©1991 S. Karger AG, Basel 0009-3157/91/0375-0382 $2.75/0
Chemotherapy 1991 ;37:382-388
Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases Ch. Blanc, J.P. Pallet, F Banters Service des Maladies du Sang. CHR, Lille, France
Key Words. Neutropenic patients • Ceftriaxone • Amikacin
Introduction
The steadily improving prognosis for a number of malignant blood diseases, in cluding acute leukemia (AL) and ad vanced non-Hodgkin’s lymphoma (NHL), is due to the use of highly aplasia-inducing antimitotic chemotherapies which cause
unavoidable, deep and sometimes very prolonged peripheral cytopenias. Anemia can be easily corrected by red blood cell transfusions, and the risk of hemorrhage associated with thrombopenia can be prevented by transfusions of plate let units. Infections related to severe neutrope
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
Abstract. 100 febrile patients with chemotherapy-induced neutropenia ( 20 days were treated with ceftriaxone plus amikacin alone. 9 of the 23 bacte riologically documented episodes were successes (including 6 of the 11 cases due to Sta phylococcus), 1 were improvements and 7 were failures (including the 3 cases due to Pseudomonas). No side effects were seen. Ceftriaxone plus amikacin is an effective firstline antibiotic combination in the treatment of febrile neutropenic patients.
Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases
383
Patients and Methods 100 patients were included in this study, with ages ranging from 8 to 72 years (mean age 41 years). All had polymorphonuclear neutrophil counts of less than 500/mm3. The hematologic diseases were:
kacin (15 to 20 mg/kg daily given as 2 or 3 infusions per day). If necessary, the dosage of amikacin was adapted according to creatinine levels. This combi nation was maintained for at least 72 h. If successful, it was continued up to regression of aplasia or at least until polymorphonuclear neutrophil levels had recovered to 1,000/mm3. After 72 h of treatment, if ineffective, the antibiotic therapy was modified by
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
nia remain the main cause of morbidity AL (51), advanced NHL (29), Hodgkin’s disease (12) and mortality in these patients [2]. In the and other hematologic malignancies (8). Patients absence of the drastic antiseptic measures with refractory AL or on a conditioning regimen for (gut decontamination, sterile feeding), bone marrow transplantation were excluded. All pa tients were treated in conventional isolation rooms, usually reserved for patients submitted to without gut decontamination. All had a central ve a conditioning regimen for bone marrow nous line. As soon as they entered the aplastic phase, pa transplantation and treated in protected environment, microbial infection is un tients with AL or NHL were clinically monitored, avoidable when the polymorphonuclear and their axial temperature was checked every 6 h. Every time it was over 38.5 °C, or between 38 and neutrophil count drops below 5()0/mm\ 38.5 °C for more than 3 h (excluding pyrogenic reac Treatment consists in empiric intrave tions to drugs or posttransfusional temperature), we nous administration of an antibiotic com performed 3 blood cultures within 3 h, plus (when bination initiated as early as possible and appropriate) clinically relevant bacterial samples made as specific as possible, but covering (skin, otorhinolaryngological region, bronchial tract, urine, stools); then we started the antibiotic therapy. most of the pathogenic organisms; it must Other patients undergoing intensive chemotherapy also consider the local microbial ecology (consolidation or reinduction chemotherapies) were [11]. If this antibiotic therapy is used ratio allowed to return home but were instructed to come nally, death secondary to infection in non back to our department as soon as their temper refractory neutropenic patients with AL or ature reached 38.5 °C or stayed between 38 and 38.5 °C for more than 3 h. They were then submitted highly malignant NHL should not exceed to diagnostic tests as described above. 10% (excluding very old patients and pa We distinguished 4 different infectious states: tients with very severe visceral associated septicemia, characterized by at least one positive failures). Granulocyte transfusions, which hemoculturc independent of the clinical status and are difficult to prepare, vary in efficacy of the results of other bacteriological samples (13 cases); bacteriologically defined infection but with and usually generate side effects, have be out septicemia (10 cases); clinically defined infec come unusual now [3], tion, but without any identified pathogen (10 cases); According to most of the authors, the nondocumented infection (67 cases). None of the 67 cases of fever of undetermined first-line antibiotic therapy should be origin were toxic or posttransfusional. based on the combination of a [1-lactam The predominance of this latter type of febrile antibiotic and an aminoglycoside. episode with negative hemocultures is connected We report here the results obtained by with the extremely rapid initiation of antibiotic ther the combination of a third-generation ce apy, which, however, is necessary to control infec phalosporin (ceftriaxone) and amikacin in tions in neutropenic patients. The first-line antibiotic therapy was a combina 100 patients with chemotherapy-induced tion of ceftriaxone (a 2-gram infusion once a day in neutropenia. adults or 50 mg/kg once daily in children) and ami
