DIAGN MICROBIOL INFECT DIS 53 1986;4:53~3

In Vitro Activity of Cefpirome (HR810) Against Antibiotic-Resistant Gram-Positive and Gram- Negative Bacteria Including Organisms With Inducible Resistance

Patrick R. Murray and Ann C. Niles

The activity of cefpirome (HR810) was compared with seven ~-lactam antibiotics against se- lected gram-positive and gram-negative bacteria. Cefpirome was the most active antibiotic tested against all groups of Enterobacteriaceae; 46% of the isolates of Pseudomonas aeruginosa were inhibited by <~8 /~g/ml of cefpirome. Fifty percent of the oxucillin-resistant Staphylococcus aureus isolates and 82% of the Streptococcus [aecalis isolates were inhibited by <~8 ttg/ml of cefpirome. All Enterobacteriaceae and two of five P_. aerul~inosa isolates that were induced to produce ~-lactamase by prior exposure to cefoxitin remained susceptibile to cefpirome.

INTRODUCTION

Although many broad-spectrum cephalosporin and penicillin antibiotics have been developed recently, the selection of, or superinfection with, resistant bacteria (par- ticularly Enterobacter, Serratia, Providencia, Pseudomonas, and enterococci) has tempered the enthusiasm with which these antibiotics were introduced (Sanders, 1983; Sanders and Sanders, 1983). The growth of resistant subpopulations of organ- isms has been previously observed in vitro and in viva after exposure of susceptible isolates to the [3-1actam antibiotics. Although the precise mechanism for this resis- tance is unknown, it has been postulated that after exposure to the [3-1actam antibiotic, [3-1actamase production is stimulated, which then either hydrolyzes susceptible an- tibiotics or binds to the antibiotics that are resistant to hydrolytic destruction (Sanders and Sanders, 1983; Then and Angehrn, 1982). Thus, it is desirable for new antibiotics that are developed to have a broad spectrum of activity, as well as resistance to [3- lactamase hydrolysis, and a low binding affinity for 13-1actamases.

Cefpirome (HR810; Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) is a new cephalosporin that fulfills these criteria (Siebert et al., 1983a,b; Jones et al., 1984a,b; Bertram et al., 1984; Klesel et al., 1984). Cefpirome is active against most common gram-negative and gram-positive bacteria. In addition, HR810 is resistant to hydrolysis by chromsomal and plasmid-mediated B-lactamases and has a low binding affinity for these enzymes. Thus, the selection or induction of resistant organisms during therapy with cefpirome may be uncommon.

From the Washington University School of Medicine and Barnes Hospital Clinical Micro- biology Laboratory, Saint Louis, MO.

Address reprint requests to: Dr. Patrick R. Murray, Clinical Microbiology Laboratory, Barnes Hospital, Saint Louis, MO 63110.

Received February 28, 1985; revised and accepted May 21, 1985.

© 1986 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Avenue, New York, NY 10017 0732-8893/86/$03.50

54 P.R. Murray and A.C. Niles

The purpose of this study was to determine the in vitro activity of cefpirome against: (1) selected gram-negative bacilli and gram-positive cocci and (2) gram- negative bacilli with inducible resistance to 13-1actam antibiotics.

MATERIALS AND METHODS

Antibiotics Pharmaceutical-grade powders of the following antibiotics were supplied by the manufacturers and used in these studies: azlocillin, cefamandole, cefoperazone, ce- fotaxime, cefoxitin, cefpirome, ceftazidime, ceftriaxone, gentamicin, moxalactam, oxacillin, piperacillin, and vancomycin.

Organisms All organisms used in this study were isolated from blood cultures received in the Barnes Hospital Clinical Microbiology Laboratory. The organisms were identified by conventional methods and then stored at - 80°C. Gram-negative bacilli tested in this study were subdivided into gentamicin-resistant [minimal inhibitory concentration (MIC) MIC > 8 lag/ml] and gentamicin-susceptible strains, and isolates of Staphy- lococcus were subdivided into oxacillin-resistant (MIC > 2 ~.g/ml) and oxacillin- susceptible strains.

Susceptibility Tests

The MICs were determined by the broth microdilution method recommended by the National Committee for Clinical Laboratory Standards (1983). The test inoculum was - 1 0 s colony-forming units (CFU)/ml, unless otherwise stated. Microdilution trays were prepared in house and after inoculation were incubated at 35°C for 18-24 hr.

