistant Branhamella catarrhalis were 0-50 and 1 mg/1, respectively. The MIC^s for penicillin-sensitive pneumococci, 0-haemolytic streptococci and Streptococcus agalactiae were 0-06, 0-06 and 0-12 mg/1, respectively. The inhibitory activity against penicillin-resistant pneumococci was limited; the MIC*, was 4 mg/1.
2
H. Dabernat et at
cefaclor (Eli Lilly and Co.); cefuroxime (Glaxo); cefixime (Pharmuka); and benzylpenicillin (Specia). The sensitivity testing medium used was Mueller-Hinton agar supplemented with haemin (15 mg/1), NAD (15 mg/1) and yeast extract (5 g/1) for H. influenzae (Jorgensen et al., 1987) and 5% horse blood medium for streptococci and B. catarrhalis. Inocula were prepared in brain heart infusion broth, supplemented with 1 % Fildes' digest for H. influenzae. Methods
Results The in-vitro inhibitory activity of cefpodoxime and of various /Mactams against H. influenzae and B. catarrhalis is presented in Table I. Strains of H. influenzae, whether or not they produced /Mactamase, were inhibited by 05 mg/1 cefpodoxime. This activity was greater than that of amoxycillin, amoxycillin plus clavulanic acid, cefaclor and cefuroxime and slightly less than that of cefixime which inhibited all strains at 012 mg/1. Where isolates were resistant to ampicillin without production of 0-lactamase (five strains), the MICs were increased for all antibiotics tested. The MIQo of cefixime and cefpodoxime for these strains was 1 mg/l. All strains of B. catarrhalis were inhibited by 1 mg/1 cefpodoxime . This activity was slightly greater than that of cefuroxime and less than that of cefixime. The production of /Mactamase affected the in-vitro sensitivity to all cephalosporins and the MICs were increased two-fold or four-fold. Activity against streptococci is shown in Table II. Cefpodoxime was the most active cephalosporin against penicillin-sensitive pneumococci. For penicillin-resistant pneumococci, the MICs of all the antibiotics tested were considerably increased; cefpodoxime showed some activity, slightly less than that of amoxycillin. Enterococcus faecalis and E.faecium were only moderately sensitive to amoxycillin and were resistant to the cephalosporins tested. Cefpodoxime had comparable activity to that of amoxycillin against streptococci of Lancefield groups A, B, C and G, a-haemolytic streptococci and non-haemolytic streptococci. The kinetics of bacterial killing by cefpodoxime were studied with four strains of H. influenzae including two /?-lactamase-producing strains. MICs of cefpodoxime were 0-06 mg/1 for these strains. The killing curves obtained with MICx 1, MICx2 and MIC x 4 are presented as concentration kill curves rather than the usual time kill curve
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
MICs were determined by an agar dilution method in supplemented Mueller-Hinton agar. A final inoculum of 10* to 105 colony forming units (cfu) per spot was prepared by dilution of a fresh overnight broth culture, and applied to agar with a replicating spot device. The MIC was defined as the lowest concentration of antibiotic that inhibited visible growth after 18 h incubation at 37°C in air. Kinetics of killing of H. influenzae were determined by inoculation to give 106 to 107cfu/ml in supplemented Mueller-Hinton broth containing M I C x l , MICx2 or MICx4 of cefpodoxime (0O6, 0-12 and 0-25 mg/1). At 0, 1, 2, 4, 6 and 18h during incubation at 35°C in air, aliquots were removed and serial ten-fold dilution plate counts were performed on chocolate agar. /?-Lactamase production was detected with a chromogenic cephalosporin (Nitrocefin, Cefinase, BioMerieux).
