Mezlocillin for Treatment of Infections in Cancer Patients

Transcription

1 ANTIMICROBIAL AGENTs A CHEMOTHERAPY, June 98, p /8/-8/$./ Vol. 7,. Mezlocillin for Treatment of Infections in Cancer Patients BRIAN F. ISSELLt A GERALD P. BODEY* Department ofdevelopmental Therapeutics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Thmor Institute, Houston, Texas 77 Mezlocillin, at a dose of g intravenously over a -h period every h, was used for the treatment of 9 episodes of documented infections in 7 myelosuppressed cancer patients. The response rate in 9 evaluable bacterial infections- was %. Eight of patients with septicemia (%) responded. The response rates for Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli, the three most common gram-negative infections, were,, and 7%, respectively. Mezlocillin was well tolerated; the only toxicity attributable to this antibiotic was a skin rash in one patient. The formation of a false-positive urine protein reaction by mezlocillin was noted. This study demonstrated that mezlocillin administered as a single agent was effective against some infections in myelosuppressed cancer patients. The response rate for Klebsiella sp. infections was especially encouraging. However, because it had limited or little activity against many infections, especially those caused by P. aeruginosa and, the general use of mezlocillin as a single agent for treatment of infections in immunocompromised cancer patients cannot be recommended. Infection, a major cause of morbidity and mortality in cancer patients, is related to the degree and duration of neutropenia (). Thus, patients with hematological malignancies and those receiving intensive chemotherapy are particularly prone to develop infectious complications. The gram-negative bacilli have been shown to be the major cause of infection, accounting for 9% of all etiological organisms in a recent study of 9 consecutive leukemia patients (9). Escherichia coli, Klebsiella sp., and Pseudomonas aeruginosa accounted for 8% of the gram-negative bacillary infections. Before the introduction of semisynthetic antipseudomonal penicillins such as carbenicillin and related compounds, P. aeruginosa had been reported to account for % of fatal septicemias in this patient population (). The introduction of carbenicillin substantially reduced the frequency of Pseudomonas infections at our institution, but this reduction was associated with an increase in fatalities from infections caused by other gram-negative bacilli, most notably E. coli, Klebsiella spp., and Serratia marcescens (9). This increase occurred despite routine usage of the antipseudomonal penicillins in combination with aminoglycosides or cephalosporins. In our experience, the semisynthetic penicillins have been the most effective antibiotics for the treatment of infections caused by susceptible organisms in neutropenic patients (8, ). Although the aminoglycosides provide a broader t Present address: Bristol Laboratories, Syracuse, NY. 8 spectrum of activity against gram-negative bacilli in vitro, less than % of infections caused by susceptible organisms, occurring in severely neutropenic patients (< neutrophils per mm), have responded to intermittent schedules of these antibiotics (, ). Likewise, the administration of cephalosporins by conventional schedules has produced disappointing results in neutropenic patients (, ). It has become the accepted practice to administer a combination of antibiotics as initial therapy when fever, presumed to be due to infection, occurs in neutropenic patients. The most commonly used regimens produced cure rates of to 7% (,,, 8, ). In prospective randomized trials, the results with various antibiotic combinations have been similar (, ). Although some investigators have reported that synergistic combinations of antibiotics produce higher cure rates than nonsynergistic combinations, this has not been our experience (, 7). Our results with carbenicillin and ticarcillin alone against Pseudomonas infections in neutropenic patients have been as good as results obtained with one of these agents plus an aminoglycoside. In a small study comparing single antibiotics with combinations against infections caused by susceptible organisms in neutropenic patients, the results with combinations were only slightly better (). In two randomized trials, the combination of an antipseudomonal penicilin plus a cephalosporin was as effective as the combination of an antipseudomonal penicillin plus an aminoglycoside (, ). An advantage of

