ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1975, p. 640-645 Copyright 0 1975 American Society for Microbiology
Vol. 7, No. 5 Printed in U.SA.
Empiric Therapy for Cancer Patients: Comparative Study of Ticarcillin-Tobramycin, Ticarcillin-Cephalothin, and Cephalothin-Tobramycin J. KLASTERSKY,* C. HENSGENS, AND L. DEBUSSCHER Service de Medecine et Laboratoire d'Investigation Clinique, Section des Maladies Infectieuses, Institut Jules
Bordet,
1000 Brussels,
Belgium
Received for publication 30 January 1975
Three combinations of antibiotics (cephalothin-tobramycin, cephalothinticarcillin, and ticarcillin-tobramycin) were administered empirically to 186 patients with cancer who were suspected of having a life-threatening infection. In approximately one-half of these patients, gram-negative infection was documented bacteriologically and consisted of septicemia in 50% of these patients. The three antimicrobial regimens were similarly effective and resulted in a favorable clinical response in approximately 55% of the patients. The administration of the cephalothin-tobramycin combination was associated with a significantly higher frequency of nephrotoxicity than that of the other two regimens. In patients with cancer, especially when neutropenia is present, gram-negative bacterial infections are a major cause of death (1, 8). Under these clinical circumstances, various antimicrobial regimens have been recommended; among them are the combinations of carbenicillin with gentamicin (15), carbenicillin with cephalothin (12), cephalothin with gentamicin (7), and multiple drug regimens including carbenicillin, cephalothin, and gentamicin (9) or carbenicillin, cephalothin, gentamicin, methicillin, and clindamycin (17). In the present study we have compared the combination of ticarcillin with cephalothin (Tic-Cef) to that of ticarcillin with tobramycin (Tic-Tob) and of cephalothin with tobramycin (Cef-Tob). Ticarcillin and tobramycin are very similar to carbenicillin a,nd gentamicin, respectively, from the microbiological and pharmacological points of view. Both drugs are more active, however, against Pseudomonas in vitro, and tobramycin is effective on some gentamicin-resistant Enterobacteriaceae and Pseudomonas strains. (Presented at the 14th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 11-13 September 1974.) MATERIALS AND METHODS All the patients in this series were hospitalized at the Institut Jules Bordet. Only patients with disseminated cancer and recent onset of clinical symptoms suggestive of severe infection (rectal temperature higher than 101 F [38.3 C], shaking chills, hypo-
tension) were admitted to the study if their serum creatinine level was C.)
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ANTIMICROB. AGENTS CHEMOTHER.
penic patients, as were results in patients whose condition was critical at the onset of therapy. A gram-negative etiology could be determined in 38 patients treated with Cef-Tob, 33 patients who received Tic-Tob, and 30 who were treated with Tic-Cef. Table 3 shows that a favorable clinical response was observed in 53, 64, and 73% of these patients, respectively. These differences, however, are not statistically significant, and no major differences could be found in the clinical effectiveness of the three regimens tested in patients with gram-negative septicemia. In pulmonary and postoperative wound infections, Cef-Tob was associated with poorer clinical results than were the other two regimens. The type of the offending microorganisms did not noticeably influence the clinical effectiveness of the three antimicrobial regimens that were used here, although Cef-Tob gave worse results in infections caused by Pseudomonas aeruginosa than did Tic-Tob and Tic-Cef. Better results with Tic-Tob and Tic-Cef were also observed in patients who were seriously or critically ill at the onset of antimicrobial therapy. Therapy with Tic-Tob and Tic-Cef resulted in 61 and 62%, respectively, favorable responses in these patients who presented gram-negative infections; on the other hand, Cef-Tob was associated with a favorable response in 34% of the patients (x2 = 4.7; P < 0.05). Death occurred in a similar proportion of the patients in the three