Activity against respiratory pathogens
3
in Figure 1 for strain A, which produces 0-lactamase and strain B which is sensitive to amoxycillin. An approximately 3 x log)0 reduction in bacterial count was obtained from the sixth hour onwards. The bacterial kill appeared greater for the strain that did not produce /Mactamase. Killing was similar whether the antibiotic concentration was 1, 2 or 4 times the MIC, corresponding to an antibiotic which is active as a function of time (time-dependent), with little variation in activity according to the concentration of antibiotic present. Table I. Activity of cefpodoxime and other oral /)-lactam antibiotics against H. influenzae and B. catarrhalis
range
H. influenzae ampicillin sensitive (65)amoxydllin co-amoxiclav ccfaclor cefuroxime cefixime cefpodoxime
012-2 0-06-2 0-50-16 0-12-2 003-012 0-03-0-50
O50 O50 4 1 012 006
1 1 16 2 012 012
ampicillin resistant /Mactamase ( + ) (38) amoxycillin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
4-128 0-12-8 2-64 0-25-8 0-03-0-12 003-050
8 050 4 1 O03 006
128 2 32 4 012 025
ampicillin resistant /Mactamase ( - ) (5) amoxycillin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
2-32 2-16 8-64 1-16 0-06-1 012-1
16 8 32 2 012 025
B. catarrhalis 0-lactamase ( - ) (21) amoxyciUin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
025-2 O03-1 025-1 025-1 003-025 012-1
025 012 1 050 006 025
O50 025 1 1 025 050
0-lactamase( + )(33) amoxycillin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
8-128 003-2 1-4 050-2 006-050 025-1
32 012 2 1 025 050
64 1 4 2 O50 1
MIQ.
32 16 64 8 1 1
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
MIC (mg/1) MIQo
Organism (no. of strains)
H. Dabernat et aJ. Table II. Activity of cefpodoxime and other oral /?-lactam antibiotics against streptococci and enterococci MIC (mg/1) Organism (no. of strains)
range
MICJO
< 0-01-0-03 < 001-006 O12-I 006-025 O06-1 001-025
001 64 cefaclor >64 cefuroxime >64 cefixime >64 cefpodoxime
1 >64 >64 >64 >64
8 >64 >64 >64 >64
a-Haemolytic and non-haemolytic streptococci (23)* amoxycillin O03-1 cefaclor O50-8 cefuroxime 003-O50 cefixime 006-16 cefpodoxime 006-1
012 1 012 025 012
050 2 050 4 O50
025 1-2 003-0-12 006-2 0-O6-O-50
*S. mitis (15 strains), S. sanguis (4 strains), and S. salirarius (4 strains).
Discussion Our results are in line with those previously described (Chin & Neu, 1988; Fass & Helsel, 1988; Jones & Barry, 1988). The stability of the molecule to /J-lactamases (Utsui et al., 1987) allows it to retain its activity against strains of H.influenzae that are
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
S. pneumoniae Penicillin sensitive (83) penicillin amoxycillin cefaclor cefuroxime ccfiximc cefpodoxime
MIQo
Activity against respiratory pathogens
4 -
E
0
Control MIC
Control
IMC
Figure 1. Concentration kill curves (]og,0 cfu/ml at various times after inoculation plotted against drug concentration, expressed as multiples of the MIC) for (a) a /Mactamase-positive and (b) a /Mactamasenegative strain of H.influtnzae. D. 1 h; • . 2h; O. 4h; A, 6h; • , 18 h.
resistant to amoxycillin by the production of /Mactamase. This is the most frequent kind of resistance of H. inftuenzae. However, there are strains that are resistant to ampicillin without production of /Mactamase. In these isolates the mechanism of resistance is a reduction in the affinity of certain penicillin binding proteins (PBPs) for ampicillin (Mendelman et al.. 1984). Resistance to other /Mactam antibiotics then also occurs. In H. inftuenzae, Mendelman et al. (1989) showed that resistance to cephems also occurs by this mechanism. The three antibiotics studied, cefixime, cefpodoxime and ceftibuten were very active against ampicillin sensitive and /Mactamase producing, strains of H. inftuenzae but for non /Mactamase producing ampicillin resistant strains, the MIQQS of these antibiotics increased by 12 to 192 times. These strains were the only ones to show a significant inoculum effect when the inoculum increased from 103 to 10*cfu. With the ampicillin resistant non /Mactamase producing strains in our study, the MICs of cephems were increased by four to 16 times.
