tazobactam against isolates from patients enrolled in clinical trials

tazobactam against isolates from patients enrolled in clinical trials

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Antimicrobial Agents International Journal of Antimicrobial Agents 7 (1996) 15-21

against isolates from patients In vitro activity of piperacillinhazobactam enrolled in clinical trials Nydia A. Kuck, Nilda V. Jacobus, Michael D. Spengler, Raymond T. Testa* Wyeth-A.verst Research, Lederle Laborutories. Pearl River, New York, NY lO%.(. CISA

Accepted 27 December 1995

Abstract The in vitro activity of piperacillin alone or titrated with a constant concentration of 4 @ml tazobactam was evaluated against 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical trial studies in North America. Tazobactam increased susceptibility rates of piperacillin for Enterobacteriuceae from 81% to 96%. Staphylococcus (methicillin susceptible) spp. from 6% to lOO%, Bacteroidesfragilis group from 79% to >99% and Haemophilus from 85% to 98%. The excellent activity of piperacillin against Pseudomonas, Streptococcus and Enterococcus was maintained in the presence of tazobactam. Overall piperacillinltazobactam had better activity than ticarcillinklavulanic acid, ceftazidime, and in general equaled the activity of imipenem. The excellent in vitro. extended-spectrum activity of piperacillin/tazobactam suggests its utility for various infections. Keywords:


In vitro susceptibility

1. Introduction

2. Materials and methods

Piperacillin is a /I-lactam antibiotic with an extensive spectrum of activity but is susceptible to hydrolysis by some &lactamases. Tazobactam, a novel triazolymethyl penicillanic sulfone, is a potent inhibitor of a wide range of commonly encountered /3-lactamases of the plasmid-mediated and chromosomal types including the extended spectrum enzymes [l-3]. Early studies of piperacillin/tazobactam combinations showed remarkably effective activity against a broad variety of j%lactamase-producing organisms [4-61. As part of the program for the development of piperacillin/tazobactam for clinical use, 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical protocols were tested for in vitro susceptibility to piperacillin with and without the enzyme inhibitor. Protocol alternate drugs were included in the evaluation. The isolates were provided by 175 investigators located in geographically diverse medical centers in the United States and Canada.

From 1989 to 1994, investigators sent isolates to Lederle Laboratories for confirmation of identification and antibiotic susceptibility. Cultures were processed immediately upon receipt or stored in skim milk at -70°C until tested. All referred isolates were tested but antibacterial activity was assessed only on baseline isolates. Organisms were identified by conventional methods using commercial kits and identification schemes described in the Manual of Clinical Microbiology [7]. Anaerobes were identified by procedures described in Wadsworth Anaerobic Bacteriology Manual [8] or by Rapid ANA II System (Innovative Diagnostic Systems, Inc., Norcross, GA). /3-Lactamase activity was detected by assays using the chromogenic cephalosporin, nitrocefin. Standard powders of piperacillin and tazobactam were provided by Lederle Laboratories (Pearl River, NY). Ceftazidime was obtained from Glaxo (Ware, UK), clavulanic acid from SmithKline Beecham (Philadelphia, PA), imipenem from Merck (Rahway, NJ) and ticarcillin. gentamicin and clindamycin from Sigma Chemical Co. (St. Louis, MO). SensititreTM investigational panels

*Corresponding 132-5536.



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Science B.V. All rights


N. A. Kuck et al. IInternational Journal of Antimicrobial Agents 7 (1996)


containing the various test antibiotics were obtained from Radiometer/Copenhagen (Westlake, OH); SceptorTM panels were provided by Becton-Dickinson (Towson, MD). Susceptibility tests included piperacillin (PIP) alone or piperacillin titrated in the medium with a constant concentration of 4 ,&/ml of tazobactam (PIP/TZB). Ticarcillin was titrated with a constant concentration of 2 ,ug/ml of clavulanic acid (TICELAV). MICs were determined by procedures described by National Committee for Clinical Laboratory Standards [9,101. Fast-growing Gram-negative aerobic rods and staphylococci were tested in the investigational panels containing MuellerHinton (M-H) medium according to manufacturer’s procedures. Streptococci, enterococci, Haemophilus, Neisseria and anaerobes were tested by NCCLS agar dilution methods. Methicillin susceptibility of staphylococci was determined according to NCCLS recommendations using an agar screen with oxacillin 6 puglml. Susceptibility to the antibiotics was determined according to NCCLS recommended breakpoints. Interpretive criteria for organisms not addressed by NCCLS for PIP or PIP/TZB are suggestions based on Wyeth-Ayerst Research data (Table 1).

