Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Trimethoprim-Sulfamethoxazole plus Amikacin as First-Line Therapy and Imipenem/Cilastatin as Second Empirical Therapy in Febrile Neutropenic Patients with Hematological Disorders P.A. Engervall, G.T. Stiernstedt, G.C. Günther & M.J. Björkholm To cite this article: P.A. Engervall, G.T. Stiernstedt, G.C. Günther & M.J. Björkholm (1992) Trimethoprim-Sulfamethoxazole plus Amikacin as First-Line Therapy and Imipenem/Cilastatin as Second Empirical Therapy in Febrile Neutropenic Patients with Hematological Disorders, Journal of Chemotherapy, 4:2, 99-106, DOI: 10.1080/1120009X.1992.11739148 To link to this article: http://dx.doi.org/10.1080/1120009X.1992.11739148
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Date: 20 March 2017, At: 03:41
Vol. 4 - n. 2 (99-106) - 1992
Journal of Chemotherapy
TrimethoprimSulfamethoxazole plus Amikacin as First-Line Therapy and lmipenem/Cilastatin as Second Empirical Therapy in Febrile Neutropenic Patients with Hematological Disorders
during TMP/SMZ +AMI therapy and (b) 18 episodes with a second fever episode during initially successful TMP/ SMZ +AMI therapy. The response rate for all 40 1/C treated episodes was 80%. One neutropenic patient in the whole series died from infectious complications within four weeks from institution of therapy. TMP/SMZ +AMI seems to be a safe and inexpensive «standard» antibiotic regimen in neutropenic patients. I/C appears to have good efficacy when used as secondary therapy after failure with TMP/SMZ +AMI. Key words: Imipenem/cilastatin, trimethoprim-sulfa· methoxazole, amikacin, neutropenia, leukemia, septicemia.
INTRODUCTION
P.A. ENGERVALL * - G.T. STIERNSTEDT ** G.C. GUNTHER** - M.J . BJORKHOLM *
Summary ----------------------- -------One hundred and thirty-nine consecutive episodes of fever were evaluated in 55 patients with hematological disorders during persistent neutropenia. In 121 instances, pa· tients were given trimethoprim-sulfamethoxazole + amikacin (TMP/SMZ +AMI) as an initial antibiotic regimen with clini· cal success in 51% (i.e. antibiotic treatment was not changed within the first 7 days). lmipenem/cilastatin (1/C) therapy was instituted in: (a) 22 episodes with clinical failure and fever of unknown origin
* Division of Hematology and Immunology, Department of Medicine, Karolinska Hospital, Stockholm, Sweden . ** Department of Infectious Diseases, Danderyd Hospital, Danderyd, Sweden.
Requests for reprints and correspondence should be addressed to: Per Engervall, M.D., Division of Hematology and Immunology, Department of Medicine, S-104 01 Stockholm, Sweden . © Edizioni Riviste Sc.ientifiche - Firenze
Karolinska
Hospital,
Infection remains an important cause of morbidity and mortality in patients with hematological malignancies. Though many factors may contribute to the increased susceptibility to various infectious agents in this patient population, the most important predisposing factor is severity and duration of neutropenia 1 • 2 • Routine use of early empirical antibiotic therapy for newly febrile neutropenic patients has decreased infection-related morbidity and mortality in this population 3 • The isolation of grampositive pathogens has increased over the past years, with many of these strains, especially Staphylococcus epidermidis, being resistant or inadequately covered by most empirical regimens used today. Nevertheless, the devastating complications of gram-negative septicemia still remain the major concern. In most studies of empirical antibiotic therapy in neutropenic patients regimens containing both (3-lactam and aminoglycoside antibiotics have been used 3 " 9 • Monotherapy with ceftazidime or imipenem/ ISSN 1120-009X
100
P.A.