Blanc/Pollet/Bauters
384 Table 1. Results by hematologic disease AL (induction chemotherapy)
Hodgkin's disease
NHL
Myeloma
Other diseases
Total
Success Improvement Primary failure Secondary failure
20 14 7 10
2 7 1 2
14 11 4 0
0 0 0 1
3 4 0 0
39 36 12 13
Total
51
12
29
1
7
100
Tabic 2. Results by duration of aplasia
Success Improvement Primary failure Secondary failure Total
6-10 days
10-20 days
> 20 days
Total
9 4 0 0
22 16 3 0
6 7 6 7
2 9 3 6
39 36 12 13
13
41
26
20
100
addition of other antibiotics such as vancomycin and amphotericin B. This choice, although sometimes based on bacteriological data, was mostly empiric. Ceftriaxone was either maintained or replaced by another ¡5-lactam antibiotic such as piperacillin or ceftazidime. All patients underwent clinical and special ex aminations (hemogram and main laboratory param eters) every day.
Results
Evaluation of the results was based on the following definitions: - Success: temperature decrease within 72 h, with normothermia lasting until reso lution of aplasia, under the ceftriaxone plus amikacin combination only
- Improvement: apyrexia obtained with in 72 h after modifying the first-line anti biotic combination therapy but without substituting ceftriaxone and amikacin (ad dition of vancomycin or amphotericin B) - Primary failure: persistence of fever after 72 h and need for different antibiotic therapy - Secondary failure: transient apyrexia under ceftriaxone plus amikacin within 72 h, but recurrence of fever requiring ad ministration of a different antibiotic ther apy The following results were obtained: suc cess, 39; improvement, 36; primary failure, 12; secondary failure, 13. Only 4 patients died of infections. The results, correlated to the underly
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< 6 days
385
Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases
Table 3. Results correlated to the primary infec tion status Septi cemia
BDI
CDI
7 3
2 4
3 6
27 23
39 36
1
1
1
9
12
2
3
0
8
13
13
10
10
67
100
Success Improvement Primary failure Secondary failure Total
Fever
Total
BD1 = Bacteriologically defined infection (not septicemic); CDI = clinically defined infection (no pathogen isolated); fever = of undetermined origin.
Ototoxicity was not systematically investi gated, but no case of loss of auditive acuity was reported. In 3 patients we noticed a moderate increase in creatinine levels which required a reduction in amikacin dosage.
Discussion
Three main advantages justify the use of a first-line antibiotic therapy based on the synergic combination of a (Tlactam and an aminoglycoside in neutropenic pa tients: a broad antibacterial spectrum, high bactericidal activity and limited occurrence of resistant bacterial strains [7-11]. The main disadvantage of the combina tion is the nephrotoxicity of the aminogly cosides, especially when they are pre scribed with other nephrotoxic drugs like ciclosporin or cisplatin (such cases did not
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
ing hematologic disease, are to be found in table 1. Primary and secondary failures were twice as frequent in patients with AL (all patients with induction chemotherapy) than in patients with NHL plus Hodgkin’s disease (17/51 vs. 7/41, i.e. 33.5 vs. 17%). The results related to the duration of aplasia are reported in table 2. The failure rate was zero when aplasia was of short duration (less than 6 days). It was low be tween 6 and 10 days (3/41, i.e. 7%) but be came higher when the aplasia lasted more than 10 days (22/46, i.e. 48%). When the aplasia lasted more than 20 days, only 2 patients out of 20 (10%) experienced reso lution of aplasia without modification of the antibiotic combination therapy. The results correlated to the initial in fectious status are summarized in table 3. No significant difference was found be tween bacteriologically documented and nondocumented infections (septicemia 4bacteriologically documented infections = 7 failures/23, i.e. 30%, vs. 18 failures/77, i.e. 23%, for clinically documented infection + fever of undetermined origin). Table 4 relates the results to the patho gens initially identified: 6/11 documented Staphylococcus infections were cured by the ceftriaxone plus amikacin combina tion. 4 failures occurred in patients in whom gram-negative bacilli had been identified (1 Escherichia coli, 3 Pseudomo nas aeruginosa). No particular side effect of the ceftriax one plus amikacin combination was noted in the 39 patients who did not require ad dition of vancomycin or amphotericin B (both of these agents almost always cause various side effects). 2 cases of allergic cu taneous eruption were reported, but did not necessitate withdrawal of treatment.