2 VOL. 7, 98 MEZLOCILLIN IN CANCER PATIENTS 9 the former combination is the lack of nephrotoxicity, which may occur in to % of patients receiving an aminoglycoside (, ). Mezlocillin is a new semisynthetic penicillin with a broad spectrum of activity against gramnegative bacilli in vitro. At a concentration of pug/ml, this antibiotic inhibited 7% of isolates of Enterobacter spp., S. marcescens, and E. coli, 8% of isolates of Klebsiella spp., and 9% of isolates of P. aeruginosa cultured from the blood of patients at this institution (7). Pharmacological studies indicated that infusion of g of mezlocillin over a -h interval, repeated every h, produced mean peak serum concentrations of over,ug/ml at the end of the infusion and maintained serum concentrations above ug/ml (). Hence, at these doses, mezlocillin provided a spectrum of activity against gram-negative bacilli equivalent to that of carbenicillin (ticarcillin) plus a cephalosporin. Since the majority of infections in neutropenic patients in previous studies had been caused by gram-negative bacilli, a trial of mezlocillin was considered appropriate. This decision was reinforced by a preliminary study in which a number of infections that had failed to respond to antibiotic combinations responded favorably to treatment with mezlocillin. MATERIALS A METHODS This study was conducted in patients with metastatic cancer, including acute and chronic leukemias, solid tumors, and lymphomas, who were receiving chemotherapy and who were admitted to the University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, between October 977 and June 978. All patients were neutropenic (<,/ pl) at the start of therapy or were expected to become neutropenic within a few days of starting therapy. Patients were eligible for study entry if they developed fever of F (ca. 8. C) or greater which was not due to blood product transfusion or the administration of other known pyrogenic agents. Mezlocillin was given intravenously at a dose of g in ml of % dextrose solution over h, repeated every h. All patients who responded to mezlocillin received the antibiotic for at least days after all signs of infection had resolved, provided that the total course had exceeded 7 days. Patients with infections caused by organisms that were resistant to mezlocillin in vitro (minimum inhibitory concentration [MIC] > yig/ml) were changed to more appropriate antibiotics when this information became available and were considered to have failed with mezlocillin unless they had already shown a definite response. As a general practice, patients infected by were changed to methicillin as soon as the infecting organism was identified. Mezlocillin was discontinued and other antibiotics were substituted after days in patients with continuing fever but without documented infection, in patients with objective evidence of infection without identification of causative organisms, and in patients with infections caused by organisms susceptible to mezlocillin in vitro but who were not responding, as defined by continuing fever or lack of improvement at sites of infection with persistent positive cultures. Before antibiotic administration, cultures were obtained from the throat, blood, sputum, and other appropriate sites, and chest X-ray examinations and urinalyses were performed. These were repeated as appropriate during and after the course of mezlocillin to determine response. Complete blood counts were obtained at least twice weekly, and an SMA blood chemistry profile was obtained weekly. The MIC of mezlocillin was determined in vitro in Mueller-Hinton broth by a broth dilution technique (), and serum concentrations of mezlocillin were determined by an agar well method using a spore suspension of Bacillus subtilis supplied by Difco Laboratories (). Episodes were considered evaluable for response if definite clinical or radiological evidence of infection in addition to fever was documented, unless it was due to an identified nonbacterial organism. Evaluable episodes, therefore, included documented infections where no organisms were identified and infections caused by identified bacteria. Patients who received less than h of antibiotic therapy were considered inevaluable. Response was defined as the disappearance of all clinical and laboratory evidence of infection at the time the antibiotic was discontinued. An infection was considered to have relapsed if there was a recurrence with the same causative bacteria within 7 days of discontinuing antibiotics. Patients dying of malignant disease or noninfectious causes while receiving the antibiotic, and whose infection had responded before their death, were considered to have responded if no evidence of infection was found at autopsy examination. Superinfection was defined as the presence of an infection with a new organism, at either the same or different sites, which occurred during mezlocillin therapy. RESULTS Characteristics of patients and episodes of infection. There were 9 episodes of documented infection in 9 patients. In 9 episodes (9 patients), the etiological organism could be identified, and in episodes ( patients), no causative organism could be identified despite clinical and radiological evidence of either pneumonia, upper respiratory tract infection, or softtissue infection. The median age of the patients was 7 years (range, to 7 years), and 8% of the patients were male. Most patients had received no prior antibiotics for their infections. Sixty-one percent of the patients had acute or chronic leukemia, % had solid tumors, and 9% had lymphoma. Seven percent of the patients were undergoing either bone marrow transplantation or autologous bone marrow rescue. The most common documented infections were pneumonias (%) and septicemias (%).