Table 2 Incidence

of fi-lactamase

Organism group (No. isolates tested)






Number of /3-lactamase positive (%)

% B-Lactamase-positive isolates resistant to: PIP


954 (83.2)



(497) Klebsiella pneumoniae

437 (87.9)



(190) Staphylococcus aureus (332) methicillin susceptible Staphylococcus coag. neg. (179) methicillin susceptible Morasella catarrhalis

170 (89.5)



290 (87.3)



95 (53.1)



(28) Haemophilus injuenzae

21 (75)



(136) Bacteroides fragilis group (200)

29 (21.3)





Enferobacreriuceae (1146) Eseherichia co/i

184 (92)

Staphylococcus, Moraxella catarrhalis, Haemophilus influenzae and the Bacteroides fragilis group.

3. Results In this study the incidence of /3-lactamase-producing isolates was high and ranged from 92% for the Bacteriodes fiagilis group to 21% for Haemophilus infuenzae (Table 2). Tazobactam reduced the rate of piperacillin resistance from 17% to 2% among 954 p-lactamase-producing Enterobacteriaceae isolates. The largest unit in this group was the E. coli where 25% of 437 /?-lactamaseproducing isolates were resistant to piperacillin but less than 1% when tested with tazobactam. Tazobactam also produced significant reduction in piperacillin resistance among B-lactamase-producing methicillin-susceptible Table 1 Criteria for susceptibility with 4 ,&nl tazobactam Organism group susceptible


and piperacillin

MIC @ml Resistant

tl aeruginosa” Other Gram-negative organisms” Staphylococci”.b HaemophiluslNeisseria”” Anaerobes” Enterococcus’ Streptococcus’

for piperacillin



2128 2128 216 22 2128 216 22




’ NCCLS recommended guidelines. bPiperacillin alone susceptible MIC is SO.25 ,@ml ’ Wyeth-Ayerst Research recommendations.

516 <8 11 532 G3 11

The predominant organisms isolated from patients enrolled in the 9 protocols are listed in Table 3. The PIP/ TZB-resistant isolates are shown in Table 4. The most frequent Enterobacteriaceae species resistant to PIP and PIP/TZB was Enterobacter cloacae, referred from lower respiratory, skin/soft tissue, urinary tract, septicemia, neutropenia and community-acquired pneumonia studies. Most isolates of Pseudomonas aeruginosa were susceptible to piperacillin and 3% of the PIP-resistant isolates were rendered susceptible by the addition of tazobactam. PIP/TZB-resistant Pseudomonas aeruginosa cultures were obtained from patients in the lower respiratory, urinary tract, intraabdominal and community-acquired pneumonia protocols. Staphylococcal isolates were provided mainly from skin/soft tissue and bone/joint infections. They had a high rate of resistance to PIP. All methicillin-susceptible isolates were susceptible to PIP/TZB as well as to the alternate B-lactam. Staphylococci that were resistant to methicillin (n = 1460) were considered resistant to PIP and PIP/TZB although MICs were 0.5-~256 [email protected] and 0.06-<256 &ml, respectively. NCCLS guidelines indicate that these organisms should be considered resistant to all p-lactam antibiotics with or without a /?-lactamase inhibitor. Haemophilus cultures came from lower respiratory and community-acquired pneumonia studies. All but three isolates from the latter study were susceptible to PIP/TZB as well as to TICELAV. The intraabdominal infection studies provided the

N.A. Kuck et al. IInternational Journal of Antimicrobial Agents 7 (1996)

Table 3 Predominant isolates by protocol: resistance to piperacillin, piperacillinltazobactam Protocol (Total No. Patients)

Total No isolates

Isolate group

and alternate agents


No. resistant to PIP



Gynecology (267)

Lower respiratory (27 I )

Skin/soft tissue (220)





Bacteroides fragilis group E. coli Klebsiella spp. Enterococcus spp. Pseudomonas spp.

