Journal of Chemotherapy

ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20

Piperacillin/Tazobactam Plus Gentamicin as Empirical Therapy for Febrile Neutropenic Patients with Haematological Malignancy S.M. Kelsey, B. Weinhardt, C.E. Pocock, E. Shaw & A.C. Newland To cite this article: S.M. Kelsey, B. Weinhardt, C.E. Pocock, E. Shaw & A.C. Newland (1992) Piperacillin/Tazobactam Plus Gentamicin as Empirical Therapy for Febrile Neutropenic Patients with Haematological Malignancy, Journal of Chemotherapy, 4:5, 281-285, DOI: 10.1080/1120009X.1992.11739178 To link to this article: https://doi.org/10.1080/1120009X.1992.11739178

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Journal of Chemotherapy

Piperacillin/Tazobactam Plus Gentamicin as Empirical Therapy for Febrile Neutropenic Patients with Haematological Malignancy S.M. KELSEY * - B. WEINHARDT ** C.E. POCOCK * - E. SHAW ** A.C. NEWLAND*

Summary - - - - - - - - - - - - - - - The efficacy of piperacillin/tazobactam (PIPC/TBT) in combination with gentamicin was assessed as empirical therapy in 44 febrile neutropenic patients with haematological malignancy. A favourable response to therapy was seen in 67% patients overall and in 57% of patients with microbiologically documented infection. PIPC/TBT demonstrated good clinical and in vitro activity against isolated pathogens, particularly Gram positive cocci such as Staphylococcus epidermidis. The MIC of both Gram positive and Gram negative pathogens to PIPC was reduced in the presence of TBT. PIPC/TBT plus gentamicin is a safe and effective combination for empirical therapy in febrile neutropenic patients, even in a unit with a predominance of Gram positive infections. Key words: Piperacillin/tazobactam, neutropenia.

Departments of * Haematology and ** Microbiology, The Royal London Hospital and London Hospital Medical College, Whitechapel, London El lBB , UK. Correspondence to: Dr SM Kelsey, Department of Haematology, The Royal London Hospital, London El lBB, UK. © Edizioni Ri viste Scientifiche - Firenze

Vol. 4 - n. 5 (281-285) - 1992

INTRODUCTION

A combination of an aminoglycoside with a ureidopenicillin, such as gentamicin plus piperacillin (PIPC), has provided an effective empiric antibiotic regimen for fever in neutropenic patients 1 • However, as the incidence of Gram positive infections in our unit has increased so the efficacy of this regimen has reduced. Recently, in a series with a high incidence of Gram positive pathogens (78%), the response to gentamicin plus piperacillin was poor with only 29% of documented infections resolving after three days of therapy 2 • Many Gram positive organisms exhibit resistance to both agents and a glycopeptide antibiotic, such as vancomycin or teicoplanin, may be required for their eradication. Tazobactam (TBT) is a substituted penicillin sulphone which inhibits a wide variety of betalactamases . It synergises with PIPC to increase the activity of this antibiotic against a number of Gram negative pathogens 3 • In addition, the combination of piperacillin with tazobactam (PIPC/TBT) has excellent activity against Gram positive organisms, including Staphylococcus epi-

dermidis 4 • We therefore undertook an open, single centre, non-randomised study of the clinical and in vitro efficacy of PIPC/TBT (Lederle, UK) in combination with gentamicin for the empiric treatment of infection in neutropenic patients receiving chemotherapy or bone marrow transplantation for haematological malignancy . PATIENTS AND METHODS

Forty-four neutropenic patients rece1vmg chemotherapy or bone marrow transplantation ISSN 1120-009X