ENGERVALL - G.T. STIERNSTEDT - G.C. GUNTHER -
cilastatin (1/C) has also showed good efficacy in this clinical situation 1 0 " 12 • Within the Leukemia Group of Middle Sweden the most commonly used empirical antibiotic combination has been trimethoprim-sulfamethoxazole (TMP/SMZ) plus amikacin (AMI). The rationale for this choice is multifactorial: a) The regimen has a good antibacterial coverage, especially with regard to gram-negative organisms and the broad spectrum of TMP/SMZ also includes Listeria monocytogenes, Pneumocystis carinii, and Nocardia sp. 13 b) Earlier reports on TMP/SMZ in combination with an aminoglycoside or carbenicillin as early empirical therapy have shown its adequate efficacy 14 -16 . c) The combination preserves the anaerobic intestinal microflora. d) TMP/SMZ plus AMI are administered every 12 hours and the cost is low, even when taking into consideration the expenses for determination of AMI serum concentrations. During long-standing and recurrent periods of neutropenia, patients with hematological malignancy and acute leukemia in particular, often develop repeated infections and require therapy modification when a new fever episode occurs during continuous antibiotic treatment 2 • The choice of antibiotic regimen is often difficult in this clinical situation. 1/C monotherapy has a wide spectrum of antibacterial activity and is as effective as standard combinations of ~-lactam and aminoglycoside antibiotics in primary episodes of fever in neutropenic patients 11 • 12 • The risk of gram-positive superinfections increases with prolonged neutropenia 9 • 10 and gram-pos1t1ve isolates which are resistant to both aminoglycosides and ~-lactam antibiotics may emerge. 1/C is active against all streptococcal species and methicillinsusceptible staphylococci as well as anaerobes. Some activity in vitro to methicillin-resistant staphylococci is also reported 17 • Furthermore, there is no evidence of an increased mortality rate by delaying specific therapy against grampositive infections until the causative agent is isolated 11 • 1/C has recently been shown to have good efficacy as secondary therapy in neutropenic cancer patients with documented infections who have failed to respond to primary antibiotic therapy 19 • The toxicity of 1/C is
M.J.
BJORKHOLM
mostly limited to nausea/vomiting and skin rashes in a small proportion of patients 11 • 12 • Thus, 1/C may offer an alternative after TMP/ SMZ plus AMI have failed . The aim of this study was to document the efficacy of TMP/ SMZ plus AMI as a primary empirical antibiotic treatment in a consecutive series of fever episodes in neutropenic patients. Furthermore, the role of 1/C as secondary therapy after TMP/ SMZ plus AMI failure was studied. PATIENTS AND METHODS
This study was conducted on 139 consecutive episodes of fever in 55 patients with hematological disorders admitted to the Division of Hematology and Immunology, Karolinska Hospital during 1988/ 1990. There were 27 men and 28 women (median age 60 years, range 17-83 years) with the following diagnoses: acute nonlymphoblastic leukemia (n = 31), chronic myelogenous leukemia in b1ast crisis (n = 10), acute lymphoblastic leukemia/acute undifferentiated leukemia (n = 8), malignant lymphoma (n = 3), agranulocytosis (n = 1), severe aplastic anemia (n = 1) and myelomatosis (n = 1) . Six patients with leukemia and lymphoma underwent autologous bone marrow or blood stem cell transplantation. In 136 episodes neutropenia was induced by chemotherapy. Neutropenic (absolute neutrophil count < 0.5 X 10 9/l) patients were included if they developed a temperature of ~ 38.5 °C on one occasion or ~ 38.0 °C on two occasions during a 24h period with at least a 4h interval. Fever was not associated with the administration of known pyrogenic substances (blood transfusions, immunotherapeutic agents, etc). Only episodes in patients with neutropenia persisting for more than 4 days after start of antibiotic treatment were evaluated for response. A second episode of fever (n = 18, Figure 1) during the same neutropenic period was evaluated after a minimum of 7 days only if all signs of the first infection had disappeared. Furthermore, 3 consecutive days with a temperature below 3 7.5 °C was required. Fever episodes occurring in patients with prophylactic antibiotic therapy (n = 8) and episodes caused by documented viral or fungal infections (n = 5) were excluded.
TRIMETHOPRIM-SULFAMETHOXAZOLE PLUS AMIKACIN AS FIRST-LINE THERAPY AND IMIPENEM/CILASTATIN, ETC .