(159) (145) (48) (38) (32)


Pneumonia community acquired (238)

Septicemia (202)

Bone and joint (136)






I 4


Alternate agent’

0 1 0 4 I

27/15 (CC/GM) 4 (GM)

0 1 3 0 0

7 (CC) 2 (GM) X2/38 (CC/GM) 511 (CC/GM) 0130 (CC/GM)

15 (CC) 5 (GM)

1 (GM)



(90) (88) (46) (34)

23 3 44 0

Enterobacteriaceae P aeruginosa Streptococcus spp. Haemophilus injuenzae Moraxella catarrhalis

(187) (104) (69) (53) (12)

32 23 0 7


9 17 0 0 0

Staphylococcus ~pp.~ Enterobacteriaceae Streptococcus spp.

(169) (96) (93) (58) (24)

164 10 4 8 0

0 4 I I 0

E. coli Klebsiella spp. Other Enterobacteriaceae Enterococcus spp. P aeruginosa

(132) (45) (74) (55) (43)

34 7 2 5 1

0 0 2 5 I

S. pneumoniae H. influenzae P aeruginosa K. pneumoniae Other Enterobacteriaceae

(94) (82) (19) (19) (34)

0 12 2 1 5

0 3 3 0

E. coli

(84) (81) (40) (38) (24)

21 8 1 34 0


Other Enterobacteriareae Streptococcus spp. Staphylococcus ~pp.~ P: aeruginosa

2 I 0 0

0 (IMP) 1 0 0 4

Staphylococcus ~pp.~ Enterobacteriaceae Streptococcus spp. Pseudomonas spp.

(98) (40) (34) (23) (15)

86 3 1 0 0

0 0 I 0 0

0 (TICICLAV) 1 0 0 0

Enterobacteriaceae Staphylococcus ~pp.~ Streptococcus spp. Corynebacterium JK

(39) (37) (19) (3)

3 32 2 3

1 0


Neutropenia (102)

23 I5


Enterobacteriaceae Enterococcus spp. Staphylococcus ~pp.~ Streptococcus group B

Anaerobes II aeruginosa Urinary tract (251)




I 3

I6 (CAZ) 25 0 0 0 0 (TIC/CLAV) 5 0 0 2 0 (CAZ) 0 3 53 0

0 (TWCLAV) 3 2 0 3

0 (IMP) 0 0 3 -._____

a Alternate agents: clindamycin (CC), gentamicin (GM), ticarcillinlclavulanic (TICELAV), imipenem (IMP), ceftazidime (CAZ). b Includes only oxacillin-susceptible staphylococci (methicillin susceptible).

largest number of Bacteroides jiragilis group isolates and the gynecology protocol the largest number of anaerobic Gram-positive cocci. Resistance to PIP (17%) was en-

countered only among the Bacteroidesfiagilis group cultures. All but one isolate of Bacteroides distasonis was susceptible to PIP/TZB. All other Gram-negative and

N. A. Kuck et al. IInternational Journal of Antimicrobial Agents 7 (1996)


Table 4 Piperacillin

and piperacillinltazobactam




No. PIPlTZB resistant isolates


to other agents No. resistant/No.

-tested to:’

CA2 /3-Lactamase positive Citrobacter freundii Escherichia coli Enterobacter aerogenes Enterobacter cloacae Klebsiella oxytoca Klebsiella pneumoniae





GM 012

212 o/2 l/l 14114 O/l O/l

o/2 O/I o/14 O/l O/l

212 212 NT S/8 l/l O/l

4114 O/l O/l






1 21 20


20/2 1 13120

l/l 512 1 20120

NT 414 2/11

111 612 1 13120

Haemophilus injuenzze Moraxella catarrhalis

3 1

O/l O/l

l/l l/I

313 NT

013 O/l

Bacteroides distasonis




Acinetobacter anitratus Burkholderia cepacia Pseudomonas aeruginosa Xanthomonas maltophiliu