groups treated and was caused directly by infection in five out of 38 patients who received Cef-Tob, eight out of 33 patients who were treated with Tic-Tob, and four patients out of 30 in the Tic-Cef group. Patients who were treated with combinations of antibiotics that were synergistic in vitro against the offending microorganism had a significantly better clinical outcome than the patients who received nonsynergistic combinations; favorable results were seen in 22 out of 29 (76%) patients in the former group and in 11 out of 28 patients (39%) in the latter; this difference is statistically significant (x2 = 6.39; P < 0.05). The mean bactericidal activity of the sera of the treated patients that were obtained 1 h after the administration of the antibiotics was 1/4 in the Cef-Tob group and 1/16 in the two other groups. Cutaneous rashes, or other manifestations of susceptibility to the drugs employed, bleeding, hepatic toxicity, and auditory dysfunction were not found frequently in this series, although these toxic manifestations have occasionally been reported in association with the use of ticarcillin, cephalothin, or tobramycin. Azotemia, defined as a rise of the serum
EMPIRIC THERAPY FOR CANCER PATIENTS
VOL. 7, 1975
creatinine level above 2 mg/100 ml, occurred in 10 out of 48 patients (21%) who received CefTob and in whom renal function could adequately be studied; on the other hand, azotemia was observed in 6 and 2% of the Tic-Tob and Tic-Cef groups, respectively (x2 = 5.1; P < 0.05). In the Cef-Tob group, 10 patients became azotemic during therapy; in five of them impairment of the renal function disappeared after discontinuation of therapy. The other five patients died, and death was attributed directly to renal failure in four of them. It is known that some underlying pathological condition of the urinary tract preexisted in three of these five patients; however, renal abnormalities also preexisted in a similar proportion of the patients in all three study groups. These abnormalities, defined as an initial (pretherapy) serum creatinine level higher than 1.3 mg/100 ml, a gross anatomic abnormality (nephrostomy, hydronephrosis, only one kidney, obstructive uropathy, nephrolithiasis), or recent
643
administration of potentially nephrotoxic drugs (aminoglycosides, diuretics), were present in 28, 29, and 29 patients in the Cef-Tob, Tic-Tob, and Tic-Cef groups, respectively, making it unlikely that there was a preselection of patients predisposed to renal insufficiency in the Cef-Tob group. Phlebitis, severe enough to necessitate symptomatic therapy or discontinuation of treatment, was seen in a similar proportion of patients in all three groups (Table 4). Hypokalemia, which always responded to replacement therapy or to discontinuation of the antibiotics and did not result in any serious complication, was seen in 30% of the patients who received Tic-Cef and in 16% of those who were treated with Tic-Tob, but only in 2% of the patients in the Cef-Tob group. Bacterial colonization of the primary site of infection was found in 16% of the Cef-Tobtreated patients and in 12 and 13% of the patients who received Tic-Tob or Tic-Cef, re-
TABLE 3. Clinical results in patients with gram-negative infections Cef-Tob
Clinical and bacteriological
findings
Tic-Tob
Tic-Cef
No.
Sa
%
No.
S
%
No.
No. of patients (total) Site of infection
38
16
42
33
20
60
30
19
63
Pulmonary Wound Urinary Other sites Septicemia Microorganisms Escherichia coli Klebsiella sp. P. aeruginosa
13 4 6 15 19
2 1 5 8 11
15 25 83 53 58
14 3 6 10 15
9 2 4 5 7
64 67 67 50 47
11 6 4 9 11
6 3 3 7 6
54 50 75 77 54
13 11 8 1 5
7 4 2 0 3
54 36 25 0 60
13 7 10 2 1
9 2 8 i 0
69 28 80 50 0
14 5 5 4 2
10 2 3 2 2
71 40 60 50 100
Others Bacteroides sp. a
S
S, Clinical success. TABI.E 4. Adverse reactions observed in the patients treated Cef-Tob (60)a Reaction
Azotemia Rash Phlebitis Hypokaliemia Bleeding Hepatic dysfunction Auditory dysfunction Colonization a
No evaluable
48 49 49 40 49 49 49 49
Tic-Tob (64)
Adverse effects No. %
10 0 11 1 0 0 0 8
21 0 22 2 0 0 0 16
No
evaluable
53 54 54 36 56 56 56
56
Tic-Cef (62)
Adverse effects No. %
3 2 14 6 2 0 1 7
Number in parentheses indicates total number of patients treated.