Furthermore, in 17 episodes during the study period TMP/SMZ plus AMI was not used as primary empirical therapy due to established allergy (n = 7), referral from other units within the hospital after institution of other antibiotic treatment (n = 3), or when anaerobic infection could be suspected (n = 7). None of these episodes (n = 17) will be discussed further (Figure 1).
Antimicrobial treatment All patients received TMP/SMZ plus AMI therapy when fever occurred (see definition . above). Primary empiric therapy was continued for at least 72 hours. Therapy was changed to I/C if the clinical status deteriorated in patients without documented infection or modified if susceptibility pattern in blood culture isolates revealed resistant bacteria. Persistence of fever per se did not motivate change of therapy. Empirical amphotericin B (Fungizone ®, Bristol-Myers Squibb) at a dose of 0.3 mg/kg was added when fungal infection could not be ruled out in a patient with profound neutropenia, persistence of fever and clinical deterioration. TMP/SMZ (Bactrim ®, Roche) was administered at a standard dose of 160 mg TMP plus 800 mg SMZ i.v.q. 12h. AMI (Biklin®, BristolMyers Squibb) was given at a dose of 7.5 mg/kg i.v.q. 12h. AMI dosage was adjusted, if necessary, to achieve serum concentrations of 15-35 mg/1 30 min after the end of a 30-min infusion and less than 8 mg/1 before the next scheduled dose. The 1/C (Tienam ®, Merck Sharp & Doh me) standard dose was 1 g i. v. over a period of 1h every 8h.
for the diagnosis of septicemia. Urinary tract infection was established when a patient had more than 10 5 colony forming units of a single organism per milliliter of urine. Cellulitis was defined as soft-tissue erythema, tenderness, induration or warmth, with or without microbia- . logical confirmation. Pulmonary infection was diagnosed by the occurrence of a new radiological infiltrate on chest x-ray within 72 hours from debut of fever, with or without positive cultures. Episodes were diagnosed as fever of unknown origin (FUO) if no site or isolate indicative of infection was found within 72 hours.
Criteria for response to therapy All episodes were evaluated for response 7 days after institution of antibiotic therapy. Three categories were defined : A) disappearance of fever and signs of infection within 4 days and lasting for more than 3 days B) no change of antibiotic therapy within 7 days (i.e. persistence of fever with the patient remaining in stable clinical condition) C) change of antibiotic therapy within 7 days or death due to infection.
RESULTS
One hundred and thirty-nine febrile episodes were recorded in the 55 patients (Figure 1). In 125 episodes (90 % ) neutropenia was sev169 epi sodes of fever -> ->
Bacteriological procedures Before institution of empirical antibiotic therapy, specimens for culture were collected from urine, throat, sputum (if possible) and other appropriate sites. At least three blood cultures were performed. The same procedure was repeated if fever persisted or a new episode of fever developed during therapy.
Diagnostic criteria for documented infections The isolation of the same bacterial strain from at least two blood cultures was required
101
8 eplaodes during prophylaxis 5 episodes caused by virus or fungi 17 episodes not treated with amlkacln plus trlmethoprlm sulfamethoxazo l e
,j,
139 eva luable episodes 121 ep i sodes treated with -> 18 ep isodes of "new fever" amlkacln plus trlm ethoduring amlkacln plus trl prl m -s u If a met oxazo l e methoprlm-sulfametoxazole treated with lmlpenemlcllastalln 22 ep isodes with clinical failure during am lka cln plus trlmethoprlm-sulfametoxazole treated with lmlpenemlc llastalln
Figure 1 - Schematic view of the fever episodes recorded in this study.
P.A.
102
ENGERVALL . G.T. SnERNsTEoT •
ere, reaching absolute nadir neutrophil counts < 0.1 X 10 9/l. The mean time from neutropenia (< 0.5 X 10 9/1} to institution of antibiotic treatment was 4.7 days (range 1-16 days). One hundred and twenty-one of the 139 episodes (87%) were primary, i.e. occurring in patients not receiving antibiotic treatment. In 22 of those 121 episodes secondary empirical therapy was also evaluated. Eighteen out of 139 episodes (13%) occurred as a second event of fever during the same neutropenic period in patients receiving TMP/SMZ plus AMI treatment.
c.c.