P-Lactamase negative Corynebacterium JK


O/2 O/l







Enterococcus avium Enterococcus faecalis Enterococcus faecium

2 1 8

212 l/l 818


NT 618

212 111 515

l/2 O/l 3/8

Streptococcus agalactiae Streptococcus viridans group

1 5

O/l 215

NT 215

l/l 415

a Alternate



(CC), gentamicin



Gram-positive anaerobes were susceptible to PIP and PIP/TZB. Piperacillin was highly effective against streptococci and enterococci. As expected, the few PIP-resistant isolates in these non-/%lactamase-producing groups were also resistant to PIP/TZB. Streptococcal cultures were provided by all protocols but mainly from septicemia, bone/joint and neutropenia studies. Enterococcal cultures were mainly supplied by the intraabdominal, gynecology and urinary tract studies. The PIP/TZB-resistant enterococcal cultures were also resistant to the alternate drugs in the respective protocols. Three PIP/TZB-resistant isolates of Corynebacterium jeikeium were referred from the neutropenia studies. They were resistant to PIP, PIP/TZB and the alternate drug, imipenem. Susceptibilities of PIP/TZB-resistant organisms to other antibiotics are summarized in Table 4. The antibiotic susceptibility panels varied with the protocols, thus not all isolates were tested with the same antibiotics. All of the PIP/TZB-resistant Enterobacteriaceae were SUSceptible to imipenem and generally resistant to TIC/ CLAV. Only the Escherichia coli and Klebsiella were susceptible to ceftazidime and four Enterobacter cloacae were susceptible to gentamicin. Resistance to the antibi-







otics varied among the pseudomonads and the ,&lactamase negative isolates. A comparison of the activity of PIPlTZB with the alternative broad spectrum /3-lactam antibiotics is presented in Table 5. The low rate of resistance to PIP/TZB compared to PIP among /?-lactamase-producing bacteria indicated that tazobactam successfully protected piperacilhn from inactivation by a variety ofp-lactamases. PIP/ TZB and imipenem had similar low resistance rates for most Enterobacteriaceae with the exception of Enterobatter and Citrobacter spp. where imipenem was more active. Ceftazidime had higher resistance rates than PIP/ TZB among some Gram-negative organisms, particularly Pseudomonas aeruginosa, as well as for enterococci. Overall, PIP and TICKLAV had the highest resistance rates.

4. Discussion Piperacillin is an antibacterial agent with an impressive extended spectrum of activity against most pathogenic bacteria. Tazobactam, an extended spectrum /3lactamase inhibitor, broadened the activity of pipera-

N. A. Kuck et ul. I International Journal of’ Antimicrobial Agents 7 (1996)



Table 5 Activity of piperacillin,




No. of isolates




E. coli

Piperacillin PIP/TZB Ceftazidime lmipenem TICKLAV

497 491 482 444 444

2 1 SO.5 SO.25 4

~256 2 SO.5 SO.25 32

21 1 I 0 4

K. pneumoniae

Piperacillin PIP/TZB Ceftazidime Imipenem TICICLAV

190 190 183 174 152

8 2 10.5 SO.25 4

32 8 50.5 0.5 16


Piperacillin PIPiTZB Ceftazidime Imipenem TlClCLAV

47 47 42 40 19

4 4 SO.5 0.5 4

64 32 32 1 128

II 2 17 0 II

E. cloacae

Piperacillin PIP/TZB Ceftazidime Imipenem TICICLAV

105 105 105 96 70

2 2 SO.5 0.5 4

2128 128 264 1 128

30 13 17 0 16

Serratia spp.

Piperacillin PIPITZB Ceftazidime Imipenem TICKLAV

44 44 44 44 26

2 2 50.5 0.5 4

32 8 SO.5 2 16

7 0 0 0 0

C. .freundii

Piperacillin PIPITZB Ceftazidime Imipenem TICKLAV

28 28 2-l 21 19

4 2 10.5 0.5 4

>128 64 32

21 8 I2 0 22

Proteus spp. Indole positive

Piperacillin PIPlTZB Ceftazidime Imipenem TIUCLAV

44 43 44 44 42

1 0.25 SO.5 2 22

64 2 4 4 32

Pseudomonas spp.

