Cefoperazone plus mezlocillin for empiric therapy of febrile cancer patients

Cefoperazone Plus Mezlocillin for Empiric Therapy of Febrile Cancer Patients PAULAJONES,M.D., GERALDP. BODEY.M.D.. KENNETH ROLSTON. M.D., VICTOR FAINSTEIN, M.D., SUSAN RICCARDI,

R.N. Houston, Texas

Two dosing regimens of cefoperazone plus mezlocillin were compared in a prospective, randomized trial for therapy of febrile cancer patients. The two regimens were 5 g mezlocillin plus 2 g cefoperazone intravenously every four hours (higher dose) or 3 g mezlocillin plus 1 g cefoperazone intravenously every four hours (lower dose). Although the overall response rate was higher with the higher dose regimen (78 percent versus 66 percent, p = 0.041, the two regimens were comparable in patients with documented infections (72 percent versus 68 percent). Likewise, the two regimens were equally effective against those infections in which the pathogen could be determined (82 percent versus 82 percent). Serum bactericidal titers of at least 1:32 against a known pathogen were associated with a higher response rate than were titers of less than 1:32, but the higher dose regimen did not result in higher serum bactericidal titers. Hypoprothrombinemia was a side effect, especially with the higher dose regimen, before prophylactic vitamin K was routinely administered to patients. Since there were no major benefits with the use of the higher dose regimen of mezlocillin plus cefoperazone, the lower dose regimen is more appropriate for routine usage.

nfection remains the leading cause of death in both Iingneutropenic and non-neutropenic patients undergotreatment for cancer 111. A variety of infections caused by gram-positive and gram-negative bacterial organisms can occur in these patients. Empiric antibiotic therapy is often started before the pathogen is determined when fever develops in patients with cancer. Frequently, a combination of antibiotics is used in order to provide broad-spectrum antibacterial coverage. In the past, the combination of a beta-la&m antibiotic and an aminoglycoside was often used as initial antibacterial therapy [2,3]. Recently, combinations of two broad-spectrum beta-lactams have been investigated for the treatment of febrile cancer patients, including those with neutropenia [4,5]. There has been an effort to replace aminoglycosides with broad-spectrum beta-lactam antibiotics because of the potential nephrotoxicity of the aminoglycosides, especially with the increasing use of nephrotoxic antitumor agents. This study was designed to examine the efficacy of a combination of two newer beta&tams that had not been studied together previously in patients with cancer. Cefoperazone is a third-generation cephalosporin with activity against most gram-negative bacilli, including many isolates of Pseudomonas aeruginosa [6]. This antipseudomonal activity led to interest in using cefoperazone empirically in patients with tumors. Although it has less bactericidal activity against grampositive bacilli in vitro than first-generation cephalosporins, cefoperazone was shown to be effective in the treatment of staphylococcal infections at this institution 171. Mezlocillin is a ureidopenicillin with activity against isolates of P. aeruginosa and other gramnegative bacilli [83. Two dosing regimens of cefoperazone plus mezlocillin were compared in this prospective, randomized study. We were especially interested in the efficacy of the higher dose regimen against pneumonias, since these infections frequently fail to respond to treatment in this patient population. Presumably, higher doses would result in higher antibiotic concentrations at the site of infection, which might prove to be advantageous.

MATERIALSAND METHODS

From the Section of Infectious Diseases, Department of Medical Specialties, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Requests for reprints should be addressed to Dr. Gerald P. Bodey, Department of Medical Specialties (Box 47), M.D. Anderson Hospital, 1515 Holcombe Boulevard, Houston, Texas 77030.