The clinical outcome of 121 primary fever episodes treated with TMP/SMZ plus AMI is presented in Table 1. Change or modification of treatment (response C) was required in 59/121 instances (49%). In 33/59 fever episodes (56%) the reason for change of primary TMP/SMZ plus AMI was persistence of high fever and clinical deterioration. All of these episodes were classified as FUO except four (two episodes with urinary tract infection and two episodes with pulmonary infection). In another 5/59 instances blood cultures were positive with isolates sensitive to therapy, but persistence of high fever with lack of clinical improvement motivated a change of
TABLE 1 - Response to primary and secondary empirical antibiotic therapy.
Type of therapy and clinical situation TMP/SMZ-AMib in primary fever episodes I/Cc in primary clinical TMP/SMZ-AMI therapy failures I/C in new fever episodes during TMP/SMZ-AMI therapy
Type of response" n.
n .(%)
A
121
22
B
C
42(35) 20(16) 59(49)
17(77)
0
5(23)
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BJoRKHoLM
TABLE 2 · Response to trimethoprim-sulfamethoxazole plus amikacin therapy in primary fever episodes (N = 121) with regard to documented infection or fever of unknown origin.
Type of response (n.)" Total A B C Documented infection Septicemia Urinary tract with septicemia Pulmonary with septicemia Cellulitis Total Fever of unknown origin
TMP/SMZ plus AMI therapy in 121 primary fever episodes
GuNTHER •
8 3
4 1
3
21 2 1
33 6 1
2 1
6 1
14
6
3 30
50
28
14
29
71
3
• Criteria for response to therapy: A) disappearance of fever and signs of infection within 4 days and lasting more than 3 days; B) no change of antibiotic therapy within 7 days; C) change of antibiotic treatment or death due to infection.
treatment. In 2/59 episodes the patients rapidly developed a septic shock and therapy was changed before results of blood culture were obtained. Both patients survived and the causative agents were Streptococcus milleri and Escherichia coli. In 16/59 episodes blood culture findings per se motivated change of therapy, though five of the 16 isolates were sensitive to both TMP/SMZ and AMI. In all these five episodes gram-positive bacteria were found and TMP/SMZ was changed to benzylpenicillin or cloxacillin. In the remaining 3/59 episodes treatment against anaerobic bacteria was added due to cellulitis. Documented infection was seen in 50 of 121 (40%) episodes empirically treated with TMP/SMZ plus AMI. The response rate (type A and B responses) was 40% in episodes with documented infections and 59% in episodes with FUO (Table 2). Forty isolates were found in 35 episodes with septicemia. Three isolates were resistant both to AMI and TMP/SMZ and 25 isolates were sensitive both to AMI and TMP/SMZ. The clinical outcome is depicted in
Table 3. 18
9(50)
6(33)
3(17)
• Criteria for response to therapy: A) disappearance of fever and signs of infection within 4 days and lasting more than 3 days; B) no change of antibiotic therapy within 7 days; C) change of antibiotic treatment or death due to infection. b Trimethoprim-sulfamethoxazole plus amikacin. c Imipenem/cilastatin.
I/C therapy in 22 evaluable episodes with FUO and clinical failure during TMP/SMZ plus AMI therapy I/C monotherapy was instituted in 24/29 episodes classified as FUO with persistence of
103
TRIMETHOPRIM-SULFAMETHOXAZOLE PLUS AMIKACIN AS FIRST-LINE THERAPY AND IMIPENEM/CILASTATIN, ETC .