6 4 26 16 4 0 2 12
No evaluable
47 50 51 37 51 51 51 51
Adverse effects No. %
1 5 14 11 2 2 0 7
2 10 27 30 4 4 0 13
644
KLASTERSKY, HENSGENS, AND DEBUSSCHER
spectively. The microorganisms which were involved most frequently in the colonization phenomenon were Klebsiella sp., which accounted for four, two, and five cases in the different groups, respectively. Staphylococci were involved in one case of colonization in the Tic-Tob group of patients, and Candida albicans caused colonization in one patient in the same group. All other colonizing microorganisms were gram-negative bacilli. In this study, no infection was caused by a microorganism which was resistant in vitro to both antibiotics used for therapy. On the other hand, colonizing microorganisms were usually highly resistant to ticarcillin and/or cephalothin, and some of them (P. aeruginosa, Klebsiella sp., Candida albicans, Bacteroides sp., enterococci) were also relatively resistant (minimum inhibitory concentration greater than 3 ,g/ml) to tobramycin. In no patient in the present study did a real clinical infection caused by the colonizing microorganisms develop. DISCUSSION Severe underlying disease has a major role in mortality resulting from severe infection (4). In neutropenic patients especially, therapy of presumed severe infection should be instituted early, even before recognition of the offending pathogen. There is no good evidence to show that antimicrobial therapy should be undertaken empirically in patients without neutropenia, although there are experimental data suggesting that infection can be cured more easily if treated early (13). In the present study we used empiric antimicrobial therapy in neutropenic and nonneutropenic patients when symptoms suggesting severe infection were present. A bacterial pathogen could indeed be demonstrated in two-thirds of the patients, 42% of whom were bacteremic. Three combinations of antibiotics, whose effectiveness against various aerobic gram-negative microorganisms has been documented (5, 10), were used and resulted in a favorable clinical response in 55% of the patients. It is difficult to compare these results to those obtained by other investigators in other hospitals because of the great number of variables involved. Nevertheless, our results seem to be quite similar to those reported by others; Bodey et al. found a response rate of 51% for gentamicin, 56% for gentamicin and carbenicillin, and 60% for carbenicillin and cephalothin in patients with cancer (12). Other antimicrobial regimens to be used in patients with malignant diseases have recently been discussed by Levine et al. (11).
ANTIMICROB AGENTS CHEMOTHER.
The antibiotic regimens used here provided adequate antimicrobial coverage in all the patients in this series; in addition, the combinations used were synergistic in vitro against a substantial number of the offending pathogens. This study has confirmed previous observations from this laboratory showing that the outcome of patients who are treated with combinations of antibiotics that are synergistic in vitro is significantly better than that of patients treated with nonsynergistic combinations (6). Gram-negative infections were found in approximately 50% of the patients, and in one-half of them a septicemia could be documented. Neutropenia and severe underlying disease were found to be associated with a worse clinical outcome in all treatment groups, as was the pulmonary localization of the infection. However, the numbers of patients in these various subgroups were too small to allow a significant evaluation; in the future, therefore, larger studies such as the one which is at present being undertaken on a cooperative basis by the European Organization for Research on Treatment of Cancer. Antimicrobial Therapy Group should be organized (H. Gaya, J. Klastersky, and S. Schimpff, Prog. Abstr. Intersci. Conf. Antimicrob. Agents. Chemother., 14th, San Francisco, Calif., Abstr. 289, 1974). A major complication, azotemia, was found significantly more often in patients who were treated with the Cef-Tob combination. Predisposing factors to that complication could not be detected more frequently in the Cef-Tobtreated patients to explain the frequency of azotemia in that group of patients. This observation is in accordance with previous observations from this laboratory (9) and from elsewhere (3). The mechanism by which the combination of cephalothin with aminoglycoside is nephrotoxic is unknown. The dosage of cephalothin might be important in this respect, since nephrotoxicity has not been a major problem (7) in studies in which lower doses of cephalothin have been used. Our study, therefore, suggests that the combinations Tic-Tob and Tic-Cef have similar effectiveness and tolerance as empiric therapies for gram-negative infections of patients with cancer. However, neither combination can be expected to be effective against all possible pathogens; moreover, the susceptibility of microorganisms to antibiotics changes as newer antimicrobial agents come into common use. Therefore, bacteriological monitoring of patients who are predisposed to serious infections is essential before and during antimicrobial therapy. Equally important are the investigation of more
EMPIRIC THERAPY FOR CANCER PATIENTS
VOL. 7, 1975
effective methods to detect still earlier bacterial infections and efforts to better understand the physiopathology of severe sepsis, since antimicrobial treatment, although important, is not the only measure to be taken to prevent mortality in severe sepsis. ACKNOWLEDGMENTS This investigation was supported in part by a grant from the Fonds de la Recherche Scientifique Medicale (F.R.S.M. no. 20.368), Brussels, Belgium, and partly by a grant from both Eli Lilly, Indianapolis, Ind., and Beecham, S. A., Brussels, Belgium. We thank M. J. Menne, L. Vandenborre, and L. Van Schoonbrouck for their technical assistance and R. Andries for secretarial help.