Blanc/Pollet/Bauters
386
Pathogen
Gram-positive Staphylococcus Enterococcus Streptococcus hovis Gram-negative Escherichia coli Pseudomonas aeruginosa Klebsiella Salmonella Candida albicans Total
Success
Improvement
Primary failure
Secondary failure
Total
6 0 0
3 1 1
0 0 0
2 0 0
11 1 1
2 0 1 0 0
0 0 0 1 1
1 1 0 0 0
0 2 0 1 1
3 3 1 1 2
9
7
2
5
23
occur in our study). In these cases another first-line antibiotic therapy can be pro posed: Two P-lactams [5], a (3-lactam plus a quinolone or monotherapy with ceftriax one [12], ceftazidime [13], aztreonam [10] or imipenem [14]. No other combination seems to be as satisfactory in neutropenic patients as an aminoglycoside plus a [3-iactam, but we must await the findings ob tained with the new fluoroquinolones, and also the success of monotherapy as pro posed by some authors every time a new broad-spectrum P-lactam appears on the antibiotics market [1], For this study we chose to combine cef triaxone with amikacin. Ceftriaxone is a third-generation cephalosporin. Its spec trum is '• ;ry similar to that of cefotaxime, so it has excellent efficacy against gram negative bacilli, including multiresistant strains [6], Of all the third-generation ce phalosporins, ceftriaxone has the longest half-life, with the result that it can be ad
ministered once daily. Because of its renal and hepatic clearance, the dosage does not need to be adjusted in patients with renal failure. Major side effects are very rare. It has little influence on hemostasis, unlike other cephalosporins which contain a methylthiotetrazole site and thus require prophylactic vitamin K therapy when given over longer periods. Since these results were obtained under standard therapeutic conditions in neutro penic patients who were not confined to a sterile environment, the following conclu sions may be drawn. First and foremost, we were able to confirm the reports of other investigators [4, 9] suggesting that the regression of an infection in response to treatment with a combination of a [J-lactam and an aminoglycoside depends to a large extent on the depth and duration of aplasia. When this is of short duration and consists only of granulopenia (a common situation after NHL chemotherapies or
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
Tabic 4. Results by pathogen first identified
387
Identification of a pathogen can help in AL maintenance treatment), this kind of combination therapy is usually sufficient. adjusting the antimicrobial treatment, but, It must, however, be initiated as soon as owing to the frequency of polymicrobial fever occurs. When the aplasia is deep and infections in patients with prolonged apla of long duration (as after intensive induc sia, is unlikely to reduce the need for in tion chemotherapy in AL patients), the tensive broad spectrum antibiotic therapy. failure rate increases dramatically, and The results of the combination therapy this first-line antibiotic therapy usually has are the same regardless of whether the in to be modified [11]. It is generally neces fection was initially bacteriologically docu sary to introduce antibiotics which cover mented or not. This shows once more that all gram-positive cocci, especially methicil- isolated fevers in neutropenic patients lin-resistant staphylococci, which prefer (when toxic and posttransfusional causes entially infect patients with central cathe have been excluded) are secondary to in ters. In such cases, the use of vancomycin fection. (despite its side effects) or perhaps teicoplanin (which would have less severe side effects) becomes necessary. Conclusion In patients with deep aplasia who have already been treated extensively with an The use of the combination ceftriaxone antibacterial combination, covering gram plus amikacin as first-line antibiotic ther positive cocci, but who are persistently fe apy in chemotherapy-induced neutropenia brile, amphotericin B must be added to seems to be justified and can be compared combat a possible systemic mycosis. De to other antibiotic therapies combining spite this drug’s poor tolerability, it should amikacin with another third-generation be used in such cases because it remains cephalosporin or an acylureidopenicillin the only antifungal agent that is almost al like piperacillin. The combination of cef ways effective against yeasts and Aspergil triaxone plus amikacin is effective in apla lus. The role of new triazolc drugs (itraco sia of short duration such as after lympho nazole, fluconazole) has not yet been ma chemotherapies (and, by extension, clearly defined in this type of indication. after solid tumor chemotherapies). In This progressive augmentation of the neutropenic patients after AL induction antibiotic therapy is common after AL in chemotherapy, this combination therapy duction chemotherapy and is usually has commonly to be modified by addition based on empiric assessment and on or substitution of other antibiotics capable knowledge of the local microbial ecology of extending the spectrum of action. [11]. Failure to manage a therapeutic win dow makes it even more difficult to isolate References the pathogen which was responsible for the failure of a previous antibiotic combi 1 Anaissie, E.; Rolston, K.; Bodey, G.P.: Treat nation. Immunologic assays for systemic ment of gram-negative bacteremia in patients mycosis are quite irrelevant in these imwith cancer and granulocytopenia. New Engl. J. munodcficicnt patients. Med. 318: 1694-1695 (1988).