Selection of Resistant Organisms Selected strains of Enterobacteriaceae and Pseudomonas were induced with cefoxitin to produce 13-1actamase by the method of Sanders and Sanders (1979). Four hours after exposing the bacteria to 100 ~.M of cefoxitin (42.75 lag/ml), [3-1actamase pro- duction was assayed. The susceptibility of ]3-1actamase-producing strains and the nonproducing parent strains was measured against a panel of [3-1actam antibiotics that included: cefpirome, cefotaxime, moxalactam, cefoperazone, ceftazidime, cef- triaxone, cefamandole, and piperacillin.

RESULTS

A comparison of the antimicrobial activity of cefpirome with seven cephalosporins and penicillins is presented in Table 1. A total of 147 Enterobacteriaceae, including 74 isolates resistant to gentamicin, were tested. Cefpirome was the most active an- tibiotic against this group of organisms with 145 (98.7%) susceptible to ~8 lag/ml. No difference between cefpirome activity against gentamicin-susceptible and -re- sistant organisms was observed. Seventy-one percent of the gentamicin-susceptible strains of Pseudomonas aeruginosa were susceptible to ~8 ~.g/ml of cefpirome, which was comparable to the activity of ceftazidime, piperacillin, and azlocillin and better than the activity of the other cephalosporins. Only 36% of the gentamicin-resistant isolates, however, were susceptible to cefpirome. The activity of cefpirome against other species of Pseudomonas, as well as isolates of Acinetobacter and miscellaneous

In Vi t ro A c t i v i t y o f C e f p i r o m e 55

T A B L E 1. C o m p a r a t i v e A n a l y s i s o f I n V i t ro A c t i v i t y o f C e f p i r o m e

MIC (p.g/ml}

Organ i sm (No.) Ant ibiot ic Range 50% 90% Percentage

suscep t ib le °

Escherichia coil (20) Gen tamic in MIC ~ 8 p.g/ml

Escherichia coil (11) Gen tamic in MIC > 8 p.g/ml

Klebsiella spec ies (19) Gen tamic ln MIC > 8 p.g/ml

Klebsiella spec ies (15) Gen tamic in MIC > 8 p.g/ml

Enterobacter spec ies (20) G e n t a m i c m MIC ~< 8 p.g/ml

Enterobacter spec ies (31) Gen tamic in MIC ~ 8 ~.g/ml

Cefpi rome Cefotaxime Moxa lac t am Cefoperazone Cef taz id ime Ceftr iaxone Piperaci l l in Azloci l l in

Cefpi rome Cefotaxime Moxa lac tam Cefoperazone Cef taz id ime Ceftr iaxone Piperaci l l in Azloci l l in

Cefp i rome Cefotaxime Moxa lac tam Cefoperazone Cef taz id ime Ceftr iaxone Piperaci l l in Azloci l l in

Cefp i rome Cefotaxime Moxa lac tam Cefoperazone Cef taz id ime Ceftr iaxone Piperaci l l in Azloci l l in

Cefp i rome Cefotaxime Moxa lac tam Cefoperazone Cef taz id ime Ceft r iaxone Piperaci l l in Azloci l l in

Cefp i rome Cefotaxime Moxa lac t am Cefoperazone Cef taz id ime Ceftr iaxone Piperaci l l in Azloci l l in

~<0.12-0.5 ~<0.12 0.25 100 ~ 0 . 1 2 - 1 ~<0.12 1 100 ~ 0 . 1 2 - 4 ~0 .12 0.5 100 ~ 0 . 1 2 - 1 2 8 2 32 85 ~0.12--4 ~<0.12 2 100 ~0.12-2 ~<0.12 0.5 100

1 - > 1 2 8 64 > 1 2 8 55 8 - > 1 2 8 >128 >128 35

~0.12--0.25 ~0 .12 ~0 .12 100 ~0.12-2 ~0.12 ~0 .12 100 ~0.12--0.5 ~0 .12 0.25 100

2 - > 1 2 8 64 >128 36 ~0.12--4 ~0 .12 1 100 ~0.12--0.5 ~<0.12 ~0 .12 100 ~ 0 . 1 2 - > 1 2 8 64 >128 9 ~ 0 . 1 2 - > 1 2 8 > 1 2 8 >128 9