LITERATURE CITED 1. Bodey, G. P., J. Hart, E. J. Freireich, and E. Frei. 1966. Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia. Ann. Int. Med. 64:328-340. 2. Bodey, G. P., E. Middleman, T. Umsawadi, and V. Rodriguez. 1972. Infections in cancer patients. Result with gentamicin sulfate therapy. Cancer 29:1697-1701. 3. Fillastre, J. P., R. Laumonier, G. Humbert, D. Dubois, J. Metayer, A. Delpech, J. Leroy, and M. Robert. 1973. Acute renal failure associated with combined gentamicin and cephalothin therapy. Br. Med. J. 2:396-397. 4. Freid, M. A., and K. L. Vosti. 1968. The importance of underlying disease in patients with gram negative bacteremia. Arch. Int. Med. 121:418-423. 5. Klastersky, J. 1973. Effectiveness of the carbenicillincephalothin combination against gram negative bacilli. Am. J. Med. Sci. 265:45-53. 6. Klastersky, J., R. Cappel, and D. Daneau. 1972. Clinical significance of in vitro synergism between antibiotics in gram-negative infections. Antimicrob. Agents Chemother. 2:470-475.
645
7. Klastersky, J., R. Cappel, G. Swings, and L. Vandenboffe. 1971. Bacteriological and clinical activity of the ampicillin/gentamicin and cephalothin/gentamicin combinations. Am. J. Med. Sci. 262:273-380. 8. Klastersky, J., D. Daneau, and A. Verhest. 1972. Causes of death in patients with cancer. Eur. J. Cancer 8:149-154. 9. Klastersky, J., A. Henri, C. Hensgens; and D. Daneau. 1974. Gram negative infections in cancer. Study of empiric therapy comparing carbenicillin-cephalothin with and without gentamicin. J. Am. Med. Assoc. 227:45-48. 10. Klastersky, J., A. Henri, and L. Vandenborre. 1973. Antimicrobial activity of tobramycin and gentamicin used in combination with cephalothin and carbenicillin. Am. J. Med. Sci. 266:13-21. 11. Levine, A. S., S. C. Schimpff, R. G. Graw, and R. C. Young. 1974. Hematologic malignancies and other marrow failure states. Progress in the management of complicating infections. Semin. Hetnatol. 11:141-202. 12. Middlemans, E. L., A. Watanak, H. Kaizer, and G. P. Bodey. 1972. Antibiotic combinations for infections in neutropenic patients. Evaluation of carbenicillin plus either cephalothin of kanamycin. Cancer 30:573-679. 13. Perry, J. E., and L. E. Cluff. 1966. The effect of penicillin upon experimental lethal pneumococcal infection. Tex. Rep. Biol. Med. 24:141-152. 14. Richards, F., C. McCall, and C. Cox. 1971. Gentamicin treatment of staphylococcal infections. J. Am. Med. Assoc. 215:1297-1300. 15. Schimpff, S., W. Satterlee, V. M. Young, and A. Serpick. 1971. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N. Engl. J. Med. 284:1061-1065. 16. Steers, E., E. L. Foltz, and B. S. Graves. 1959. Inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother. 3:307-311. 17. Tattersall, M. H. N., A. S. D. Spiers, and J. H. Darell. 1972. Initial therapy with combination of five antibiotics in febrile patients with leukemia and neutropenia. Lancet 1:162-165.