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
2 -
6
H. Dabernat et al.
References Chin, N.-X. & Neu, H. C. (1988). In vitro activity of an oral iminomethoxy aminothiazolyl cephalosporin, R-7346. Antimicrobial Agents and Chemotherapy 32, 671-7. Fass, R. J. & Helsel, V. L. (1988). In vitro activity of U-76252 (CS-807), a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 32, 1082-5. Geslin, P., Fremaux, A. & Sissia, G. (1989). Resistance du pneumocoque aux antibiotiques. La Lettre de I'lnfectiologue 4, 695-704. Jones, R. N. & Barry, A. L. (1988). Antimicrobial activity and disk diffusion susceptibility testing of U-76, 253 A (R-3746), the active metabolite of the new cephalosporin ester, U-76, 252 (CS-807). Antimicrobial Agents and Chemotherapy 32, 443-9. Jorgensen, J. H., Redding, J. S., Maher, L. A. & Howell, A. W. (1987). Improved medium for antimicrobial susceptibility testing of Haemophiius influenzae. Journal of Clinical Microbiology 25, 2105-13. Knapp, C. C , Sierra-Madero, J. & Washington, J. A. (1988). Antibacterial activities of cefpodoxime, cefixime and ceftriaxone. Antimicrobial Agents and Chemotherapy 32, 1896-8. Mendelman, P. M., Chaffin, D. O., Stull, T. L., Rubens, C. E., Mack, K. D. & Smith, A. L. (1984). Characterization of non-beta-lactamase-mediated ampicillin resistance in Haemophiius influenzae. Antimicrobial Agents and Chemotherapy 26, 234—44.
Mendelman, P. M., Henritzy, L. K., Chaffin, D. O., Lent, K., Smith, A. L., Stull, T. L. et al. (1989). In vitro activities and targets of three cephem antibiotics against Haemophiius influenzae. Antimicrobial Agents and Chemotherapy 33, 1878-82. Utsui, Y., Inoue, M. & Mitsuhashi, S. (1987). In vitro and in vivo antibacterial activities of CS807, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 1085-92. Zighelboim, S. & Tomasz, A. (1981). Multiple antibiotic resistance in South African strains of Streptococcus pneumoniae: mechanism of resistance to 0-lactam antibiotics. Review of Infectious Diseases 3, 267-76.
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
Resistance of pneumococci to penicillin is a phenomenon that has been well known for many years. Its incidence varies considerably in different countries (Geslin, Fremaux & Sissia, 1989). The resistance mechanism is a modification of the PBPs (Zighelboim & Tomasz, 1981). This modification in the PBPs leads to a reduction in activity of all /Mactam antibiotics. Penicillin-resistant pneumococci were less sensitive to the cephalosporins tested than penicillin-sensitive pneumococci. Cefpodoxime was the most active of the cephalosporins tested, with MICM and MIC*, of 1 and 4 mg/1, respectively, but this activity was ten to 16 times weaker than that observed against penicillin-sensitive strains. Cefixime and cefaclor had considerably reduced activity against penicillin-resistant pneumococci. Cefpodoxime is a new cephalosporin with a particularly broad spectrum of activity against /Mactamase producing organisms (Utsui et al., 1987; Jones & Barry, 1988; Knapp, Sierra-Madero & Washington, 1988). The ester form cefpodoxime proxetil can be given orally. The in-vitro data presented here indicate that cefpodoxime proxetil may be useful in the treatment of community-acquired respiratory tract infections. Its activity against H. influenzae and S. pneumoniae may be particularly important. The only limitation is its low activity against penicillin-resistant strains of pneumococci and ampicillin-resistant non-/Mactamase producing strains of H. influenzae.