~ 0 . 1 2 - 0 . 5 ~0 .12 0.5 100 ~ 0 . 1 2 - 0 . 2 5 ~0 .12 0.25 100 ~ 0 . 1 2 - 0 . 5 ~0 .12 2 100 ~ 0 . 1 2 - 6 4 1 64 80 <~0.12-2 0.25 1 100 <~0.12-0.5 0.12 0.25 100

4 - > 1 2 8 32 >128 55 1 6 - > 1 2 8 >128 > 1 2 8 32

<~0.12-2 ~0 .12 0.25 100 ~ 0 . 1 2 - 1 6 ~0 .12 <~0.12 93 ~ 0 . 1 2 - > 1 2 8 ~0 .12 0.5 93

8 -128 64 128 40 ~ 0 . 1 2 - 2 0.25 0.5 100 ~ 0 . 1 2 - 0 . 5 ~0 .12 ~0 .12 100 6 4 - > 1 2 8 128 >128 40

>128 >128 >128 0

~ 0 . 1 2 - 1 6 0.25 2 95 ~ 0 . 1 2 - > 1 2 8 1 128 65 ~ 0 . 1 2 - 3 2 1 32 80 ~ 0 . 1 2 - > 1 2 8 8 128 65 ~ 0 . 1 2 - > 1 2 8 1 64 60 <~0.12->128 0.5 128 65

1 - > 1 2 8 32 >128 70 4 - > 1 2 8 >128 >128 35

~0.12---8 0.25 4 100 ~ 0 . 1 2 - > 1 2 8 0.25 16 90 ~ 0 . 1 2 - > 1 2 8 0.25 8 94

4 - > 1 2 8 32 >128 45 ~ 0 . 1 2 - > 1 2 8 0.5 16 87 ~ 0 . 1 2 - > 1 2 8 0.25 64 84

4 - > 1 2 8 128 >128 42 4 - > 1 2 8 ~ 1 2 8 >128 6

{continuedJ

56 P.R. M u r r a y a n d A.C. N i l e s

T A B L E 1. C o m p a r a t i v e A n a l y s i s of In V i t ro A c t i v i t y o f C e f p i r o m e (continued)

Organ i sm (No.) Ant ib io t ic

MIC (~.g/ml) Percentage

Range 50°/,, 90% suscep t ib le ~

Serratia spec ies (14) Gen tamic in MIC ~ 8 ~tg/ml

Cefp i rome <~0.12-64 0.25 8 93 Cefo tax ime <~0.12->128 2 >128 79 Moxa lac t am 0 . 2 5 - > 1 2 8 4 >128 57 Cefoperazone 1 - > 1 2 8 16 >128 50 Cef taz id ime ~<0.12-16 0.5 2 93 Cef t r iaxone ~<0.12->128 2 128 79 Piperaci l l in 1 - > 1 2 8 32 >128 50 Azloci l l in 8 - > 1 2 8 >128 >128 29

Serratia spec ies (8) Gen tamic in MIC ~ 8 ~.g/ml

Cefp l rome Cefo tax ime Moxa lac t am Cefoperazone Cef taz id ime Ceft r iaxone Piperaci l l in Azloc i l l in

<~0.12--0.5 0.25 0.5 100 0 .5 -32 1 16 63 0 .25 -128 2 128 88 8 - > 1 2 8 >128 >128 13

~0.12--64 0.5 64 87 0 .5 -64 4 16 63 > 1 2 8 >128 >128 0 > 1 2 8 >128 >128 0

Citrobacter spec ies (11) Gen t amic in M1C ~ 8 ~.g/ml

Cefp l rome Cefo tax ime Moxa lac t am Cefoperazone Cef laz id ime Cef t r iaxone Piperaci l l in Azloci l l in

~<0.12-2 0.5 2 100 ~<0.12-32 16 32 45 ~<0.12-8 2 4 100

1 - > 1 2 8 32 128 36 0 .25 -128 64 128 45 0 . 2 5 - > 1 2 8 32 128 45 3 2 - > 1 2 8 >128 >128 36

>128 >128 >128 0

Pseudomonas aeruginosa (28) Gen tamic in MIC ~ 8 p.g/ml

Cefp l rome Cefotaxime Moxa lac t am Cefoperazone Cef taz id ime Cef t r iaxone Piperaci l l in Azloci l l in