Hospitalized patients with cancer (neutropenic and non-neutropenic) were considered to be eligible for this study if a temperature of at least 1Ol’F (38.3%) developed that persisted for more than two hours and was presumed or proved to be due to infection. Patients with proven infection (pneumonia, cellulitis) who were not febrile were also eligible. Only those patients with a fever that was seriously considered to be due to infection and, in the assessment of the physician, required prompt antibiotic therapy were eligible; patients with prolonged fevers of unknown origin July 25, 1988

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SYMPOSIUM

ON CEFOPERAZONE / JONES ET AL

TABLE I Malignancies of Study Patients Diagnosis

Higher Dose

Lower Dose

4”;

ii

:; 13

:: 12

i 4

1:

Breast cancer Lung cancer Leukemia Lymphoma Sarcoma Head/neck cancer GI cancer GU cancer Myeloma Other

: A

6

= gastrointestinal; GU = genitourinary.

were excluded. Patients were also excluded for the following reasons: history of a previous immediate hypersensitivity reaction to a penicillin or cephalosporin, age less than 15 years, pregnancy, creatinine level of more than 3.0 mg/dl, and prior treatment with systemic antibiotics for the same clinical episode, unless previous therapy was shown to be ineffective against a documented pathogen and the regimen utilized did not include broad-spectrum penicillins or cephalosporins. Patients were randomly assigned to receive one of two dosing regimens of cefoperazone plus mezlocillin: 1 g of cefoperazone plus 3 g of mezlocillin intravenously every four hours (lower dose) or 2 g of cefoperazone plus 5 g of mezlocillin intravenously every four hours (higher dose). Cefoperazone and mezlocillin were mixed together in 250 ml of normal saline or 5 percent glucose solution and administered over a twohour period. Prior studies showed the two antibiotics to be compatible in solution (unpublished observations). All patients with proven infections were treated for a minimum of seven days, or four days after becoming afebrile and with all signs of infection resolvedwhichever was longer, unless untoward reactions, death, or clinical deterioration occurred. Treatment was discontinued and other appropriate antibiotics were instituted after three days in patients with proven infections who had no response to therapy; nonresponse was defined as continuing fever without improvement at the site of the infection, such as increasing pulmonary infiltrates, shock, or persistently positive results from blood culture specimens. Therapy was altered sooner if the organism was determined to be resistant in vitro to both antibiotics and the patient’s clinical condition was rapidly worsening. Patients who received less than 12 hours of antibiotic therapy were not included in this evaluation. Blood, throat, urine, and other appropriate culture specimens were obtained prior to starting the antibiotic treatment. The following laboratory tests were also obtained at the start of therapy: blood cell count with white blood cell differential count, platelet count, electrolyte levels, blood urea nitrogen levels, creatinine levels, liver function tests, prothrombin time, partial thromboplastin time, chest roentgenographic examination, and urinalysis. Blood culture specimens were obtained daily as long as a temperature of at least 101°F persisted. Other cultures were repeated twice weekly in persistently febrile patients. Blood and urine tests performed at the start of therapy were repeated twice weekly dur4

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ing the study. Follow-up culture specimens from documented sites of infections were obtained within 24 hours of the completion of therapy. Blood and urine tests were also repeated. Serum was collected on Day 3 or 4 for testing of bactericidal activity against known pathogens. Schlicter and MacLean’s [9] method was adapted to a microtiter system using Mueller-Hinton broth as the diluent. The evaluation of response to therapy was assessed by an investigator who was not involved in the care of the patients and was blinded regarding the regimen administered. Episodes during which no clinical, radiographic, or bacteriologic evidences of infection were found were called fevers of unknown origin. Response was defined as disappearance of all clinical and laboratory evidence of infection when the antibiotic treatments were discontinued. Relapse was defined as the same infection reappearing within seven days after the discontinuation of therapy. Those patients who died of malignant disease or of other noninfectious causes were considered to have had a response if the original infection had resolved and no evidence of infection was present at postmortem examination. Super-infection was defined as infection caused by a different organism (except oral moniliasis) that occurred during treatment or that was found at autopsy examination. For ease of presentation, the terms episodes and patients will be used interchangeably, although some patients actually experienced more than one episode of infection. Differences between means were examined using the Student t test. Univariate analysis of differences between proportions were computed using two-sided chi-square tests. Data were analyzed using the Statistical Package for the Social Sciences, Version 9.