Vol. 7, No. 5 Printed in U.SA.
Empiric Therapy for Cancer Patients: Comparative Study of Ticarcillin-Tobramycin, Ticarcillin-Cephalothin, and Cephalothin-Tobramycin J. KLASTERSKY,* C. HENSGENS, AND L. DEBUSSCHER Service de Medecine et Laboratoire d'Investigation Clinique, Section des Maladies Infectieuses, Institut Jules
Bordet,
1000 Brussels,
Belgium
Received for publication 30 January 1975
Three combinations of antibiotics (cephalothin-tobramycin, cephalothinticarcillin, and ticarcillin-tobramycin) were administered empirically to 186 patients with cancer who were suspected of having a life-threatening infection. In approximately one-half of these patients, gram-negative infection was documented bacteriologically and consisted of septicemia in 50% of these patients. The three antimicrobial regimens were similarly effective and resulted in a favorable clinical response in approximately 55% of the patients. The administration of the cephalothin-tobramycin combination was associated with a significantly higher frequency of nephrotoxicity than that of the other two regimens. In patients with cancer, especially when neutropenia is present, gram-negative bacterial infections are a major cause of death (1, 8). Under these clinical circumstances, various antimicrobial regimens have been recommended; among them are the combinations of carbenicillin with gentamicin (15), carbenicillin with cephalothin (12), cephalothin with gentamicin (7), and multiple drug regimens including carbenicillin, cephalothin, and gentamicin (9) or carbenicillin, cephalothin, gentamicin, methicillin, and clindamycin (17). In the present study we have compared the combination of ticarcillin with cephalothin (Tic-Cef) to that of ticarcillin with tobramycin (Tic-Tob) and of cephalothin with tobramycin (Cef-Tob). Ticarcillin and tobramycin are very similar to carbenicillin a,nd gentamicin, respectively, from the microbiological and pharmacological points of view. Both drugs are more active, however, against Pseudomonas in vitro, and tobramycin is effective on some gentamicin-resistant Enterobacteriaceae and Pseudomonas strains. (Presented at the 14th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 11-13 September 1974.) MATERIALS AND METHODS All the patients in this series were hospitalized at the Institut Jules Bordet. Only patients with disseminated cancer and recent onset of clinical symptoms suggestive of severe infection (rectal temperature higher than 101 F [38.3 C], shaking chills, hypo-
tension) were admitted to the study if their serum creatinine level was C.)
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ANTIMICROB. AGENTS CHEMOTHER.
penic patients, as were results in patients whose condition was critical at the onset of therapy. A gram-negative etiology could be determined in 38 patients treated with Cef-Tob, 33 patients who received Tic-Tob, and 30 who were treated with Tic-Cef. Table 3 shows that a favorable clinical response was observed in 53, 64, and 73% of these patients, respectively. These differences, however, are not statistically significant, and no major differences could be found in the clinical effectiveness of the three regimens tested in patients with gram-negative septicemia. In pulmonary and postoperative wound infections, Cef-Tob was associated with poorer clinical results than were the other two regimens. The type of the offending microorganisms did not noticeably influence the clinical effectiveness of the three antimicrobial regimens that were used here, although Cef-Tob gave worse results in infections caused by Pseudomonas aeruginosa than did Tic-Tob and Tic-Cef. Better results with Tic-Tob and Tic-Cef were also observed in patients who were seriously or critically ill at the onset of antimicrobial therapy. Therapy with Tic-Tob and Tic-Cef resulted in 61 and 62%, respectively, favorable responses in these patients who presented gram-negative infections; on the other hand, Cef-Tob was associated with a favorable response in 34% of the patients (x2 = 4.7; P < 0.05). Death occurred in a similar proportion of the patients in the three groups treated and was caused directly by infection in five