3 ISSELL A BODEY Gram-negative bacilli accounted for % of the causative organisms (see listing in Table ). Response. The overall response rate for patients with documented infections was 9%. The response rate for infections in which no etiological bacteria were isolated was slightly higher than for infections where causative bacteria were identified (8% versus %). Forty-seven of the 9 total episodes of documented infection failed to respond to mezlocillin. Forty of these responded upon retreatment with another antibiotic; seven patients failed to respond to further therapy and died of their infections. There were ANTIMICROB. AGENTS CHEMOTHER. no documentable relapses after termination of therapy with mezlocillin. The response rate for the 9 evaluable bacterial infections was % and is detailed according to site of infection, infecting organism, and in vitro susceptibility in Table. The best results were obtained in urinary tract infections, where six of seven patients responded. s and septicemias were the most difficult infections to treat: only of (%) and 8 of (%) patients responded, respectively. The response rates for P. aeruginosa, Klebsiella pneumoniae, and E. coli, the three most common gram-neg- TABLE. Response to mezlocillin according to infection, organism, and in vitro susceptibility (MIC < pg/ ml) Infection and organism Septicemia Pseudomonas aeruginwsa Escherichia coli Acinetobacter calcoaceticus Bacteroides fragilis Clostridium perfringens Corynebacterium sp. Enterococcus Bacilus cereus E. coli and Proteus sp. E. coli and Citrobacter sp. E. coli and S. pneumoniae Serratia marcescens and Streptococcus pyogenes Klebsiella pneumoniae Pseudomonas aerugiosa Enterobacter cloacae Escherichia coli Serratia marcescens Soft tissue Pseudomonas aeruginosa Klebsiellapneumoniae episodes" episodes Episodes with su- Susceptible epitreated responding ceptible organims sodes responding Escherichia coli Klebsiellapneumoniae Pseudomonas aeruginosa 7 a Number of episodes = number of patients. b In vitro susceptibility not determined in one patient b b b ob

4 VOL. 7, 98 MEZLOCILLIN IN CANCER PATIENTS ative infections, were,, and 7%, respectively. Among the E. coli infections were three mixed-organism septicemias, two of which responded. In vitro susceptibilities of the infecting organisms were determined in of the 9 infections. Organisms isolated from of episodes were susceptible to mezlocillin in vitro (MIC <,ug/ ml). Mezlocillin therapy was continued in these cases. Eighteen (%) responded. Despite in vitro resistance, five infections showed an excellent early clinical response and a sustained response on continued therapy with mezlocillin. The three Klebsiella sp. infections for which in vitro susceptibilities were not determined also responded. The neutrophil count at the start of therapy did not influence response in patients whose infections were susceptible to mezlocillin in vitro; 9 of 8 patients with absolute neutrophil counts of </l responded. More responses were observed in patients whose neutrophils increased during therapy than in those whose neutrophils did not rise ( of 8 versus of 7 patients, respectively), but these differences were not statistically significant. In infections, serum concentrations of mezlocillin were determined immediately after drug infusion and before the next dose of mezlocillin. The median postinfusion serum concentration (maximum) was,ug/ml (range, to 7,tg/ ml), whereas the median preinfusion serum concentration (trough) was,ug/ml (range, to 8,ug/ml). Table details the response of infections according to the ratio of the trough serum concentration to the organism MIC. association between this ratio and patient response was found. Infections due to the three major gram-negative organisms, P. aeruginosa, K. pneumoniae, and E. coli, are detailed according to prognostic characteristics in Table. Also listed for comparison are the in vitro susceptibilities to carbenicillin. Only one isolate of E. coli was more susceptible to carbenicillin than to mezlocilhin. Increased susceptibility to mezlocillin was especially notable for isolates of K. pneumoniae, TABLE. Response according to minimum serum mezlocillin concentration/mic ratio MSC/MIC ratioa epi-. of resodes sponmse % Response < - 9 > MSC, Minimum (trough) serum mezlocillin concentration; MIC of mezlocillin for infecting organism in vitro. which were resistant to carbenicillin. P. aeruginosa septicemias associated with an identified site of infection were especially difficult to treat. Only one of six Pseudomonas pneumonias responded to therapy, as compared with four responses among six