In-vitro activity of cefpodoxime against pathogens responsible for community-acquired respiratory tract infections H. Dabernaf, J. L. AvriP and Y. Boussouganr 'Laboratoire de Microbiologie, Centre Hospitalier Universitaire Purpan, Toulouse; Laboratoire de Bactiriologie, Centre Hospitalier Universitaire Pontchaillou, Rennes; c Laboratoire de Bacte'riologie, Hopital Louis Mourier, Colombes, France
b
Introduction
Cefpodoxime (R-3746, RU51746) is a methoxyimino aminothiazolyl cephalosporin available as an orally active ester prodrug, cefpodoxime proxetil (CS 807, RU 51807). It exhibits the main characteristics of the new cephalosporins, a broad spectrum of antibacterial activity and resistance to hydrolysis by many /Mactamases (Utsui, Inoue & Mitsuhashi, 1987; Jones & Barry, 1988). In this study the in-vitro activity of cefpodoxime was compared with that of other oral antimicrobial agents against pathogens isolated from patients with respiratory tract infections. Materials and methods
Bacterial strains The strains studied were clinical isolates belonging to the species, Haemophilus influenzae, Branhamella catarrhalis, Streptococcus pneumoniae, and other streptococci isolated from patients with respiratory tract infections. A total of 347 strains were examined. Antibiotics and media The /Mactam antibiotics evaluated were: cefpodoxime sodium (RU 51746) (Roussel UCLAF); amoxycillin (Beecham Laboratories); co-amoxiclav (Beecham Laboratories); 1 0305-7453/90/26E00I +06 102.00/0
© 1990 The firitish Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
The in-vitro activity of cefpodoxime, the active component of the ester prodrug, cefpodoxime proxetil, was compared with that of other antibiotics. The susceptibility of bacterial isolates from patients with respiratory tract infections was determined by an agar dilution method. The MlQoS of cefpodozime for ampitillinsensitive and /Mactamase-producing strains of Haemophilus influenzae were 0-12 and 0-25 mg/1, respectively; the MIC^s for ampicillin-resistant non-/Mactamaseproducing strains was 1 mg/1. Time-kill curves of cefpodoxime against ampicillinsensitive and ampicillin-resistant /Mactamase producing strains showed a timedependent bactericidal activity. The MIC^s for ampicillin-sensitive and ampicillinresistant Branhamella catarrhalis were 0-50 and 1 mg/1, respectively. The MIC^s for penicillin-sensitive pneumococci, 0-haemolytic streptococci and Streptococcus agalactiae were 0-06, 0-06 and 0-12 mg/1, respectively. The inhibitory activity against penicillin-resistant pneumococci was limited; the MIC*, was 4 mg/1.
2
H. Dabernat et at
cefaclor (Eli Lilly and Co.); cefuroxime (Glaxo); cefixime (Pharmuka); and benzylpenicillin (Specia). The sensitivity testing medium used was Mueller-Hinton agar supplemented with haemin (15 mg/1), NAD (15 mg/1) and yeast extract (5 g/1) for H. influenzae (Jorgensen et al., 1987) and 5% horse blood medium for streptococci and B. catarrhalis. Inocula were prepared in brain heart infusion broth, supplemented with 1 % Fildes' digest for H. influenzae. Methods
Results The in-vitro inhibitory activity of cefpodoxime and of various /Mactams against H. influenzae and B. catarrhalis is presented in Table I. Strains of H. influenzae, whether or not they produced /Mactamase, were inhibited by 05 mg/1 cefpodoxime. This activity was greater than that of amoxycillin, amoxycillin plus clavulanic acid, cefaclor and cefuroxime and slightly less than that of cefixime which inhibited all strains at 012 mg/1. Where isolates were resistant to ampicillin without production of 0-lactamase (five strains), the MICs were increased for all antibiotics tested. The MIQo of cefixime and cefpodoxime for these strains was 1 mg/l. All strains of B. catarrhalis were inhibited by 1 mg/1 cefpodoxime . This activity was slightly greater than that of cefuroxime and less than that of cefixime. The production of /Mactamase affected the in-vitro sensitivity to all cephalosporins and the MICs were increased two-fold or four-fold. Activity against streptococci is shown in Table II. Cefpodoxime was the most active cephalosporin against penicillin-sensitive pneumococci. For penicillin-resistant pneumococci, the MICs of all the antibiotics tested were considerably increased; cefpodoxime showed some activity, slightly less than that of amoxycillin. Enterococcus faecalis and E.faecium were only moderately sensitive to amoxycillin and were resistant to the cephalosporins tested. Cefpodoxime had comparable activity to that of amoxycillin against streptococci of Lancefield groups A, B, C and G, a-haemolytic streptococci and non-haemolytic streptococci. The kinetics of bacterial killing by cefpodoxime were studied with four strains of H. influenzae including two /?-lactamase-producing strains. MICs of cefpodoxime were 0-06 mg/1 for these strains. The killing curves obtained with MICx 1, MICx2 and MIC x 4 are presented as concentration kill curves rather than the usual time kill curve
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
MICs were determined by an agar dilution method in supplemented Mueller-Hinton agar. A final inoculum of 10* to 105 colony forming units (cfu) per spot was prepared by dilution of a fresh overnight broth culture, and applied to agar with a replicating spot device. The MIC was defined as the lowest concentration of antibiotic that inhibited visible growth after 18 h incubation at 37°C in air. Kinetics of killing of H. influenzae were determined by inoculation to give 106 to 107cfu/ml in supplemented Mueller-Hinton broth containing M I C x l , MICx2 or MICx4 of cefpodoxime (0O6, 0-12 and 0-25 mg/1). At 0, 1, 2, 4, 6 and 18h during incubation at 35°C in air, aliquots were removed and serial ten-fold dilution plate counts were performed on chocolate agar. /?-Lactamase production was detected with a chromogenic cephalosporin (Nitrocefin, Cefinase, BioMerieux).