out of 38 patients who received Cef-Tob, eight out of 33 patients who were treated with Tic-Tob, and four patients out of 30 in the Tic-Cef group. Patients who were treated with combinations of antibiotics that were synergistic in vitro against the offending microorganism had a significantly better clinical outcome than the patients who received nonsynergistic combinations; favorable results were seen in 22 out of 29 (76%) patients in the former group and in 11 out of 28 patients (39%) in the latter; this difference is statistically significant (x2 = 6.39; P < 0.05). The mean bactericidal activity of the sera of the treated patients that were obtained 1 h after the administration of the antibiotics was 1/4 in the Cef-Tob group and 1/16 in the two other groups. Cutaneous rashes, or other manifestations of susceptibility to the drugs employed, bleeding, hepatic toxicity, and auditory dysfunction were not found frequently in this series, although these toxic manifestations have occasionally been reported in association with the use of ticarcillin, cephalothin, or tobramycin. Azotemia, defined as a rise of the serum
EMPIRIC THERAPY FOR CANCER PATIENTS
VOL. 7, 1975
creatinine level above 2 mg/100 ml, occurred in 10 out of 48 patients (21%) who received CefTob and in whom renal function could adequately be studied; on the other hand, azotemia was observed in 6 and 2% of the Tic-Tob and Tic-Cef groups, respectively (x2 = 5.1; P < 0.05). In the Cef-Tob group, 10 patients became azotemic during therapy; in five of them impairment of the renal function disappeared after discontinuation of therapy. The other five patients died, and death was attributed directly to renal failure in four of them. It is known that some underlying pathological condition of the urinary tract preexisted in three of these five patients; however, renal abnormalities also preexisted in a similar proportion of the patients in all three study groups. These abnormalities, defined as an initial (pretherapy) serum creatinine level higher than 1.3 mg/100 ml, a gross anatomic abnormality (nephrostomy, hydronephrosis, only one kidney, obstructive uropathy, nephrolithiasis), or recent
643
administration of potentially nephrotoxic drugs (aminoglycosides, diuretics), were present in 28, 29, and 29 patients in the Cef-Tob, Tic-Tob, and Tic-Cef groups, respectively, making it unlikely that there was a preselection of patients predisposed to renal insufficiency in the Cef-Tob group. Phlebitis, severe enough to necessitate symptomatic therapy or discontinuation of treatment, was seen in a similar proportion of patients in all three groups (Table 4). Hypokalemia, which always responded to replacement therapy or to discontinuation of the antibiotics and did not result in any serious complication, was seen in 30% of the patients who received Tic-Cef and in 16% of those who were treated with Tic-Tob, but only in 2% of the patients in the Cef-Tob group. Bacterial colonization of the primary site of infection was found in 16% of the Cef-Tobtreated patients and in 12 and 13% of the patients who received Tic-Tob or Tic-Cef, re-
TABLE 3. Clinical results in patients with gram-negative infections Cef-Tob
Clinical and bacteriological
findings
Tic-Tob
Tic-Cef
No.
Sa
%
No.
S
%
No.
No. of patients (total) Site of infection
38
16
42
33
20
60
30
19
63
Pulmonary Wound Urinary Other sites Septicemia Microorganisms Escherichia coli Klebsiella sp. P. aeruginosa
13 4 6 15 19
2 1 5 8 11
15 25 83 53 58
14 3 6 10 15
9 2 4 5 7
64 67 67 50 47
11 6 4 9 11
6 3 3 7 6
54 50 75 77 54
13 11 8 1 5
7 4 2 0 3
54 36 25 0 60
13 7 10 2 1
9 2 8 i 0
69 28 80 50 0
14 5 5 4 2
10 2 3 2 2
71 40 60 50 100
Others Bacteroides sp. a
S
S, Clinical success. TABI.E 4. Adverse reactions observed in the patients treated Cef-Tob (60)a Reaction
Azotemia Rash Phlebitis Hypokaliemia Bleeding Hepatic dysfunction Auditory dysfunction Colonization a
No evaluable
48 49 49 40 49 49 49 49
Tic-Tob (64)
Adverse effects No. %
10 0 11 1 0 0 0 8
21 0 22 2 0 0 0 16
No
evaluable
53 54 54 36 56 56 56
56
Tic-Cef (62)
Adverse effects No. %
3 2 14 6 2 0 1 7
Number in parentheses indicates total number of patients treated.