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Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases
2 Bodey, G.P.: Antibiotics in patients with neutro penia. Archs Intern. Med. 144: 1845-1851 (1984). 3 Buckner, C.D.; Clift, R.A.: Prophylaxis and treatment of infection in the immunocompro mised host by granulocyte transfusions; in Clin ics in haematology, pp. 557-572 (Saunders, Phil adelphia 1984). 4 Calvo, F.; De Castro, H.; Brice P.: Traitement des episodes infectieux chez les malades neutropéniques par l’association pipcracilline et amikacine. Presse méd. 15: 2353-2357 (1986). 5 Dejongh, C.A.; Joshi, J.H.; Thompson, B.W.; et al.: A double beta-lactam combination versus an aminoglycoside-containing regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients. Am. J. Med. 80: suppl., pp. 101— 111 (1986). 6 Donowitz, G.R.; Mandell, G.L.: Beta-lactam an tibiotics. New Engl. J. Med. 318: 490-500 (1988). 7 EORTC: Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. New Engl. J. Mcd. 317: 1692-1698 (1987). 8 Guy, H.; Caillot, D.; Solary, E.; Bielefeld, P.; Portier, H.; Kazmierczak, A.: Association d’unc céphalosporine de troisième génération (céfotaxime ou ceftazidime) et d’une nouvelle quinolone (péfloxacinc) dans le traitement des épi sodes fébriles des malades neutropéniques. Presse méd. 16: 2172-2175 (1987). 9 Hcrbrecht, R.; Jehl, F.; Bergerat, J.P.; Dufour, P.; Duclos, B.; Lang, J.M.; Oberling, F.: Etude de l’association ceftriaxone-netilmicinc dans le traitement des infections chez les patients agranulocytaires. Méd. Mal. infect. 8: 520-523 (1986).
Blanc/Pollet/Bauters 10 Jones. P.G.; Rolston, K.V.; Fainstein, V.; Elting, L.; Walters, R.S.; Bodey, G.P.: Aztreonam ther apy in neutropenic patients with cancer. Am. J. Mcd. 81: 243-248 (1986). 11 Klastcrsky, J.: Concepts of empiric therapy with antibiotic combinations: indications and limits. Am. J. Mcd. 80: suppl. pp. 2-12 (1986). 12 Pasternak, J.: Ceftriaxona no tratamento de infeccoes en pacientes neutropenicos. Fohla mcd. 94: 275-277 (1987). 13 Pizzo, P.A.; Hathorn. J.W.; Hiemcnz, J.; et al.: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. New Engl. J. Mcd. 315: 552-558 (1986). 14 Wade, J.; Bustamante, C.; Devlin, A.; et al.: Imipenem versus piperacillin plus amikacin, empiric therapy for febrile neutropenic patients. Proc. 27th lntersci. Conf. Antimicrob. Agents Chemother., New York 1987.