RESULTS There were 333 cases entered into the study. Forty cases could not be evaluated for the following reasons: documented drug or tumor fever and no infection (15 cases), protocol violation (12 cases), inadequate trial of antibiotics (eight cases), or documented viral or fungal infection (five cases). The inevaluable cases were equally distributed between the higher dose and lower dose regimens (28 versus 18). Thus, there were 293 evaluable febrile episodes in 261 patients. Some patients were entered in the study more than once with completely separate episodes of suspected infection. There were 112 men and 149 women. The median age was 52 years, with a range of 16 to 78 years. There was a similar distribution of malignant diseases among the patients in each of the two study groups (Table I). The most common malignancies were breast and lung carcinomas, which together comprised 52 percent of the total group. There were 36 patients with leukemia in the study (27 with acute leukemia) and 25 patients with lymphomas. The overall response rates for the 293 evaluable febrile episodes were 78 percent for the higher dose regimen and 66 percent for the lower dose regimen (p = 0.04). The cause of fever could not be determined during 145 episodes (49 percent of total episodes). The higher dose regimen produced a higher response rate than the lower dose regimen for the treatment of these episodes (83 percent versus 64 percent, p = 0.02). There were 148 episodes of documented infection.

SYWOSlUM

ON CEFOPERAZONE / JONES ET Al.

TABLE II Response to Therapy Higher Dose Infection

Episodes

Lower Dose % Response

Episodes

% Rssponse

Total episodes

FUOS Documented infection Pathogen determined Pathogen not determined JOs = feven of unknown origin. I = 0.07. ) = 0.006.

TABLE Ill Response According to Site of Infection Higher Dose Site of Infection

Episodes

LowerDose % Response

Pneumonia

X Response

48

93

?P &in&y tract Sofi tissue &a-abdominal Other

Episodes

Ii

1: 0

YT = ear, nose, and throat infections.

The efficacy of the higher dose and lower dose regimens was similar for the treatment of documented infections, with response rates of 72 percent and 68 percent, respectively (Table II). There were four relapses with the higher dose regimen and five relapses with the lower dose regimen. Bacterial pathogens could be determined during 95 episodes of infection (64 percent of the total infections). The response rates were higher for infections in which pathogens were determined than for infections in which the pathogens could not be determined. This was true for infections treated with the higher dose or lower dose regimen. Both regimens were equally effective against those infections in which the infecting organism could be determined. However, the higher dose regimen was more effective agamst infections in which the infecting organism could not be determined (58 percent versus 37 percent, p = 0.22). The most common site of infection was the lung (42 percent of the total documented infections). The higher dose and lower dose regimens were equally effective in the treatment of pneumonias and the response rates were only 48 percent and 45 percent, respectively (‘able III). This response rate in pneumonias in neutropenic patients is consistent with results reported in other studies. In contrast, both regimens were more effective against the 36 episodes of septicemia, with response rates of 93 percent and 86 percent, respectively. The two regimens also had similar efficacy against ear, nose, and throat; urinary tract; softtissue; and intra-abdominal infections. There were three miscellaneous infections, including one episode of bronchitis and two episodes of empyema. There were 34 documented infections due to a single gram-positive pathogen (Table IV). The higher dose regimen was more effective than the lower dose regi-

men, but the difference wm not statistically significant (94 percent versus ‘78 percent, p = 0.41). There were 49 documented infections due to a single gramnegative pathogen. Only 15 were assigned to treatment with the higher dose regimen, whereas 34 were treated with the lower dose regimen. The higher dose regimen offered no advantage over the lower dose regimen against gram-negative infections (6’7 percent versus 88 percent response rates). Escherichia coli and P. CMPY&YMMZwere the most common gramnegative pathogens, but the numbers were tdo small to permit meaningful comparisons. The higher dose and lower dose regimens were equally effective against polymicrobial infections. Responses were correlated with the initial neutrophi1 count and with the trend in neutrophil count during therapy for documented infections (Table V). Sequential blood cell counts were not available for one patient. Neutropenic patients were equally represented in the two study groups at the start of therapy. There was no correlation between initial neutrophil count and response to either regimen, and both regimens were equally effective. With both regimens, patients with neutrophil counts that increased during therapy had higher response rates than did patients with neutrophil counts that decreased or remained unchanged (p = 0.04). Serum bactericidal titers were performed against isolated pathogens for 20 infections treated with the higher dose regimen and 36 infections treated with the lower dose regimen. Some patients refused to have blood drawn for the test. Surprisingly, the distribution of serum bactericidal titers did not correlate with the dosage regimen, even taking into account the minimal inhibitory concentration of the antibiotics against the infecting organisms. However, the serum bacteriJuly 25,