6 4 26 16 4 0 2 12
No evaluable
47 50 51 37 51 51 51 51
Adverse effects No. %
1 5 14 11 2 2 0 7
2 10 27 30 4 4 0 13
644
KLASTERSKY, HENSGENS, AND DEBUSSCHER
spectively. The microorganisms which were involved most frequently in the colonization phenomenon were Klebsiella sp., which accounted for four, two, and five cases in the different groups, respectively. Staphylococci were involved in one case of colonization in the Tic-Tob group of patients, and Candida albicans caused colonization in one patient in the same group. All other colonizing microorganisms were gram-negative bacilli. In this study, no infection was caused by a microorganism which was resistant in vitro to both antibiotics used for therapy. On the other hand, colonizing microorganisms were usually highly resistant to ticarcillin and/or cephalothin, and some of them (P. aeruginosa, Klebsiella sp., Candida albicans, Bacteroides sp., enterococci) were also relatively resistant (minimum inhibitory concentration greater than 3 ,g/ml) to tobramycin. In no patient in the present study did a real clinical infection caused by the colonizing microorganisms develop. DISCUSSION Severe underlying disease has a major role in mortality resulting from severe infection (4). In neutropenic patients especially, therapy of presumed severe infection should be instituted early, even before recognition of the offending pathogen. There is no good evidence to show that antimicrobial therapy should be undertaken empirically in patients without neutropenia, although there are experimental data suggesting that infection can be cured more easily if treated early (13). In the present study we used empiric antimicrobial therapy in neutropenic and nonneutropenic patients when symptoms suggesting severe infection were present. A bacterial pathogen could indeed be demonstrated in two-thirds of the patients, 42% of whom were bacteremic. Three combinations of antibiotics, whose effectiveness against various aerobic gram-negative microorganisms has been documented (5, 10), were used and resulted in a favorable clinical response in 55% of the patients. It is difficult to compare these results to those obtained by other investigators in other hospitals because of the great number of variables involved. Nevertheless, our results seem to be quite similar to those reported by others; Bodey et al. found a response rate of 51% for gentamicin, 56% for gentamicin and carbenicillin, and 60% for carbenicillin and cephalothin in patients with cancer (12). Other antimicrobial regimens to be used in patients with malignant diseases have recently been discussed by Levine et al. (11).
ANTIMICROB AGENTS CHEMOTHER.
The antibiotic regimens used here provided adequate antimicrobial coverage in all the patients in this series; in addition, the combinations used were synergistic in vitro against a substantial number of the offending pathogens. This study has confirmed previous observations from this laboratory showing that the outcome of patients who are treated with combinations of antibiotics that are synergistic in vitro is significantly better than that of patients treated with nonsynergistic combinations (6). Gram-negative infections were found in approximately 50% of the patients, and in one-half of them a septicemia could be documented. Neutropenia and severe underlying disease were found to be associated with a worse clinical outcome in all treatment groups, as was the pulmonary localization of the infection. However, the numbers of patients in these various subgroups were too small to allow a significant evaluation; in the future, therefore, larger studies such as the one which is at present being undertaken on a cooperative basis by the European Organization for Research on Treatment of Cancer. Antimicrobial Therapy Group should be organized (H. Gaya, J. Klastersky, and S. Schimpff, Prog. Abstr. Intersci. Conf. Antimicrob. Agents. Chemother., 14th, San Francisco, Calif., Abstr. 289, 1974). A major complication, azotemia, was found significantly more often in patients who were treated with the Cef-Tob combination. Predisposing factors to that complication could not be detected more frequently in the Cef-Tobtreated patients to explain the frequency of azotemia in that group of patients. This observation is in accordance with previous observations from this laboratory (9) and from elsewhere (3). The mechanism by which the combination of cephalothin with aminoglycoside is nephrotoxic is unknown. The dosage of cephalothin might be important in this respect, since nephrotoxicity has not been a major problem (7) in studies in which lower doses of cephalothin have been used. Our study, therefore, suggests that the combinations Tic-Tob and Tic-Cef have similar effectiveness and tolerance as empiric therapies for gram-negative infections of patients with cancer. However, neither combination can be expected to be effective against all possible pathogens; moreover, the susceptibility of microorganisms to antibiotics changes as newer antimicrobial agents come into common use. Therefore, bacteriological monitoring of patients who are predisposed to serious infections is essential before and during antimicrobial therapy. Equally important are the investigation of more
EMPIRIC THERAPY FOR CANCER PATIENTS
VOL. 7, 1975
effective methods to detect still earlier bacterial infections and efforts to better understand the physiopathology of severe sepsis, since antimicrobial treatment, although important, is not the only measure to be taken to prevent mortality in severe sepsis. ACKNOWLEDGMENTS This investigation was supported in part by a grant from the Fonds de la Recherche Scientifique Medicale (F.R.S.M. no. 20.368), Brussels, Belgium, and partly by a grant from both Eli Lilly, Indianapolis, Ind., and Beecham, S. A., Brussels, Belgium. We thank M. J. Menne, L. Vandenborre, and L. Van Schoonbrouck for their technical assistance and R. Andries for secretarial help.