Received: February 20, 1990 Accepted after revision: May 22, 1991 Prof. F. Bauters Service des Maladies du Sang CHR, Hôpital Huriez 1, Place dc Verdun F-59000 Lille (France)
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388
Chemotherapy 1991 ;37:382-388
Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases Ch. Blanc, J.P. Pallet, F Banters Service des Maladies du Sang. CHR, Lille, France
Key Words. Neutropenic patients • Ceftriaxone • Amikacin
Introduction
The steadily improving prognosis for a number of malignant blood diseases, in cluding acute leukemia (AL) and ad vanced non-Hodgkin’s lymphoma (NHL), is due to the use of highly aplasia-inducing antimitotic chemotherapies which cause
unavoidable, deep and sometimes very prolonged peripheral cytopenias. Anemia can be easily corrected by red blood cell transfusions, and the risk of hemorrhage associated with thrombopenia can be prevented by transfusions of plate let units. Infections related to severe neutrope
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
Abstract. 100 febrile patients with chemotherapy-induced neutropenia ( 20 days were treated with ceftriaxone plus amikacin alone. 9 of the 23 bacte riologically documented episodes were successes (including 6 of the 11 cases due to Sta phylococcus), 1 were improvements and 7 were failures (including the 3 cases due to Pseudomonas). No side effects were seen. Ceftriaxone plus amikacin is an effective firstline antibiotic combination in the treatment of febrile neutropenic patients.
Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases
383
Patients and Methods 100 patients were included in this study, with ages ranging from 8 to 72 years (mean age 41 years). All had polymorphonuclear neutrophil counts of less than 500/mm3. The hematologic diseases were:
kacin (15 to 20 mg/kg daily given as 2 or 3 infusions per day). If necessary, the dosage of amikacin was adapted according to creatinine levels. This combi nation was maintained for at least 72 h. If successful, it was continued up to regression of aplasia or at least until polymorphonuclear neutrophil levels had recovered to 1,000/mm3. After 72 h of treatment, if ineffective, the antibiotic therapy was modified by
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
nia remain the main cause of morbidity AL (51), advanced NHL (29), Hodgkin’s disease (12) and mortality in these patients [2]. In the and other hematologic malignancies (8). Patients absence of the drastic antiseptic measures with refractory AL or on a conditioning regimen for (gut decontamination, sterile feeding), bone marrow transplantation were excluded. All pa tients were treated in conventional isolation rooms, usually reserved for patients submitted to without gut decontamination. All had a central ve a conditioning regimen for bone marrow nous line. As soon as they entered the aplastic phase, pa transplantation and treated in protected environment, microbial infection is un tients with AL or NHL were clinically monitored, avoidable when the polymorphonuclear and their axial temperature was checked every 6 h. Every time it was over 38.5 °C, or between 38 and neutrophil count drops below 5()0/mm\ 38.5 °C for more than 3 h (excluding pyrogenic reac Treatment consists in empiric intrave tions to drugs or posttransfusional temperature), we nous administration of an antibiotic com performed 3 blood cultures within 3 h, plus (when bination initiated as early as possible and appropriate) clinically relevant bacterial samples made as specific as possible, but covering (skin, otorhinolaryngological region, bronchial tract, urine, stools); then we started the antibiotic therapy. most of the pathogenic organisms; it must Other patients undergoing intensive chemotherapy also consider the local microbial ecology (consolidation or reinduction chemotherapies) were [11]. If this antibiotic therapy is used ratio allowed to return home but were instructed to come nally, death secondary to infection in non back to our department as soon as their temper refractory neutropenic patients with AL or ature reached 38.5 °C or stayed between 38 and 38.5 °C for more than 3 h. They were then submitted highly malignant NHL should not exceed to diagnostic tests as described above. 10% (excluding very old patients and pa We distinguished 4 different infectious states: tients with very severe visceral associated septicemia, characterized by at least one positive failures). Granulocyte transfusions, which hemoculturc independent of the clinical status and are difficult to prepare, vary in efficacy of the results of other bacteriological samples (13 cases); bacteriologically defined infection but with and usually generate side effects, have be out septicemia (10 cases); clinically defined infec come unusual now [3], tion, but without any identified pathogen (10 cases); According to most of the authors, the nondocumented infection (67 cases). None of the 67 cases of fever of undetermined first-line antibiotic therapy should be origin were toxic or posttransfusional. based on the combination of a [1-lactam The predominance of this latter type of febrile antibiotic and an aminoglycoside. episode with negative hemocultures is connected We report here the results obtained by with the extremely rapid initiation of antibiotic ther the combination of a third-generation ce apy, which, however, is necessary to control infec phalosporin (ceftriaxone) and amikacin in tions in neutropenic patients. The first-line antibiotic therapy was a combina 100 patients with chemotherapy-induced tion of ceftriaxone (a 2-gram infusion once a day in neutropenia. adults or 50 mg/kg once daily in children) and ami