Piperacillin PIPITZB Ceftazidime Imipenem TlClCLAV

31 31 21 25 16

4 2 2 8

16 4 8 16 128

3 3 4 30 44

I? aeruginosa

Piperacillin PIP/TZB Ceftazidime Imipenem TIClCLAV

260 260 238 228 149

4 4 2 2 32

128 64 32 8 64

11 X 12 8 9

H. inJ?uen;ae

Piperacillin PIP/TZB Ceftazidime Imipenem TIClCLAV

136 136 120 113 85

20.12 10.12 10.5 0.5 52

16 10.12 SO.5 2 22

15 3

E. aerogenes

and other


vs. clinical



I >128

I 1 1 2

5 0 5 0 3

; 0 3



N.A. Kuck et abllnternational

Journal of Antimicrobial Agents 7 11996) IS-21

Table 5 (continued)




No. of isolates


Piperacillin PIPITZB Ceftazidime Imipenem TICYCLAV

179 179 170 144 157

Piperacillin PIP/TZB Ceftazidime Imipenem TICICLAV Piperacillin PIP/TZB Ceftazidime Imipenem TICICLAV

332 332 318 300 253 174 174 174 104 160

Piperacillin PIP/TZB Imipenem TICKLAV

200 200 200 200

coag. neg.

S. aureus

E. faecalis

B. fragilis group

cillin to include most p-lactamase-producing bacteriaceae, Staphylococcus, Haemophilus, and Bacteroides. Bush et al. [3] demonstrated

- M&o


Percent resistant

1 0.5 8 $0.25 12

8 2 16 50.25 <2

85 0 7 0


64 2 16 SO.25 <2 4 4 >64 4 32

99 0 0 0

93 3 70

>256 8 0.5 8

17 0 0 3

1 8 SO.25 12 4

2 >64 1 16 16 2 10.12



the effectiveness of tazobactam against the /?-lactamases produced by these bacterial groups. In a study that characterized thep-lactamases produced by the resistant E. coli and K. pneumoniae strains shown in Table 4, the authors concluded that resistance to PIP/TZB was mainly associated with high-level production of j?-lactamase or the presence of multiple enzymes within one isolate as no extended-spectrum B-lactamases (ESBL) were found in this sub-set of organisms [l l]. Piperacillin alone was very effective against Z? aeruginosa, and the PIP/TZB combination reduced the MIC& by two fold and the resistance rate of piperacillin by 3%. Similar results have been reported by Murray et al. (3%) Marshall et al. (2.7-2.9%), and Baron/Jones (5%) indicating that a subset of P: aeruginosa isolates exist which have /?-lactamases inhibited by tazobactam [12-141. Tazobactam does not significantly enhance the activity of piperacillin against non-/?-lactamase producers such as streptococci and enterococci. The high level of activity of piperacillin alone for these bacteria is maintained in the combination. Our in vitro results are in agreement with those of other North American and European multicenter studies. In a multicenter study in the United States PIP/TZB inhibited 93.5% of 2946 Enterobacteriaceae with MICs of 116 pg/ml [15]. A five-year follow-up of this same study that included 5029 aerobic isolates found that 95.8% of the Enterobacteriaceae were inhibited by 216 pug/ml of PIP/TZB [13]. Two other large-scale multicenter studies both including >40 000 aerobic isolates con-



I 1 I

eluded that PIP/TZB and imipenem were the most active agents with susceptibility rates of ~90% for all isolates tested [12,14]. One of these studies involved an evaluation of 11 /?-lactam antibiotics and reported lower susceptibility rates of 84% for ceftazidime and TIC/CLAV [12]. In a study of 539 Gram-positive and Gram-negative anaerobic isolates from patients, PIP/TZB had a 99% susceptibility rate [16]. In a larger study with anaerobes from 10 geographically separate sites in the United States, the results showed that the addition of tazobactam reduced the resistance rates for piperacillin from 16 and 15% to 0.4 and 0.2% for the years 1990 and 1991, respectively [17]. A multicenter study in Germany showed that 98.1% of 3559 Enterobacteriaceae and 99.8% of 1038 Bacteroides species were inhibited by MICs of 132 ,@ml of PIP/TZB [ 181.The excellent widespectrum in vitro activity of PIPiTZB was also documented in France and England [19,20]. The impressive broad in vitro spectrum of PIP/TZB suggests the consideration of the combined agents for empirical treatment of infections. The combination has been effective treatment in multicenter clinical trials. In North America, Sweden and Finland, investigators reported excellent responses with piperacillin plus tazobactam in patients with intraabdominal infections [21l23]; favorable outcomes were obtained in studies of lower respiratory tract infections in North America and Europe [24,25] and data from a multicenter clinical trial in North America support the use of the combined agents for initial empiric therapy of hospitalized patients with complicated skin and skin structure infections [26]. The extended broad spectrum of in vitro activity and favorable responses in clinical trials support the consid-