. TABLE 3 - Response to "!"!~thoprim-sulfamethoxazole plus amlkacin therapy in septic fever episodes with regard to bl00 d l tsolates (n = 40) and suscepttbtltty. cu ture
Antibiotics• Resistant(R)/Susceptible(S) Type of responseb
TMP/SMZ +AMI R to Both A
B
c
AMI
TMP/SMZ
s
A
B
TMP/SMZ +AMI S to Both
s
c
A
3 1
1
B
c
A
B
c
Isolates S. epidermidis S. mitis
2 2
1
S. aureus
Other gram-positive cocci
4 2
E. coli
2
K. pneumoniae
3
Other gram-negative rods
1
3
6 1
1
\Criteria/or ~b_po~se to therapy: !"l dis appearance of fever and signs of infection within 4 days and lasting more than 3 da s· B) no oh a~tl tot tc therapy wtthm 7 days ; C) change of antibiotic treatment or death due to infection y ' nmet opnm-su1famethoxazole + amikacin. ·
~ Ta~ge
high fever and clinical deterioration (response C) during TMP/SMZ plus AMI therapy (Figure 1, Table 1). In two episodes neutrophil count was restituted within 4 days and consequently response was not evaluated. Median duration of therapy before change to I/C was 4 days (range 3-7). I/C therapy was successful (type A and B responses) in 17/22 episodes (77%; Table 1). I/C therapy was modified (response C) in four episodes due to either persistence of high fever and poor clinical status (n = 3) or skin rash (n = 1). One patient expired after three doses of I/C (see below). In six of the 17 episodes with a successful outcome (type A and B responses) concomitant amphotericin B was instituted. In three of the six episodes antifungal therapy was started before I/C. In 5/29 episodes with FUO and clinical failure during TMP/SMZ plus AMI therapy I/C therapy was not started due to: allergy to I/C (n = 1), positive blood cultures during initial therapy (n = 2), suspicion of P. carinii infection (n = 1) and, in one episode, a patient with a refractory leukemia who received oral antibiotics on an outpatient basis. Evaluation after 72 hours of I/C therapy revealed four documented infections, one septicemia and three cases with pneumonia. The clinical outcome of these episodes was: A (n = 2) and C (n = 2). In the remaining 18 episodes with FUO the results were: A (n = 15) and C (n = 3).
I/C therapy in 18 episodes of a second fever during initially successful TMP/SMZ plus AMI therapy Eighteen episodes appeared during initially successful TMP/SMZ plus AMI therapy (Figure 1). Although three of the 18 episodes were cl~ssified as documented when primary antibiotic therapy was started, no signs of the initial infection were present when the new fever episode started. I/C monotherapy was instituted after 9 days (median, range 7-22) of TMP/SMZ plus. AMI tre~tment. The clinical response to I/C 1s shown m Table 1. Modification of antibiotic therapy was required (response C) in three of 18 new fever episodes due to persistence of high fever and clinical deterioration. In six of the 15 episodes with successful outcome (type A and B responses) concomitant amphotericin B was instituted. In two of the six episodes antifungal therapy was started more than 48 hours before I/C. Evaluation after 72 hours of I/C therapy reve.aled four .documented infections: one septicemia, one unnary tract infection and two cases of pneumonia. The therapeutic results for these episodes were: A (n = 2) and B (n = 2). For the remaining 14 episodes with FUO, the clinical outcome was: A (n = 7), B (n = 4) and C (n = 3) .
I/C therapy in 18 plus 22 episodes (see above) after TMP/SMZ plus AMI therapy The overall response rate to I/C (type A and B responses) after primary and secondary failure
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ENGERVALL - G.T. STIERNsTEoT - G.c . GuNTHER -
with TMP/SMZ plus AMI was 32/40 (80%). In 12 of these 32 episodes concomitant parenteral amphotericin B therapy was instituted. For documented infections the corresponding response (type A and B) was six out of eight.
Side eHects TMP/SMZ plus AMI therapy was not associated with any life-threatening side effects. No allergic events resulting in change of therapy occurred. There were no serious side effects during 1/C therapy. One patient experienced a rash which motivated a change in therapy. Some patients experienced nausea during 1/C infusion but this was reduced with an extended infusion time.