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SYMPOSIUMON CEFOPERAZONE I JONESET AL TABLE IV Response Related to Infecting Organism Higher Dose Organisms

Lower Dose

Episodes

% Response

Episodes

16

Totjl~gamitiies

% Response

18 ii

S epkiermdis .S$kXCCCUS

:“6

;

SP.

To;lgran.negatives

;

100

41

100 K

61

Fl

154

2

14 34

88

3

61

:

ii 50

:

lOi

:

50 61

: 7

ii 86

1

86

5

60

Pseudomonassp. K/ebsi& sp. .Mefobecfer sp. HemcpMs sp. Other Poiymicrobial

TABLE V Response Related to tieutrophil

Counts for Documented Infections LowerDose

Higher Dose

Neutrophil Count/mm3

Trend

< loo

Number

K Response

Number

X Response

Total

8

1:

8

75

;sd

:

86

:

860

lOl-l,Lw

Total Decreased Increased

> 1,octl

Total Decreased U&WJ

Total Total

Decreased Increased

40 78

TABLE Vl Peak Serum Bactericidal Titers Related to Response Rates Higher Dose Ractericidal Titer

Episodes

Undiluted 1:2-1:16 192-1:1,024

LowerDose

X Response

Total % Response

Epib

6

8

86

1;

Epiuxks

% Response

TABLE VII Response Related to in Y&o Susceptibility

/ HigM Dose

Mezlocillin

Cefoperazone

:

i s

! = sensitii;

6

R

Number

23 2 A

Lower Dose

%Rwponre

50 91 -

0

R = resistant.

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Number

40 8 t

Total

% Response

83 75 tE

Number

% Response

10 63

86

2

ii 100

1

SYMPOSIUM

tidal titers did correlate with response to the antibiotic regimens (Table VI). Twenty-seven patients had peak serum bactericidal titers of 1:32 or greater against their infecting organism and all of these patients had responded to treatment. Among the 14 patients with sera that were bactericidal only when undiluted, the response was only 57 percent. The pathogens causing these 14 infections included Staphylococcus aureus (seven isolates), P. aeruginosa (four isolates), and one isolate each of Pseudomonas sp., Haemqhilus parainfuenzae, and Campylobacter sp. Trough serum bactericidal activities were also examined and the results were similar (data not shown). In vitro susceptibility testing was performed against infecting organisms (Table VII). Organisms were considered to be sensitive if the minimum inhibitory concentration for cefoperazone was no more than 12.5 pg/ml and for mezlocillin was no more than 50 pg/ml. Among the 76 organisms tested, 96 percent were susceptible in vitro to mezlocillin, and 86 percent were susceptible to cefoperazone. The response rate was higher if the infecting organism was susceptible to both antibiotics than if it was susceptible to only one (86 percent versus 67 percent, respectively). Three organisms were resistant to both antibiotics, yet the patients with all three infections had responses. One infection was a streptococcal perirectal abscess, one a Staphylococcus epidermidis bacteremia (catheterrelated), and one a Campylobacter bacteremia. The higher dose regimen offered no advantages over the lower dose regimen against sensitive or resistant pathogens. Toxicity was associated with 33 percent of the episodes treated with higher dose and with 31 percent of the episodes treated with lower dose therapy. The most common toxicity was diarrhea, which occurred in 19 percent of the higher dose treatment episodes and 21 percent of the lower dose treatment episodes. Hypoprothrombinemia occurred in 13 percent of the total group of study patients. During the early phases of the study, patients were not given vitamin K routinely. Hypoprothrombinemia was detected in 15 (28 percent) of the first 53 patients receiving the higher dose regimen. Three of these patients experienced nonfatal hemorrhagic episodes. Subsequently, 72 patients receiving the higher dose regimen were randomly assigned to receive a single oral lo-mg dose of menadione or 10 mg of menadione orally every other day during antibiotic therapy. Hypoprothrombinemia developed in one of the 34 patients (3 percent) who received single-dose menadione and in three of 38 patients (8 percent) who received multiple-dose menadione. In none of the four patients with hypoprothrombinemia did hemorrhagic complications develop. Hypoprothrombinemia was detected in 15 percent of the 130 patients receiving the lower dose regimen who did not receive vitamin K prophylaxis. In none of these patients did hemorrhagic complications develop. There were only two superinfections in the study. An episode of urinary tract infection due to a Citrobacter sp. occurred in a patient receiving higher dose therapy and an episode of folliculitis due to S. aureus occurred in a patient receiving lower dose therapy. COMMENTS A number of beta-la&am