N. A. Kuck et al. I International

Journal of Antimicrobial

eration of piperacillin combined with tazobactam for therapy of infections, particularly when mixed flora may be present.

Acknowledgements The authors are grateful to L.F. Campione for processing the data and his assistance in the preparation of tables used in this paper. Part of this work was presented in a poster session at the 94th General Meeting of the American Society for Microbiology (Abstract No. 133) Las Vegas, Nevada, 23-21, May, 1994.

References [II Arnoff SC, Jacobs MR, Johenning SC, Yamabe S. Comparative activities of the /I-lactamase inhibitors YTR-830, sodium clavulanate and sulbactam combined with amoxacillin or ampicillin. Antimicrob Agents Chemother 1984;26:[email protected] [21Jacobs MR. Arnoff SC, Johenning S, Shlaes DM. Yamaba S. Comparative activities of the ,fI-lactamases inhibitors YTR-830, clavulanate. and sulbactam combined with ampicillin and broadspectrum penicillins against defined B-lactamase-producing aerobic gram-negative bacilli. Antimicrob Agents Chemother 1986; 29:980-985. [31 Bush K, Macalintal C, Rasmussen BA, Lee VJ, Yang Y. Kinetic interactions of tazobactam with/%lactamases from all major structural classes. Antimicrob Agents Chemother 1993;37:851-858. [41 Appelbaum PC, Jacobs MR, Spangler SK, Yamobe S. Comparative activity of p-lactamase inhibitor YTR-830. clavulanate and sulbactam combined with B-lactams against /_I-lactamase producing anaerobes. Antimicrob Agents Chemother 1986;30:789-791. [51 Fass RJ, Prior RB. Comparative in vitro activities of piperacillin/ tazobactam and ticarcillin/clavulanate. Antimicrob Agents Chemother 1989;33:1268-1274. PI Kuck NA, Jacobus NV. Petersen PJ, Weiss WJ, Testa RT. Comparative in vitro and in vivo activities of piperacillin combined with /%lactamase inhibitors tazobactam. clavulanic acid and sulbactam. Antimicrob Agents Chemother 1989;33:196&1969. [7] D’Amato RF. Bottone FJ, Amsterdam D. Substrate profile systems for the identification of bacteria and yeasts by rapid and automated approaches. In: Balows A. Hausler WJ, Hermmann KL, Isenberg HD, Shadomy HJ (eds) Manual of Clinical Microbiology. American Society for Microbiology, Washington, DC, 1991, pp. 1288136. [8] Sutter VL. Citron DM, Edelstein MAC, Finegold SM. Wadsworth Anaerobic Bacteriology Manual, 4th ed. Star Publishing Co., Belmont. CA, 1985. [9] National Committee for Clinical Laboratory Standards (NCCLS). Methods for Antibacterial Susceptibility Testing of Anaerobic Bacteria, 3rd ed. M-l l-A2. Villanova, PA, 1993. [lo] National Committee for Clinical Laboratory Standards (NCCLS). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 3rd ed. M7-A2. Villanova, PA, 1993. [l I] Jacobus NV, Labthavikul P, Spengler MD, Bradford PA, Bush K, Testa RT. Characterization of /J-lactamases in three collections of E. coli and K. pneumoniae as related to susceptibility to Piperacillin/Tazobactam and other extended spectrum /I-lactams. 95th General Meeting of the American Society for Microbiology. Abstract A73. Washington, DC, 1995.


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