Deaths Five patients died from tumor progression and another four died from other causes after maximal 4 weeks of neutropenia ( < 0.5 X 10 9/l; Table 4). Their median age was 77 years and only one of them died from infectious complications. This was a female patient with a mixed S. epidermidis septicemia (two different strains) who died within 24h after institution of 1/C. She had previously received TMP/SMZ plus AMI for five days.
Blood culture isolates Blood culture isolates for the 121 primary episodes are listed in Table 3. In 35/121 (29%) septicemia was documented and there was an
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BJoRKHoLM
even distribution between gram-positive and gram-negative organisms. Five mixed septicemias were observed. There was only one isolate of a Pseudomonas sp. Gram-positive bacteria were found in eight out of nine blood culture isolates obtained during antibiotic therapy (clinical failure or new fever episodes, n=74). DISCUSSION
The need for empirical antibiotic therapy for febrile, neutropenic patients evolved from the observation that delaying treatment until a pathogen had been isolated often led to rapid clinical deterioration, especially if a gram-negative organism was the causative agent 3 • In our study, using no antibiotic prophylaxis, 50% of positive primary blood culture isolates were gram-negative. No patient with a documented gram-negative septicemia who received TMP/SMZ plus AMI died. Although there has been a shift in pathogens isolated from immunocompromised patients from gram-negative to gram-positive organisms, adequate gram-negative coverage is still essential for any initial empirical antibiotic regimen as concluded from the results of this study. TMP/SMZ plus AMI has a broad gramnegative coverage and the Leukemia Group of Middle Sweden has used this antibiotic combination as empirical antibiotic treatment for several years. There were only three of 20 gramnegative isolates that were resistant to either AMI or TMP/SMZ, and no isolate was resistant
9 TABLE 4 - Clinical and bacteriological data in patients who died after maximal 4 weeks of neutropenia ( < 0.5 X 10 1) not due to tumor progression.
Cause of death (days after start of fever episode)
Diagnosis
Age
Antibiotic treatment at time of death
Septicemia isolate
ANLL"
62
Imipenem/cilastatin
S. epidermidis (two isolates)
ANLL AULb
77
Imipenem/cilastatin
Negative
Heart failure (14)
66
Imipenem/cilastatin
Not done
Toxicity related to cytostat-
ANLL
80
Amikacin/trimethoprim-
Negative
Septicemia (6)
ics (18) -sulfamethoxazole • Acute non-lymphoblastic leukemia. b Acute undifferentiated leukemia.
Myocardial infarction (5)
TRJMETHOPRIM·SULFAMETHOXAZOLE PLUS AMIKACIN AS FIRST-UNE THERAPY AND IMIPENEM/CILAST ATIN , ETC .
to both antibiotics. E. coli dominated among gram-negative blood culture isolates. Although 11/12 strains isolated were sensitive to both TMP/SMZ and AMI, therapy was changed (response C) in six episodes (Table 3). In two episodes mixed septicemia was present with Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In another episode the patient developed a septic shock and therapy was changed before results of blood cultures were available. E. coli bacteremia did not persist during TMP/SMZ and AMI therapy in any of the six episodes. It might be argued that the antibacterial coverage of this regimen against P. aeruginosa is fully dependent on its sensitivity to AMI. In this study only one P. aeruginosa was isolated and this strain was sensitive to AMI. The low incidence of Pseudomonas infection is in good agreement with previous results from other leukemia units in Sweden 19 • Gram-positive isolates were found at presentation in 19/1 21 primary fever episodes (one mixed septicemia). Although therapy was changed in 17 of those episodes, only three isolates were resistant to both primary antibiotics. No mortality was recorded. The overall response rate for TMP/SMZ plus AMI was 51% and for documented infections 40%. This is in the lower range as compared to reports using other antibiotic combinations 5 • 8 • 9 • 11 • It is, however, difficult to compare our results with other studies. In our study many elderly and severely ill patients were included and the criteria for response were very strict. Furthermore, therapy was modified in some episodes of gram-positive septicemia even if isolates were sensitive to both TMP/SMZ and AMI. From a clinical point of view survival during the neutropenic period is the most relevant endpoint for evaluating different antibiotic regimens . If data are presented emphasizing survival according to Pizzo et al., 10 successful outcome (within one month or to restitution of neutropenia) was achieved in 99.2% of the episodes. Success without modification (antifungal therapy included) was seen in 41/121 (34%). Thus, in a majority of episodes therapy had to be modified. In episodes classified as documented infections at evaluation after 72 hours, sue-