Blanc/Pollet/Bauters
384 Table 1. Results by hematologic disease AL (induction chemotherapy)
Hodgkin's disease
NHL
Myeloma
Other diseases
Total
Success Improvement Primary failure Secondary failure
20 14 7 10
2 7 1 2
14 11 4 0
0 0 0 1
3 4 0 0
39 36 12 13
Total
51
12
29
1
7
100
Tabic 2. Results by duration of aplasia
Success Improvement Primary failure Secondary failure Total
6-10 days
10-20 days
> 20 days
Total
9 4 0 0
22 16 3 0
6 7 6 7
2 9 3 6
39 36 12 13
13
41
26
20
100
addition of other antibiotics such as vancomycin and amphotericin B. This choice, although sometimes based on bacteriological data, was mostly empiric. Ceftriaxone was either maintained or replaced by another ¡5-lactam antibiotic such as piperacillin or ceftazidime. All patients underwent clinical and special ex aminations (hemogram and main laboratory param eters) every day.
Results
Evaluation of the results was based on the following definitions: - Success: temperature decrease within 72 h, with normothermia lasting until reso lution of aplasia, under the ceftriaxone plus amikacin combination only
- Improvement: apyrexia obtained with in 72 h after modifying the first-line anti biotic combination therapy but without substituting ceftriaxone and amikacin (ad dition of vancomycin or amphotericin B) - Primary failure: persistence of fever after 72 h and need for different antibiotic therapy - Secondary failure: transient apyrexia under ceftriaxone plus amikacin within 72 h, but recurrence of fever requiring ad ministration of a different antibiotic ther apy The following results were obtained: suc cess, 39; improvement, 36; primary failure, 12; secondary failure, 13. Only 4 patients died of infections. The results, correlated to the underly
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< 6 days
385
Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases
Table 3. Results correlated to the primary infec tion status Septi cemia
BDI
CDI
7 3
2 4
3 6
27 23
39 36
1
1
1
9
12
2
3
0
8
13
13
10
10
67
100
Success Improvement Primary failure Secondary failure Total
Fever
Total
BD1 = Bacteriologically defined infection (not septicemic); CDI = clinically defined infection (no pathogen isolated); fever = of undetermined origin.
Ototoxicity was not systematically investi gated, but no case of loss of auditive acuity was reported. In 3 patients we noticed a moderate increase in creatinine levels which required a reduction in amikacin dosage.
Discussion
Three main advantages justify the use of a first-line antibiotic therapy based on the synergic combination of a (Tlactam and an aminoglycoside in neutropenic pa tients: a broad antibacterial spectrum, high bactericidal activity and limited occurrence of resistant bacterial strains [7-11]. The main disadvantage of the combina tion is the nephrotoxicity of the aminogly cosides, especially when they are pre scribed with other nephrotoxic drugs like ciclosporin or cisplatin (such cases did not
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
ing hematologic disease, are to be found in table 1. Primary and secondary failures were twice as frequent in patients with AL (all patients with induction chemotherapy) than in patients with NHL plus Hodgkin’s disease (17/51 vs. 7/41, i.e. 33.5 vs. 17%). The results related to the duration of aplasia are reported in table 2. The failure rate was zero when aplasia was of short duration (less than 6 days). It was low be tween 6 and 10 days (3/41, i.e. 7%) but be came higher when the aplasia lasted more than 10 days (22/46, i.e. 48%). When the aplasia lasted more than 20 days, only 2 patients out of 20 (10%) experienced reso lution of aplasia without modification of the antibiotic combination therapy. The results correlated to the initial in fectious status are summarized in table 3. No significant difference was found be tween bacteriologically documented and nondocumented infections (septicemia 4bacteriologically documented infections = 7 failures/23, i.e. 30%, vs. 18 failures/77, i.e. 23%, for clinically documented infection + fever of undetermined origin). Table 4 relates the results to the patho gens initially identified: 6/11 documented Staphylococcus infections were cured by the ceftriaxone plus amikacin combina tion. 4 failures occurred in patients in whom gram-negative bacilli had been identified (1 Escherichia coli, 3 Pseudomo nas aeruginosa). No particular side effect of the ceftriax one plus amikacin combination was noted in the 39 patients who did not require ad dition of vancomycin or amphotericin B (both of these agents almost always cause various side effects). 2 cases of allergic cu taneous eruption were reported, but did not necessitate withdrawal of treatment.