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S.M . KELSEY - B. WEINHARDT - C.E. POCOCK - E. SHAW - A.C. NEWLAND

for haematological malignancy were entered into the study between January and September 1990. All patients were febrile as defined by a single temperature of 38.5° C or two consecutive readings of 38.0° C two hours apart not associated with administration of blood products. Neutropenia was defined as a total neutrophil count of less than 1.0 x 10 9/l. All patients gave informed consent for inclusion in the study, and the study protocol was approved by the local Ethics committee. Pregnant or nursing women, patients with a history of allergy to trial antibiotics, and patients who had received antibiotics within the preceding five days, other than gut decontamination, were excluded from the study. Eligible patients received an intravenous antibiotic combination of gentamicin plus PIPC/TBT. A 120 mg loading dose of gentamicin was followed by 80 mg 8 hourly to achieve pre-dose troughs of < 2 mg/ml and peaks of > 5 mg/ml. PIPC/TBT was administered as 4 g/500 mg 6 hourly as a 50 ml infusion over 30 minutes. All patients received gut decontamination with colistin 1.5 Mu 12 hourly plus cotrimoxazole 960mg 12 hourly and this was continued throughout study therapy . A full blood count, biochemical profile and chest X ray were performed at entry to the trial; microbiological analysis was performed on peripheral vein and Hickman line-derived blood, urine, throat swab and any other appropriate specimens. Antibiotics were continued until patients had been apyrexial for at least three full days. Empirical therapy was deemed to have failed if antibiotics had to be modified at evaluation, including the addition of intravenous amphotericin B. Modification was performed if: a) a pathogen was isolated which was resistant to both study antibiotics; b) deterioration in the patients' clinical state before 72 hours was thought to be due to bacterial infection; c) no significant clinical improvement was seen at 72 hours; d) study drugs were withdrawn due to toxicity or severe adverse reaction. Clinical resolution of febrile episode was defined as disappearance of all signs and symptoms related to the infection. Improvement was defined as a marked reduction in the symptoms and signs of infection without resolution, or temporary (but complete) resolutiqn (for > 48 hours) with subsequent relapse. Patients violat-

ing study protocol were evaluated for toxicity only. Febrile episodes were classified as microbiologically documented, clinically documented or pyrexia of unknown origin (PUO) s. Microbiologically documented infections were evaluated as indeterminate if follow up cultures could not be performed. Superinfections were defined as the presence of a new organism during or at the end of therapy judged to be causing an infectious process. All bacterial pathogens were tested for in vitro susceptibility to both PIPC and PIPC/TBT by the NCCLS disc diffusion susceptibility procedure 6 • Minimum inhibitory concentrations (MICs) were determined by the Agar Dilution method. Doubling dilutions of PIPC were prepared in phosphate buffer to provide a final concentration in agar over the range 0.03 to 1024 mg/1. TBT was used at a constant concentration of 8 mg/ml. Strains to be tested were cultured in nutrient broth overnight. Cultures were then diluted in Isosensitest broth to provide a final inoculum of 10 s CFU/ml. After inoculation of plates and overnight culture MIC was determined as the lowest concentration of antibiotic inhibiting > 90% of original inoculum. RESULTS

Forty-four patients were entered into the study of which 43 (98%) were evaluable for efficacy; one patient was not neutropenic at entry. Twenty-nine males and 15 females were entered with a mean age of 39 years (range 1573) (Table 1). Mean duration of study drug therapy for all patients was 6.5 ( + - 3) days. There were 23 microbiologically documented infections, three clinically documented infections and 17 PUO's. Documented infections

TABLE

1 - Presenting diagnoses of patients at entry to study.

Acute myeloid leukaemia (AML) Acute lymphoblastic leukaemia (ALL) Post-bone marrow transplant (BMT) High grade non-Hodgkins lymphoma Hodgkins disease Transforming chronic granulocytic leukaemia

25 4

Total

44

4 6 3 2

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PIPERACILLIN/TAZOBACTAM PLUS GENTAMICIN AS EMPIRICAL THERAPY, ETC.

were predominantly bacteraemias although there was one primary chest infection, two Hickman line entry site infections, one cellulitis of the upper leg and one mouth abscess. Overall a favourable response to study therapy was seen in 29 patients (67%). 22 (51%) episodes resolved completely, 7 (16%) showed significant improvement and 14 episodes (33%) failed to respond. Resolution coincided with regeneration of peripheral blood neutrophils ( > 0.5 x 10 9/1) in ten cases. 27 bacterial pathogens were isolated from 23 microbiologically documented infective episodes (19 (70%) Gram positive pathogens and 8 (30%) Gram negative). 57% of microbiologically documented episodes had a favourable outcome on study therapy, with 8/23 (35%) resolving and 5/23 (22%) significantly improving (Table 2). In 18 episodes (78%) the primary infecting pathogen was eradicated and in only one case (4%), a Staphylococcus epidennidis bacteraemia, was persistence of the primary pathogen documented. Eight of 18 patients (44%) with a Gram positive pathogen resolved on study therapy and a further 4 (22%) improved. In vitro disc sensitivities and minimum inhibitory concentrations (MICs) were studied in 24 of 27 bacterial pathogens (Table 3). 15 of 24 pathogens (63%) were sensitive by disc testing to PIPC and 22 (92%) were sensitive to

TABLE 2 - Isolated pathogens and clinical and microbiological response for all microbiologically doc11mented febrile episodes. Isolate

Staph. epidermidi.l Staph. a11re11s Alpha haemolytic Strep.