pneumonias due to K. pneumoniae. The only toxic reaction that could be attributed to mezlocillin was a morbilliform skin rash in one patient. Positive proteinurias, obtained with the sulfosalicylic acid precipitation test, were common. Negative bromophenol blue tests (Albustix) and, in some patients, negative protein electrophoretic determinations suggested that these were false-positive reactions. This suggestion found direct support from the demonstration that adding mezlocillin directly to urine in a concentration in excess of,,ug/ml produced a positive sulfosalicylic acid reaction. Two episodes of therapy were associated with superinfections. There were one fatal Candida tropicalis septicemia and one S. aureus softtissue infection which responded to other antibiotic therapy. DISCUSSION This study demonstrated that mezlocillin, when given as a single agent, was effective therapy for some of the infections occurring in myelosuppressed cancer patients, although a significant number failed to respond. Also, a substantial proportion of the organisms infecting the patients of this study proved to be resistant to mezlocillin in vitro, and this was higher than expected from our previous in vitro data (7). In contrast to our previous experience with antipseudomonal semisynthetic penicillins, which were ineffective against Klebsiella sp. infections (, ), mezlocillin was effective against % of the Klebsiella infections in this study. Also, the response rate of 7% for E. coli infections was higher than those observed for carbenicillin and ticarcillin in our previous experience (% and %, respectively). A comparison of this study with historical studies should be made with a degree of caution, since clearly patient and infection characteristics have changed. Characteristics conferring a disadvantage for this study included a higher proportion of patients receiving very intensive chemotherapy, which was sometimes combined with attempted bone marrow transplantation. These procedures often resulted in severe and prolonged immunosuppression and myelosuppression. Mezlocillin, like the majority of semisynthetic penicillins, was well tolerated. The pseudoproteinuria found in this study was initially described with nafcillin (9) and more recently has

5 ISSELL A BODEY ANTIMICROB. AGENTS CHEMOTHER. TABLE. Characteristics ofpredominant gram-negative infections Infection and site Mezlocllin Carbeniciin Mezilocilin Neutrophil Respo MWc MW MSC/MIC- increase Rsos P. aeruginosa Septicemia, pneumonia Septicemia, pneumonia Septicemia, pneumonia Septicemia, soft tissue Septicemia, soft tissue Septicemnia Soft tissue Soft tissue K. pneumoniae E. coli Septicemia Septicemia Septicemiac Septicemiac' Septicemiac I > > >.9. > MSC, Minimum (trough) serum mezlocillin concentration. b, t determined. 'Mixed infections: see Table. also been reported to occur with meziocillin as well as with penicillin G and azlocillin (). The overall response rate of 9% with mezlocillin was disappointing and indicates that this antibiotic should not be used alone for initial therapy of presumptive infection in neutropenic patients. Mezlocillin did not produce results that were comparable to the combination of carbenicillin plus cephalothin in previous studies, in which the cure rates were 9 and 7% (, ). The lower than anticipated response rate was due in part to the increased frequency of infections caused by resistant organisms. Furthermore, there has been an increase in the number of infections caused by unusual organisms such as Corynebacterium sp. and Bacillus cereus, and the incidence of S. aureus < < < < < b < < 7 8 > < > < >. infections was considerably higher in this study than in our previous experience (, ). In fact, the use of mezlocillin alone as empiric therapy would not have been undertaken if the increased incidence of S. aureus infections had been anticipated. Once the transient microepidemic of S. aureus was recognized, strict hygienic measures were implemented, which corrected the problem. Two recent studies (, ) have reported that mezlocillin showed in vitro synergism when combined with the aminoglycoside antibiotics gentamicin, tobramycin, netilmicin, sisomicin, and amikacin. Synergy was observed against E. coli, Klebsiella, Serratia, Citrobacter, and Enterobacter and was found for isolates that were both susceptible and resistant to mezlocillin. Hence,