Blanc/Pollet/Bauters
386
Pathogen
Gram-positive Staphylococcus Enterococcus Streptococcus hovis Gram-negative Escherichia coli Pseudomonas aeruginosa Klebsiella Salmonella Candida albicans Total
Success
Improvement
Primary failure
Secondary failure
Total
6 0 0
3 1 1
0 0 0
2 0 0
11 1 1
2 0 1 0 0
0 0 0 1 1
1 1 0 0 0
0 2 0 1 1
3 3 1 1 2
9
7
2
5
23
occur in our study). In these cases another first-line antibiotic therapy can be pro posed: Two P-lactams [5], a (3-lactam plus a quinolone or monotherapy with ceftriax one [12], ceftazidime [13], aztreonam [10] or imipenem [14]. No other combination seems to be as satisfactory in neutropenic patients as an aminoglycoside plus a [3-iactam, but we must await the findings ob tained with the new fluoroquinolones, and also the success of monotherapy as pro posed by some authors every time a new broad-spectrum P-lactam appears on the antibiotics market [1], For this study we chose to combine cef triaxone with amikacin. Ceftriaxone is a third-generation cephalosporin. Its spec trum is '• ;ry similar to that of cefotaxime, so it has excellent efficacy against gram negative bacilli, including multiresistant strains [6], Of all the third-generation ce phalosporins, ceftriaxone has the longest half-life, with the result that it can be ad
ministered once daily. Because of its renal and hepatic clearance, the dosage does not need to be adjusted in patients with renal failure. Major side effects are very rare. It has little influence on hemostasis, unlike other cephalosporins which contain a methylthiotetrazole site and thus require prophylactic vitamin K therapy when given over longer periods. Since these results were obtained under standard therapeutic conditions in neutro penic patients who were not confined to a sterile environment, the following conclu sions may be drawn. First and foremost, we were able to confirm the reports of other investigators [4, 9] suggesting that the regression of an infection in response to treatment with a combination of a [J-lactam and an aminoglycoside depends to a large extent on the depth and duration of aplasia. When this is of short duration and consists only of granulopenia (a common situation after NHL chemotherapies or
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:23:34 PM
Tabic 4. Results by pathogen first identified
387
Identification of a pathogen can help in AL maintenance treatment), this kind of combination therapy is usually sufficient. adjusting the antimicrobial treatment, but, It must, however, be initiated as soon as owing to the frequency of polymicrobial fever occurs. When the aplasia is deep and infections in patients with prolonged apla of long duration (as after intensive induc sia, is unlikely to reduce the need for in tion chemotherapy in AL patients), the tensive broad spectrum antibiotic therapy. failure rate increases dramatically, and The results of the combination therapy this first-line antibiotic therapy usually has are the same regardless of whether the in to be modified [11]. It is generally neces fection was initially bacteriologically docu sary to introduce antibiotics which cover mented or not. This shows once more that all gram-positive cocci, especially methicil- isolated fevers in neutropenic patients lin-resistant staphylococci, which prefer (when toxic and posttransfusional causes entially infect patients with central cathe have been excluded) are secondary to in ters. In such cases, the use of vancomycin fection. (despite its side effects) or perhaps teicoplanin (which would have less severe side effects) becomes necessary. Conclusion In patients with deep aplasia who have already been treated extensively with an The use of the combination ceftriaxone antibacterial combination, covering gram plus amikacin as first-line antibiotic ther positive cocci, but who are persistently fe apy in chemotherapy-induced neutropenia brile, amphotericin B must be added to seems to be justified and can be compared combat a possible systemic mycosis. De to other antibiotic therapies combining spite this drug’s poor tolerability, it should amikacin with another third-generation be used in such cases because it remains cephalosporin or an acylureidopenicillin the only antifungal agent that is almost al like piperacillin. The combination of cef ways effective against yeasts and Aspergil triaxone plus amikacin is effective in apla lus. The role of new triazolc drugs (itraco sia of short duration such as after lympho nazole, fluconazole) has not yet been ma chemotherapies (and, by extension, clearly defined in this type of indication. after solid tumor chemotherapies). In This progressive augmentation of the neutropenic patients after AL induction antibiotic therapy is common after AL in chemotherapy, this combination therapy duction chemotherapy and is usually has commonly to be modified by addition based on empiric assessment and on or substitution of other antibiotics capable knowledge of the local microbial ecology of extending the spectrum of action. [11]. Failure to manage a therapeutic win dow makes it even more difficult to isolate References the pathogen which was responsible for the failure of a previous antibiotic combi 1 Anaissie, E.; Rolston, K.; Bodey, G.P.: Treat nation. Immunologic assays for systemic ment of gram-negative bacteremia in patients mycosis are quite irrelevant in these imwith cancer and granulocytopenia. New Engl. J. munodcficicnt patients. Med. 318: 1694-1695 (1988).