Strep. mitis Enterococc11s spp. Staph. epidermidis + Corynebacteri11m Staph. epidermidis + Klebsiella sp. Staph. epidermidis + Klebsiella sp. + Acinetobacter sp. Ps. aernginosa Other Pse11domonas spp.

Esch. coli Total (% )

Erad Persist

Ind

Res

Imp

Fail

3 1 1

2 0 0

4 0 1

6 1 2

1 0 0

2 0 0

1 0 0

0 0 0

2 1 1

0 0 0

0 0 0

0

0

0

0

3 0

0 0

0 1

0

0

0

0

0

0

0 0

1 0

0

0

2 1

4 10 18 1 8 5 (35%) (22 % ) (43 % ) (78 % ) (4 % ) (17 % )

TABLE 3 - Disc sensitivities and MICs to both PIPC and

PIPC/TBT. Disc sensitivities

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Staph. Staph. Staph. Staph. Staph. Staph. Staph. Staph. Staph. Staph. Staph. Strep. Strep.

epidermidis epidermidis epidermidis epidermidis epidermidis epidermidis epidermidis epidermidis epidermidis epidermidis at1re11s mitis mitis

Alpha haem. Strep. Enterococc11s sp. Corynebacteri11m sp.

Pse11d. aernginosa Pse11d. aernginosa Pse11d. aernginosa Other Pseud. sp.

Klebsiella sp. Klebsiella sp. Esch. coli Acinetobacter sp .

MICS

Pip.

Pip/tazo

Pip.

Pip/tazo

R R R R R

s s s s I s s s s s s s s s s R s s s s s s R s

2 1 4 16 1 0.5 64 1 0.12 0.5 4 0.12 4 0.25

0.5 0.5 0.5 4 0.12 0.03 1 0.12

s s s s

R R

s s s s R s s s s I s R s

8 16 4 4 4 64 2 128 8

O.Q3

0.03 0.25 0.12 0.5 0.12 4 16 4 4 4 2 0.5 2 O.Q3

PIPC/TBT. Of Gram positive pathogens 50% were sensitive to PIPC while 94% were sensitive to PIPC/TBT. All isolates of Staph. epidermidis were sensitive to PIPC/TBT while six of ten (60%) were resistant to PIPC alone. Many isolates, excluding the Pseudomonas species, exhibited a reduction in MIC for PIPC in the presence of TB T. Reasons for failure to respond to study antibiotic therapy, and eventually successful antimicrobial therapy, were documented for the 14 patients in whom a favourable response to treatment was not seen. One patient was withdrawn due to severe adverse drug reaction (acute renal failure). Fever in five patients (36%) resolved when antibacterial therapy was changed whereas in a further eight cases (57%) systemic antifungal therapy was required before resolution of fever was seen. There were two documented fungal superinfections. One patient developed disseminated infection with Trichophyton begleii which was manifest as persistent fever after eradication of the original bacterial pathogen. A further patient developed aspergillus pneumonia after three days of study antibiotics. Drug related

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S.M. KELSEY - B. WEINHARDT - C.E. POCOCK - E. SHAW - A.C. NEWLAND

adverse reactions were seen in four (9%) patients. One patient developed acute renal failure after receiving gentamicin plus PIPC/TBT during an episode of septic shock (systolic blood pressure less than 90mm of mercury) and subsequently died. Three further patients had mild adverse reactions; two showed a rise in serum creatinine from normal to between 150 and 177 Jl.mol/1 and one had an increase in liver transaminases (alanine transaminase and aspartate transaminase) . DISCUSSION