~ 0 . 1 2 - 1 2 8 4 64 71 ~ 0 . 1 2 - > 1 2 8 32 >128 14

0 . 5 - > 1 2 8 32 >128 21 0 . 5 - > 1 2 8 16 >128 50

~<0.12->128 2 32 75 ~ 0 . 1 2 - > 1 2 8 32 >128 14

0 . 2 5 - > 1 2 8 16 >128 75 ~ 0 . 1 2 - > 1 2 8 8 >128 79

Pseudomonos aeruginosa (72) Gen t amic in MIC ~ 8 ~.g/ml

P s e u d o m o n a s spec ies (13) Gen t amic in MIC ~ 8 ~.g/ml

Cefp l rome Cefo tax ime Moxa lac t am Cefoperazone Cef taz id ime Cef t r iaxone Piperaci l l in Azloci l l in

Cefp i rome Cefo tax ime Moxa lac t am Cefoperazone

~ 0 . 1 2 - > 1 2 8 16 64 36 0 . 5 - > 1 2 8 32 >128 13 0 . 2 5 - > 1 2 8 32 >128 18 2 - > 1 2 8 32 >128 49 0 . 5 - > 1 2 8 4 >128 57 1 - > 1 2 8 64 >128 17

0 . 2 5 - > 1 2 8 32 >128 58 0 . 2 5 - > 1 2 8 64 >128 53

0 . 5 - > 1 2 8 128 >128 23 4 - > 1 2 8 64 >128 23 1 -128 4 64 62 2 - > 1 2 8 64 > 1 2 8 38

In Vitro Ac t iv i ty of Ce fp i rome 57

TABLE 1. Compara t i ve Ana ly s i s of In Vitro Ac t iv i ty of Ce fp i rome (con t inued)

MIC (wg/mI} Percentage

Organism {No.) Antibiotic Range 50% 90% susceptible u

Ceftazidime 1->128 4 64 54 Ceftriaxone 4->128 >128 >128 15 Piperacillin 0.25->128 64 >128 54 Azlocillin 0.25->128 >128 >128 46

Acinetobacter species (8) Gentamicin MIC > 6 ~g/ml

Cefpirome ~<0.12-32 16 16 38 Cefotaxime ~<0.12-32 8 32 86 Moxalactam ~0.12-64 16 64 38 Cefoperazone 4->128 64 64 25 Ceftazidime ~<0.12-8 4 8 100 Ceftriaxone ~<0.12-32 8 16 50 Piperacillin 16->128 32 >128 88 Azlocillin 32->128 64 >128 50

Other organisms b (32} Gentamicin MIC > 8 ~g/ml

Staphylococcus aureus (16} Oxacillin MIC > 8 p.g/ml

Staphylococcus aureus (100) Oxacillin Gentamicin M1C > 2 ~g/ml

Streptococcus faecalis (82)

Cefpirome ~<0.12->128 2 >128 55 Cefotaxime ~<0.12->128 16 128 45 Moxalactam <~0.12->128 1 16 85 Cefoperazone 0.5-> 128 8 128 70 Ceftazidime ~<0.12-64 2 32 79 Ceftriaxone ~<0.12->128 16 >128 48 Piperacillin ~<0.12->126 4 >128 76 Azlocillin ~<0.12->128 16 >128 58

Cefpirome 0.25-126 1 2 94 Cefotaxime 0.5-64 8 32 69 Moxalactam 4->128 16 128 44 Cefoperazone 1-128 2 64 88 Ceftazidime 2->126 16 128 38 Ceftriaxone 1->128 4 64 63 Piperacillin 1->128 32 >128 19 Azlocillin 0.25->128 32 >128 19

Cefpirome 0.5->128 8 64 50 Cefotaxime 1->128 32 >128 27 Moxalactam 8->128 128 >128 1 Cefoperazone 4->128 64 >128 27 Ceftazidime 8->128 64 >128 1 Ceftriaxone 2->126 64 >128 8 Piperacillin 16->128 128 >128 1 Azlocillin 4->128 64 >128 1

Cefpirome 0.25--64 8 16 62 Cefotaxime <~0.12->128 >128 >128 7 Moxalactam 128->128 >128 >128 0 Cefoperazone 2-64 16 32 60 Ceftazidime 2->128 >126 >128 2 Ceftriaxone 0.25->128 128 >128 6 Piperacillin 0.5-32 2 4 94 Azlocillin 0.25-4 1 2 100