6 VOL. 7, 98 MEZLOCILLIN IN CANCER PATIENTS it was anticipated that the combination of mezlocillin plus an aminoglycoside would produce better results than mezlocillin. Unfortunately, in a subsequent clinical study, the results with mezlocillin plus tobramycin were not better than with mezlocillin alone (R. Lawson and G. P. Bodey, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 9th, Boston, Mass., abstr. no. 8, 979). Perhaps better results could be obtained if higher doses of mezlocillin were administered to maintain a better ratio of serum concentration to MIC. It is also possible that mezlocillin is not as effective an agent in this clinical situation. ACKNOWLEDGMENTS This work was supported by a Grant-In-Aid from Delbay Pharmaceuticals, Inc., Bloomfield, N.J., and by Public Health Service grant CA-8, Appropriation, from the National Cancer Institute. We thank Linda Miller and Suzanne Weaver for their excellent technical assistance and Mary Silverstein and Judi Brinck for assisting in the preparation of this manuscript. LITERATURE CITED. Anderson, E. T., L. S. Young, and W. L. Hewitt Antimicrobial synergism in the therapy of gram-negative rod bacteremia. Chemotherapy :-.. Andrassay, K., E. Ritz, J. Kaderisch, W. Salzmann, and J. Bommer Pseudoproteinuria in patients taking penicillin. Lancet ii:.. Bodey, G. P. 97. Infections in cancer patients. Cancer Treat. Rev. : Bodey, G. P., R. Feld, and M. A. Burgess. 97.,B- Lactam antibiotics alone or in combination with gentamicin for therapy of gram-negative bacillary infections in neutropenic patients. Am. J. Med. Sci. 7: Bodey, G. P., and S. J. Ketchel A randomized trial of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. Am. J. Med. 7:8-.. Bodey, G. P., E. Middleman, T. Umsawasdi, and V. Rodriguez. 97. Infections in cancer patients-results with gentamicin sulfate therapy. Cancer 9: Bodey, G. P., and T. Pan Mezlocillin: in vitro studies of a new broad-spectrum penicillin. Antimicrob. Agents Chemother. : Bodey, G. P., and V. Rodriguez The role of antipseudomonal penicilins in the management of infections in cancer patients, p. -7. In Ticarcillin (BRL 88). International Symposium, Switzerland. Excerpta Medica, Geneva. 9. Bodey, G. P., V. Rodriguez, H. Y. Chang, and G. Narboni Fever and infection in leukemic patients. A study of 9 consecutive patients. Cancer : -.. Bodey, G. P., V. Rodriguez, and J. K. Luce. 99. Carbenicillin therapy of gram-negative bacilli infections. Am. J. Med. Sci. 7:8-.. Bodey, G. P., M. Valdivieso, R. Feld, V. Rodriguez, and K. McCredie Carbenicillin plus cephalothin or cefazolin as therapy for infections. Am. J. Med. Sci. 7:9-8.. Bodey, G. P., J. P. Whitecar, Jr., E. Middleman, and V. Rodrigeuz. 97. Carbenicillin therapy of pseudomonas infections. J. Am. Med. Assoc. 8:-.. EORTC International Antimicrobial Therapy Project Group Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. J. Infect. Dis. 7:-9.. Grove, D. A., and W. A. Randall. 97. Assay methods of antibiotics, a laboratory manual, p New York Medical Encyclopedia, Inc., New York.. Issell, B. F., G. P. Bodey, and S. Weaver Clinical pharmacology of mezlocillin. Antimicrob. Agents Chemother. :8-8.. Keating, M. J., G. P. Bodey, M. Valdivieso, and V. Rodriguez A randomized comparative trial of three aminoglycosides-comparison of continuous infusions of gentamicin, amikacin and sisomicin combined with carbenicillin in the treatment of infections in neutropenic patients with malignancies. Medicine 8: Klastersky, J., R. Cappel, G. Swings, and L. Vandenborre. 97. Bacteriological and clinical activity of the ampicillin/gentamicin and cephalothin/gentamicin combinations. Am. J. Med. Sci. : Lau, W. K., L. S. Young, R. E. Black, D. J. Winston, S. R. Linne, R. J. Weinstein, and W. L. Hewitt Comparative efficacy and toxicity of amikacin/ carbenicillin versus gentamicin/carbenicillin in leukopenic patients. A randomized prospective trial. Am. J. Med. : Line, D. E., S. Adler, D. S. Fraley, and F. J. Burns. 97. Massive pseudoproteinuria caused by nafcillin. J. Am. Med. Assoc. :9.. Middleman, E. A., A. Watanabe, H. Kaizer, and G. P. Bodey. 97. Antibiotic combinations for infections in neutropenic patients. Evaluation of carbenicillin plus either cephalothin or kanamycin. Cancer 9: Neu, H. C., and K. P. Fu Synergy of azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporins. Antimicrob. Agents Chemother. : Rodriguez, V., G. P. Bodey, N. Horikoshi, J. Inagaki, and K. B. McCredie. 97. Ticarcillin therapy of infections. Antimicrob. Agents Chemother. :7-.. Schassan, H. H., K. Koperski, and H. Scherf Mezlocillin: a new acyl ureidopenicillin. Chemotherapy :-.. Schimpff, S., W. Satterlee, V. M. Young, and A. Serpick. 97. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N. Engl. J. Med. 8:-.. Valdivieso, M., N. Horikoshi, V. Rodriguez, and G. P. Bodey. 97. Therapeutic trials with tobramycin. Am. J. Med. Sci. 8:9-.