The combination of PIPC/TBT with gentamicin is an attractive combination for empirical therapy in febrile neutropenic patients. As well as established broad spectrum, dual activity against Gram negative organisms it has the added advantage of activity against Gram positive organisms which account for the majority of infecting pathogens in these patients 4 • 7 • We have shown a favourable response to gentamicin plus PIPC/TBT in 67% of febrile episodes overall and in 57% of microbiologically documented infective episodes. This compares favourably with our recently documented poor response to standard PIPC plus gentamicin 2 • It also compares well with the efficacy of newer antibiotic combinations contammg agents with specific anti-Gram positive activity, such as vancomycin 8 and ticarcillin-clavulanate 9 , which have produced favourable responses in 60-77% of febrile episodes. That gentamicin plus PIPC/TBT has clinical activity against Gram positive infection is shown by our finding that 68% of infective episodes from which Gram positive organisms were isolated either resolved or significantly improved on this antibiotic combination. Similarly all but one of these Gram positive pathogens, accounting for 94% of Gram positive isolates overall, were eradicated by this antibiotic combination. One third of patients failed to improve with empirical gentamicin plus PIPC/TBT. Three patients (21%), two with documented Staphylococcus epidermidis bacteraemia and one with PUO, responded to a second line therapy which included vancomycin. Eight of 14 patients (57%) failed to respond due to presumed or documented fungal infection. These data sug-

gest that PIPC/TBT in combination with gentamicin may fail to eradicate the primary bacterial infecting pathogen only in a minority of cases and a high index of suspicion of fungal infection is required in cases of treatment failure. The overall rate of drug-related adverse reactions of 9% in this study compares favourably with that of other empiric antibiotic combinations used in neutropenic patients 9 • 10 • Nevertheless one patient died of acute renal toxicity; substitution of the aminoglycoside for a less nephrotoxic broad spectrum agent such as ciprofloxacin or ceftazidime may be a more attractive option. Previous studies have demonstrated the in vitro efficacy of PIPC/TBT against the spectrum of Gram negative pathogens commonly infecting neutropenic patients 11 ' 12 • 13 • Disc sensitivity testing and MIC analysis confirmed the efficacy of PIPC/TBT against the Gram negative and the more prevalent Gram positive organisms, including Staphylococcus epidermidis, isolated from neutropenic patients in this study. PIPC/TBT, in combination with gentamicin, may therefore provide a safe and effective alternative to the use of glycopeptide antibiotics for the empirical treatment of infection in neutropenic patients. REFERENCES ' Barnes R, Rogers T. An evaluation of empirical antibiotic therapy in febrile neutropenic patients . Br J Haematol 1987; 66, 137-140. 2 Kelsey SM, Weinhardt B, Collins PN, Newland AC . Teicoplanin plus ciprofloxacin versus gentamicin plus piperacillin in the treatment of febrile neutropenic patients . Eur J Clin Microbial Infect Dis 1992; 11 : 509-514. 3 Jacobs MR, Aronoff SC, Johenning S, Yamabe S. Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate and sulbactam combined with extended-spectrum penicillins against ticarcillin- resistant Enterobacteriaceae and pseudomonads . J Antimicrob Chemother 1986; 18: 177-184 . • Jones RN, Pfaller MA, Fuchs PC, Aldridge K, Allen SD, Gerlach EH. Piperacillin/tazobactam (YTR 830) combination. Diag Microbial Infect Dis 1989; 12: 489-494 . ' Pizzo PA, for the Immunocompromised Host Society Consensus Panel. Design, analysis and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. J Infect Dis 1990; 161 : 397-401. ' National Committee for Clinical Laboratory Standards . Performance standards for antimicrobial disc susceptibility tests third edition . Approved Standard NCCLS document M2-A3. NCCLS, Villanova, PA 1984. 7 Fass RJ and Prior RB. Comparative in vitro activities of piperacillin-tazobactam and ticarcillin-clavulanate. Antimicrob Agent Chemother 1989; 33: 1268-1274 .

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8 Smith GM, Leyland MJ, Farrell ID, Geddes AM . A clinical, microbiological and pharmacokinetic study of ciprofloxacin plus vancomycin as initial therapy of febrile episodes in neutropenic patients. J Antimicrob Chemother 1988; 2 1: 647-655. ' Shenep JL, Hughes WT, Roberson PK, et a!. Vancomycin, ticarcillin and amikacin compared with ticarcillin-clavulanate and amikacin in the empirical treatment of febrile neutropenic children with cancer. New EnglJ Med 1988; 319: 1053-1058. 10 DePauw BE, Novakova IRO, Donelly JP. Options and limitations of teicoplanin in febrile granulocytopenic patients.

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