Activity against respiratory pathogens
3
in Figure 1 for strain A, which produces 0-lactamase and strain B which is sensitive to amoxycillin. An approximately 3 x log)0 reduction in bacterial count was obtained from the sixth hour onwards. The bacterial kill appeared greater for the strain that did not produce /Mactamase. Killing was similar whether the antibiotic concentration was 1, 2 or 4 times the MIC, corresponding to an antibiotic which is active as a function of time (time-dependent), with little variation in activity according to the concentration of antibiotic present. Table I. Activity of cefpodoxime and other oral /)-lactam antibiotics against H. influenzae and B. catarrhalis
range
H. influenzae ampicillin sensitive (65)amoxydllin co-amoxiclav ccfaclor cefuroxime cefixime cefpodoxime
012-2 0-06-2 0-50-16 0-12-2 003-012 0-03-0-50
O50 O50 4 1 012 006
1 1 16 2 012 012
ampicillin resistant /Mactamase ( + ) (38) amoxycillin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
4-128 0-12-8 2-64 0-25-8 0-03-0-12 003-050
8 050 4 1 O03 006
128 2 32 4 012 025
ampicillin resistant /Mactamase ( - ) (5) amoxycillin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
2-32 2-16 8-64 1-16 0-06-1 012-1
16 8 32 2 012 025
B. catarrhalis 0-lactamase ( - ) (21) amoxyciUin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
025-2 O03-1 025-1 025-1 003-025 012-1
025 012 1 050 006 025
O50 025 1 1 025 050
0-lactamase( + )(33) amoxycillin co-amoxiclav cefaclor cefuroxime cefixime cefpodoxime
8-128 003-2 1-4 050-2 006-050 025-1
32 012 2 1 025 050
64 1 4 2 O50 1
MIQ.
32 16 64 8 1 1
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
MIC (mg/1) MIQo
Organism (no. of strains)
H. Dabernat et aJ. Table II. Activity of cefpodoxime and other oral /?-lactam antibiotics against streptococci and enterococci MIC (mg/1) Organism (no. of strains)
range
MICJO
< 0-01-0-03 < 001-006 O12-I 006-025 O06-1 001-025
001 64 cefaclor >64 cefuroxime >64 cefixime >64 cefpodoxime
1 >64 >64 >64 >64
8 >64 >64 >64 >64
a-Haemolytic and non-haemolytic streptococci (23)* amoxycillin O03-1 cefaclor O50-8 cefuroxime 003-O50 cefixime 006-16 cefpodoxime 006-1
012 1 012 025 012
050 2 050 4 O50
025 1-2 003-0-12 006-2 0-O6-O-50
*S. mitis (15 strains), S. sanguis (4 strains), and S. salirarius (4 strains).
Discussion Our results are in line with those previously described (Chin & Neu, 1988; Fass & Helsel, 1988; Jones & Barry, 1988). The stability of the molecule to /J-lactamases (Utsui et al., 1987) allows it to retain its activity against strains of H.influenzae that are
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
S. pneumoniae Penicillin sensitive (83) penicillin amoxycillin cefaclor cefuroxime ccfiximc cefpodoxime
MIQo
Activity against respiratory pathogens
4 -
E
0
Control MIC
Control
IMC
Figure 1. Concentration kill curves (]og,0 cfu/ml at various times after inoculation plotted against drug concentration, expressed as multiples of the MIC) for (a) a /Mactamase-positive and (b) a /Mactamasenegative strain of H.influtnzae. D. 1 h; • . 2h; O. 4h; A, 6h; • , 18 h.
resistant to amoxycillin by the production of /Mactamase. This is the most frequent kind of resistance of H. inftuenzae. However, there are strains that are resistant to ampicillin without production of /Mactamase. In these isolates the mechanism of resistance is a reduction in the affinity of certain penicillin binding proteins (PBPs) for ampicillin (Mendelman et al.. 1984). Resistance to other /Mactam antibiotics then also occurs. In H. inftuenzae, Mendelman et al. (1989) showed that resistance to cephems also occurs by this mechanism. The three antibiotics studied, cefixime, cefpodoxime and ceftibuten were very active against ampicillin sensitive and /Mactamase producing, strains of H. inftuenzae but for non /Mactamase producing ampicillin resistant strains, the MIQQS of these antibiotics increased by 12 to 192 times. These strains were the only ones to show a significant inoculum effect when the inoculum increased from 103 to 10*cfu. With the ampicillin resistant non /Mactamase producing strains in our study, the MICs of cephems were increased by four to 16 times.