(continued)

58 P.R. Murray and A.C. Niles

TABLE 1. Comparat ive Analys is of In Vitro Activi ty of Cefpirome

MIC (p.g/ml] Percentage

Organism (No.) Antibiotic Range 50% 90% susceptible ~'

Streptococcus faecium (18] Cefpirome 1->128 128 >128 22 Cefotaxime 2-128 >128 >128 5 Moxalactam >128 >128 :>128 0 Cefoperazone 8->128 32 >128 22 Ceftazidime >128 >128 :~-128 0 Ceftriaxone 2->128 >128 >128 22 Piperacillin 2-128 16 64 6 Azlocillin 1-32 8 16 44

°Organisms were defined as susceptible if: MIC <~ 8 p.~ml for cefpirome, celotaxime, moxalactam, cef- tazidime, and ceftriaxone: MI(" <~ 16 p.g/ml for cefoperazone; MIC for azlocillin and piperacillin was ~<2 p.g,' ml for Staphylococcus. <~4 p.g/ml for S. fuecalis and S. faecium, ~<64 p.g/ml for gram-negative bacilli.

blncludes Achramolmcter [11 isolates), Pravidencia stuortii (4), Providencia rettgeri (2), Proteus mirabilis (1). Morganella morganii (3), Flavc~bacter (4]. AIcaligenes (2). group [I-F [4). ami group EO-2 (1).

gram-negative bacill i , was also modest and comparable to that observed with the other cepha lospor ins that were tested. Cefpirome was the most active ant ibiot ic against Staphylococcus and Streptococcus.

The effect of cefoxi th in- induced 13-1actamase product ion on the activi ty of cefpi- rome is presented in Table 2. All test isolates were suscept ible to ~<8 p.g/ml of cefpirome before induct ion, and the 15 Enterobacteriaceae that were tested remained suscept ible after induct ion. Three of five Pseudomonas isolates, however, became resistant to cefpirome after induct ion, inc luding two isolates with high-level resis- tance (MIC/> 128 p.g/ml). In contrast with these results, cefoxi th in-mediated induc- tion of [3-1actamase product ion was associated with the deve lopment of resistance to p iperaci l l in and to many of the cephalospor ins inc luding cefotaxime, cefopera- zone, ceftazidime, ceftriaxone, and cefamandole. Induct ion of resistance was also associated with cross-resistance to some other 13-1actam antibiotics.

DISCUSSION

Although many new cepha lospor in and penic i l l in antibiot ics with expanded spectra of act ivi ty have been in t roduced during the last decade, resistant organisms have arisen. This is due in part to the select ion with the antibiot ic of natural ly resistant organisms (e.g., enterococcus, oxacillin-resistant staphylococci, Pseudomonas, yeast), as well as the selection of subpopula t ions of resistant organisms after exposure of suscept ib le isolates to the 13-1actam antibiotic. This selection of resistance has been observed most commonly in the group of bacteria for which these ant ibiot ics were developed, namely, Enterobacter, Serratia, Providencia, and Pseudomonas . Studies by Sanders and others have suggested that the inducib le resistance is media ted by [3-1actamase, and, al though most of the cephalospor in antibiot ics are resistant to [3- lactamase hydrolysis , these ant ibiot ics are inactivated by nonhydro ly t ic b inding to the enzymes. If this theory is correct, ant ibiot ics that are not suscept ible to 13-1acta- mase hydrolys is and have a low affinity for b inding to the [3-1actamases should remain active against many bacteria inc luding those organisms that develop resistance to other [3-1actam antibiot ics during therapy.

Cefpirome is an ant ibiot ic that is not only active against a wide spectrum of organisms, but is also resistant to B-lactamase hydrolys is (Siebert et al., 1983a; Jones et al., 1984a) and has a low affinity for b inding to these enzymes (Tolxdorff-Neutzling and Wiedemann, 1983). The studies reported herein confirm and extend previous

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62 P.R. Murray and A.C. Niles

reports about the in vitro activity of cefpirome. Virtually all gentamic:in-susceptible and -resistant Enterobacteriuceae were susceptible, and cefpirome was one of the most active cephalosporins against isolates of P. aeruginosa, although only 36% of the gentamicin-resistant isolates were susceptible to <~8 ~g/ml. Fifty percent of the oxacillin-resistant S. aureus isolates and 82% of the S. faecalis isolates were inhibited by ~8 ~g/ml of cefpirome. Even though cefpirome should not be usect to treat in- fections with these organisms, inhibi t ion at clinically achievable concentrat ions may prevent superinfections with these isolates.