antibiotics

with broad-

ON CEFOPERAZONE I JONES ET AL

spectrum activity against gram-negative bacilli have been introduced into clinical practice recently [lO,ll]. Several recent studies have shown double beta-la&am combinations to be as effective as the combination of a beta-lactam plus an aminoglycoside in the treatment of febrile oncologic patients [4,5]. For example, moxala&am plus ticarcillin was as effective as moxalactam plus tobramycin in the treatment of febrile neutropenic cancer patients at this institution [4]. Similarly, Winston et al [5] reported that moxalactam plus piperacillin was as effective as moxalactam plus amikacin in the empiric treatment of febrile cancer patients. There are many reasonable combinations of antibiotics that can be used empirically in patients with tumors. Because broad-spectrum coverage can be readily achieved with a number of regimens, it is difficult to demonstrate superiority of one regimen over another. In addition, a variety of dosing schedules have been used when treating patients with tumors, including those with severe neutropenia. There have been few recent clinical studies that compare dosing schedules used in these patients. This study was designed to compare the efficacies of two dosing regimens of mezlocillin plus cefoperazone. The higher dose regimen was chosen in an attempt to improve the response rates for difficult infections, particularly pneumonias. It was postulated that higher doses would result in higher tissue concentrations, resulting in greater efficacy. The most striking difference in response rates between the two regimens was with fever of unknown cause. This finding suggests that many of these episodes of fever represented bacterial infections that could not be. detected, such as super-infected necrotic tumors. Unfortunately, the higher dose regimen did not improve the response rate of pneumonias, which were the infections least responsive to either regimen. The results suggest that achieving a serum bactericidal titer of 1:32 or better may be correlated with a better response to therapy. Unfortunately, bactericidal titers could not be determined in all patients, due to lack of patient cooperation. It is difficult to explain why the serum bactericidal titers were similar with the two dosing regimens, rather than higher with the higher dose regimen. The higher dose regimen was not associated with more bacterial superinfections and there were no fungal superinfections in the study: Previous studies have suggested that the use of multiple antibiotics promotes superinfections by suppressing the normal endogenous flora of the host 1121. The two antibiotics used in this study are both excreted in the bile, leading to high concentrations of drug in the bowel with marked changes in stool flora [13]. Despite these changes, there were almost no superinfections in this large study. Hypoprothrombinemia was the most significant side effect encountered and occurred more frequently in the group receiving the higher dose regimen. At the start of this study, the incidence of hypoprothrombinemia with cefoperazone treatment was not known. When this toxicity was documented (after approximately 50 patients had been entered in the study), all subsequently treated patients assigned to the higher dose regimen were given prophylactic vitamin K. This experience has been reported elsewhere 1141. The mechanism of this coagulopathy is not well underJuly 25, 1988