LITERATURE CITED 1. Bodey, G. P., J. Hart, E. J. Freireich, and E. Frei. 1966. Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia. Ann. Int. Med. 64:328-340. 2. Bodey, G. P., E. Middleman, T. Umsawadi, and V. Rodriguez. 1972. Infections in cancer patients. Result with gentamicin sulfate therapy. Cancer 29:1697-1701. 3. Fillastre, J. P., R. Laumonier, G. Humbert, D. Dubois, J. Metayer, A. Delpech, J. Leroy, and M. Robert. 1973. Acute renal failure associated with combined gentamicin and cephalothin therapy. Br. Med. J. 2:396-397. 4. Freid, M. A., and K. L. Vosti. 1968. The importance of underlying disease in patients with gram negative bacteremia. Arch. Int. Med. 121:418-423. 5. Klastersky, J. 1973. Effectiveness of the carbenicillincephalothin combination against gram negative bacilli. Am. J. Med. Sci. 265:45-53. 6. Klastersky, J., R. Cappel, and D. Daneau. 1972. Clinical significance of in vitro synergism between antibiotics in gram-negative infections. Antimicrob. Agents Chemother. 2:470-475.
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7. Klastersky, J., R. Cappel, G. Swings, and L. Vandenboffe. 1971. Bacteriological and clinical activity of the ampicillin/gentamicin and cephalothin/gentamicin combinations. Am. J. Med. Sci. 262:273-380. 8. Klastersky, J., D. Daneau, and A. Verhest. 1972. Causes of death in patients with cancer. Eur. J. Cancer 8:149-154. 9. Klastersky, J., A. Henri, C. Hensgens; and D. Daneau. 1974. Gram negative infections in cancer. Study of empiric therapy comparing carbenicillin-cephalothin with and without gentamicin. J. Am. Med. Assoc. 227:45-48. 10. Klastersky, J., A. Henri, and L. Vandenborre. 1973. Antimicrobial activity of tobramycin and gentamicin used in combination with cephalothin and carbenicillin. Am. J. Med. Sci. 266:13-21. 11. Levine, A. S., S. C. Schimpff, R. G. Graw, and R. C. Young. 1974. Hematologic malignancies and other marrow failure states. Progress in the management of complicating infections. Semin. Hetnatol. 11:141-202. 12. Middlemans, E. L., A. Watanak, H. Kaizer, and G. P. Bodey. 1972. Antibiotic combinations for infections in neutropenic patients. Evaluation of carbenicillin plus either cephalothin of kanamycin. Cancer 30:573-679. 13. Perry, J. E., and L. E. Cluff. 1966. The effect of penicillin upon experimental lethal pneumococcal infection. Tex. Rep. Biol. Med. 24:141-152. 14. Richards, F., C. McCall, and C. Cox. 1971. Gentamicin treatment of staphylococcal infections. J. Am. Med. Assoc. 215:1297-1300. 15. Schimpff, S., W. Satterlee, V. M. Young, and A. Serpick. 1971. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N. Engl. J. Med. 284:1061-1065. 16. Steers, E., E. L. Foltz, and B. S. Graves. 1959. Inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother. 3:307-311. 17. Tattersall, M. H. N., A. S. D. Spiers, and J. H. Darell. 1972. Initial therapy with combination of five antibiotics in febrile patients with leukemia and neutropenia. Lancet 1:162-165.