In contrast with the other cephalosporins and piperacillin, induct ion of 13-1acta- mase production in the Enterobacteriaceae did not result in resistance to cefpirome. Resistance was observed with three of the five isolates of P. aeruginosa that were tested, including two isolates that become highly resistant to cefpirome. All five isolates, however, also became resistant to all of the other cephalosporins and pi- peracill in after induction. Although cefpirome has a low affinity for the Richmond and Sykes type 1-induced 13-1actamase, resistance may be related to alterations in the cell permeabili ty or b inding of the antibiotic to specific receptors, as has been observed in other P. aeruginosa strains (Godfrey et al., 1981).

CONCLUSION

Cefpirome is a potent cephalosporin with activity against a variety of gram-positive and gram-negative bacteria inc luding most strains with inducible resistance to 13- lactam antibiotics that were tested.

REFERENCES

Bertram MA, Bruckner DA, Young LS (1984) In vitro activity of cefpirome, a new cephalosporin. Antimicrob Agents Chemother 26:277.

Godfrey AJ, Bryan LE, Rabin HR (1981) 13-Lactam-resistant Pseudomonas aeruginosa with mod- ified penicillin-binding proteins emerging during cystic fibrosis treatment. Antimicrob Agents Chemother 19:705.

Jones RN, Thornsberry C, Barry AL (1984a) In vitro evaluation of cefpirome, a new wide- spectrum aminothiazolyl-methoxyimino cephalosporin. Antimicrob Agents Chemother 25:710.

Jones RN, Thornsberry C, Barry AL, Ayers L, Brown S, Daniel J, Fuchs PC, Gavan TL, Gerlach EH, Matsen JM, Relier LB, Sommers HM (1984b} Disk diffusion testing, quality control guidelines, and antimicrobial spectrum of cefpirome, a fourth-generation cephalosporin, in clinical microbiology laboratories, l Clin Microbiol 20:409.

Klesel N, Limbert M, Schrinner E, Seeger K, Seibert G, Winkler I (1984) Chemotherapeutic properties of the new cephalosporin antibiotic cefpirome in laboratory animals. Infection 12:286.

National Committee for Clinical Laboratory Standards (1983) M7-T. Methods for dilution an- timicrobial susceptibility tests for bacteria that grow aerobically. NCCLS. Villanova, PA.

Sanders CC (1983) Novel resistance selected by the new expanded-spectrum cephalosporins: a concern, l Infect Dis 147:585.

Sanders CC, Sanders WE Jr (1979) Emergence of resistance to cefamandole: possible role of cefoxitin-inducible 13-1actamase. Antimicrob Agents Chemother 15:792.

Sanders CC, Sanders WE Jr (1983) Emergence of resistance during therapy with the newer ~3- lactam antibiotics: role of inducible 13-1actamases and implications for the future. Rev Infect Dis 5:639.

Siebert G, Klesel N, Limbert M, Schrinner E, Seeger K, Winkler I, Lattrell R, Blumback J, Durckheimer W, Fleischmann K, Kirrstetter R, Mencke B, Ross BC, Scheunemann I(H, Schwab W, Wieduwilt M (1983a} HR810, a new parenteral cephalosporin with a broad antibacterial spectrum. Arzneimittelforsch. 33:1084.

Siebert G, Limbert M, Winkler I, Dick T (1983b) The antibacterial activity in vitro and 13- lactamase stability of the new cephalosporin HR810 in comparison with five cephalosporins and two aminoglycosides. Infection 11:275.

In Vitro Activi ty of Cefpirome 63

Then RL, Angehrn P (1982) Trapping of nonhydrolyzable cephalosporins by cephalosporinases in Enterobacter cloacae and Pseudomonas aeruginosa as a possible resistance mechanism. Antimicrob Agents Chemother 21:711.

Tolxdorff-Neutzling RM, Wiedemann B (1983) Cefpirome, a cephalosporin with low affinity for Enterabacter cloacae beta-lactamase. Eur J Clin Microbiol 2:352.