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Ceftriaxone plus Amikacin in Neutropenic Patients: A Report on 100 Cases
2 Bodey, G.P.: Antibiotics in patients with neutro penia. Archs Intern. Med. 144: 1845-1851 (1984). 3 Buckner, C.D.; Clift, R.A.: Prophylaxis and treatment of infection in the immunocompro mised host by granulocyte transfusions; in Clin ics in haematology, pp. 557-572 (Saunders, Phil adelphia 1984). 4 Calvo, F.; De Castro, H.; Brice P.: Traitement des episodes infectieux chez les malades neutropéniques par l’association pipcracilline et amikacine. Presse méd. 15: 2353-2357 (1986). 5 Dejongh, C.A.; Joshi, J.H.; Thompson, B.W.; et al.: A double beta-lactam combination versus an aminoglycoside-containing regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients. Am. J. Med. 80: suppl., pp. 101— 111 (1986). 6 Donowitz, G.R.; Mandell, G.L.: Beta-lactam an tibiotics. New Engl. J. Med. 318: 490-500 (1988). 7 EORTC: Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. New Engl. J. Mcd. 317: 1692-1698 (1987). 8 Guy, H.; Caillot, D.; Solary, E.; Bielefeld, P.; Portier, H.; Kazmierczak, A.: Association d’unc céphalosporine de troisième génération (céfotaxime ou ceftazidime) et d’une nouvelle quinolone (péfloxacinc) dans le traitement des épi sodes fébriles des malades neutropéniques. Presse méd. 16: 2172-2175 (1987). 9 Hcrbrecht, R.; Jehl, F.; Bergerat, J.P.; Dufour, P.; Duclos, B.; Lang, J.M.; Oberling, F.: Etude de l’association ceftriaxone-netilmicinc dans le traitement des infections chez les patients agranulocytaires. Méd. Mal. infect. 8: 520-523 (1986).
Blanc/Pollet/Bauters 10 Jones. P.G.; Rolston, K.V.; Fainstein, V.; Elting, L.; Walters, R.S.; Bodey, G.P.: Aztreonam ther apy in neutropenic patients with cancer. Am. J. Mcd. 81: 243-248 (1986). 11 Klastcrsky, J.: Concepts of empiric therapy with antibiotic combinations: indications and limits. Am. J. Mcd. 80: suppl. pp. 2-12 (1986). 12 Pasternak, J.: Ceftriaxona no tratamento de infeccoes en pacientes neutropenicos. Fohla mcd. 94: 275-277 (1987). 13 Pizzo, P.A.; Hathorn. J.W.; Hiemcnz, J.; et al.: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. New Engl. J. Mcd. 315: 552-558 (1986). 14 Wade, J.; Bustamante, C.; Devlin, A.; et al.: Imipenem versus piperacillin plus amikacin, empiric therapy for febrile neutropenic patients. Proc. 27th lntersci. Conf. Antimicrob. Agents Chemother., New York 1987.
Received: February 20, 1990 Accepted after revision: May 22, 1991 Prof. F. Bauters Service des Maladies du Sang CHR, Hôpital Huriez 1, Place dc Verdun F-59000 Lille (France)
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