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
2 -
6
H. Dabernat et al.
References Chin, N.-X. & Neu, H. C. (1988). In vitro activity of an oral iminomethoxy aminothiazolyl cephalosporin, R-7346. Antimicrobial Agents and Chemotherapy 32, 671-7. Fass, R. J. & Helsel, V. L. (1988). In vitro activity of U-76252 (CS-807), a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 32, 1082-5. Geslin, P., Fremaux, A. & Sissia, G. (1989). Resistance du pneumocoque aux antibiotiques. La Lettre de I'lnfectiologue 4, 695-704. Jones, R. N. & Barry, A. L. (1988). Antimicrobial activity and disk diffusion susceptibility testing of U-76, 253 A (R-3746), the active metabolite of the new cephalosporin ester, U-76, 252 (CS-807). Antimicrobial Agents and Chemotherapy 32, 443-9. Jorgensen, J. H., Redding, J. S., Maher, L. A. & Howell, A. W. (1987). Improved medium for antimicrobial susceptibility testing of Haemophiius influenzae. Journal of Clinical Microbiology 25, 2105-13. Knapp, C. C , Sierra-Madero, J. & Washington, J. A. (1988). Antibacterial activities of cefpodoxime, cefixime and ceftriaxone. Antimicrobial Agents and Chemotherapy 32, 1896-8. Mendelman, P. M., Chaffin, D. O., Stull, T. L., Rubens, C. E., Mack, K. D. & Smith, A. L. (1984). Characterization of non-beta-lactamase-mediated ampicillin resistance in Haemophiius influenzae. Antimicrobial Agents and Chemotherapy 26, 234—44.
Mendelman, P. M., Henritzy, L. K., Chaffin, D. O., Lent, K., Smith, A. L., Stull, T. L. et al. (1989). In vitro activities and targets of three cephem antibiotics against Haemophiius influenzae. Antimicrobial Agents and Chemotherapy 33, 1878-82. Utsui, Y., Inoue, M. & Mitsuhashi, S. (1987). In vitro and in vivo antibacterial activities of CS807, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 1085-92. Zighelboim, S. & Tomasz, A. (1981). Multiple antibiotic resistance in South African strains of Streptococcus pneumoniae: mechanism of resistance to 0-lactam antibiotics. Review of Infectious Diseases 3, 267-76.
Downloaded from http://jac.oxfordjournals.org/ at University of Arizona on July 25, 2015
Resistance of pneumococci to penicillin is a phenomenon that has been well known for many years. Its incidence varies considerably in different countries (Geslin, Fremaux & Sissia, 1989). The resistance mechanism is a modification of the PBPs (Zighelboim & Tomasz, 1981). This modification in the PBPs leads to a reduction in activity of all /Mactam antibiotics. Penicillin-resistant pneumococci were less sensitive to the cephalosporins tested than penicillin-sensitive pneumococci. Cefpodoxime was the most active of the cephalosporins tested, with MICM and MIC*, of 1 and 4 mg/1, respectively, but this activity was ten to 16 times weaker than that observed against penicillin-sensitive strains. Cefixime and cefaclor had considerably reduced activity against penicillin-resistant pneumococci. Cefpodoxime is a new cephalosporin with a particularly broad spectrum of activity against /Mactamase producing organisms (Utsui et al., 1987; Jones & Barry, 1988; Knapp, Sierra-Madero & Washington, 1988). The ester form cefpodoxime proxetil can be given orally. The in-vitro data presented here indicate that cefpodoxime proxetil may be useful in the treatment of community-acquired respiratory tract infections. Its activity against H. influenzae and S. pneumoniae may be particularly important. The only limitation is its low activity against penicillin-resistant strains of pneumococci and ampicillin-resistant non-/Mactamase producing strains of H. influenzae.