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SYMFOSIUMON WOPEMUONE /JONES ET Al

stood, but can usually be prevented with the administration of prophylactic vitamin K [16-1’71. The results of this study do not support the routine use of the higher dose regimen for patients with cancer who have presumed or proven infection. Although the overall results with the higher dose regimen were better than with the lower dose regimen, this advantage was observed only among patients with fevers of unknown origin and infections in which the infecting pathogen could not be determined. The higher dose regimen was not more effective against documented infections, including pneumonias, in which the problem of drug penetration has been assumed to be a major factor in the poor response rate. Furthermore, the higher dose regimen was more expensive and was associated with a higher frequency of hypoprothrombinemia.

REFERENCES 1. lnagaki J, Rodriguez V, 8odey GP: Causes of death in cancer patients Cancer 1974; 33: 568-573. 2 deJongh CA, Wade JC, Schiipff SC, et a/: Empiric antibiotic therapy for suspected infection in granubcytopenic center patie& a comparison between the combinatfon of moxalactam pkrs amtkacin and ticarcillin plw amikacln. Am J Med 1982; 3: 89-96. S. Wtnston DJ. Ho WG. Young LS. Hmitt WL. Gale R Pberacillin t&s am&in therapy v carbeniciflin plus amikacii therapy in febrile. granubcytopenic p&rts. Arch Intern Med 1982; 42: 1663-1667.

4. Fainstein V, 8odey GP, 8ofivar R, EMng L, McCredie K8, Keahng MJ: Mosalactam plus ttcarcillin or tobramycin In ths treatment of febnk episodes in granulocytopenic cancer petients. Arch Intern Med 198); 144: 1766-1770. 5. Wtnston DJ, 8ames RC, Ho WG, Young LS, Champtin RE, Gate RF? Moxelactam plus piperacillin Versus moxalactam plus amikacin in febrile granubcytopenic patiints Am J Med 1984; n: 442-450. 6. HinkN AM, LeElane EM, 8odey GP: In tifro evakration of cefoperazone. Antiicrob Agents Chemother 1980; 17: 423-427. 7.8olii R. Fainstein V, 6odey Gf? Cefoperazone for ths treatment of infections in pa tiants with cancer. Rev Infect Dis 1983; 55181-SW. 8. 8odey GP, Pan T: Mezlociltin: in Wo studies of a new broadepactrum penicillii. Antimtcrob Agents Chemother 1977; 11: 74-79. 9. Schlichter JG, MecLean H: A method of determining the effective therapeutic level in the treatment of subacute bacterial endocardiiis with penicillin: a prelirnkrary report. Am Heart J 1947; 34: 209-211. 10. Eliopoulos GM, Moeltering RC Jr: Mocillin, mezlocillin, and piperacillin: new broad specttm pericilllns. Ann Intern Med 1982; 97: 755-760. 11. Neu HC Ths new &lactamase-stable cephelosportns. Ann Intern Med 1982; 97: 408419. 12 Sen P, Kapila R, Chmel H, et a/: Superinfection: another look. Am J Med 1982; 73: 706-718. 13. Carlberg H, Alestig K Nord CE. et a/: Intestinal side effects of cefoperazone. J Antimicrob f&smother 1982; 10: 483-487. 14. Jones PG, Strother SV, Rokton KVl, et a/: HypoprothromMnemia in cancer patients receiving cefoperazone and mezlocillin. Arch Intern Med 19W, 146: 1397-1399. 15. Coniy JM, Ramotar K, Chubb H, et a/: Hypoprothrombinemia in febrile, neutmpenic patients with cancel: associahion with antimicrobttl wppressbn of intestinal mtcrofloa. J Infect Dis 1984, 150: 202-212. 16. Fainstein V, 8odey GP, McCredie K8. et aI: Coagulation abnonnaliiies induced by 5lactam antibiotics in cancer oatients. J Infect Dii 1983: 148: 745-750. i7. Osborne JC: HypoprothrombMemia and bleeding due to cefopr.mone. Ann Intern Med 1985; 102: 721-722.

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