105
cess without modifications was obtained in 17/50 (34%). This finding is equivalent to the outcome in the study of Pizzo et al. 10 where the corresponding response rates were 30% for ceftazidime and 31% for the combination of gentamicin, cephalothin and carbenicillin, respecti~ vely. Only one patient died due to infection in this series of patients with profound neutropenia and a median (and mean) age of 60 years. Furthermore, there were no severe toxic/allergic reactions observed in patients treated with TMP/SMZ. The authors are fully aware of the limitations associated with a non-randomized study. This is, however, a first report on a primary empirical antibiotic therapy used by leukemia units within the Leukemia Group of Middle Sweden during the last decade . In centers with a low incidence of Pseudomonas sp., TMP/SMZ plus AMI seems to be an efficacious, safe and inexpensive «standard» antibiotic regimen in neutropenic patients with febrile episodes. The results have motivated a prospective randomized phase III trial comparing TMP/SMZ plus AMI with ceftazidime monotherapy. This study also demonstrated favorable therapeutic results with 1/C as secondary empiric therapy in patients with primary or secondary failures on TMP/SMZ plus AMI treatment. The response rate of 80% is similar to the 68% reported by Bodey et al. 20 in 1/C treated secondary fever episodes. However, in that study only episodes with a documented infection were evaluated and in 20% of the patients the neutrophil count exceeded 1.0 X 10 9/l. In contrast, all patients in this study had persistent neutropenia and only patients with clinical failure and FUO were included. The corresponding response rate in this series for 1/C monotherapy in episodes classified as documented infection after 72 hours was 75%, but there were only eight episodes evaluated. The fact that TMP/SMZ plus AMI therapy failed as primary therapy in 41% of the episodes with FUO may contribute to the high response rate for 1/C as secondary empirical therapy . Furthermore, it cannot be fully excluded that antifungal therapy contributed to the clinical response in a few of the 16 episodes where amphotericin B was administered concomitantly, although fungal infections were not
P.A.
106
ENGERVALL
documented. In patients with clinical failure or in whom a new fever episode developed during initially successful empirical therapy, gram-positive bacteria were isolated from eight of nine positive blood cultures with 5. epidermidis dominating. This finding supports the notion that grampositive septicemias dominate late in the neutropenic period and mainly in patients previously exposed to antibiotic therapy. I/C therapy was discontinued due to the appearance of skin rashes in one patient and a few patients experienced nausea during I/C administration. However, there were no serious life threatening side effects in patients treated with I/C therapy. Although this series includes a limited number of episodes, I/C monotherapy appears to be an adequate candidate for «second-line» treatment in this clinical setting. Moreover, this schematic approach to the treatment of infections in neutropenic patients does not seem to be associated with an increased infectious related mortality.
G.T . SnERNsTEnT - G.c. GuNTHER -
M.J.
BJi:iRKHoLM
'Winston DJ, Barnes RC, Ho WG, Young LS, Champlin RE, Gale RP. Moxalactam plus piperacillin versus moxalactam plus amikacin in febrile granulocytopenic patients. Am J Med 1984; 77 : 442-50. 1 The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer. Combination of arnikacin and carbenicillin with or without cefazolin as empirical treatment of febrile neutropenic patients . J Clin Oncol 1983; 1: 597-603. • The EORTC International Antimicrobial Therapy Project Group. Ceftazidirne combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. N Eng!J Med 1987; 317: 1692-8. 0 ' Pizzo PA, Hathorn JW, Hiemenz J, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Eng! J Med 1986; 315 : 552-8. " Norrby SR, Vandercam B, Louie T, et al. Imipenem/ Cilastatin versus amikacin plus piperacillin in the treatment of infections in neutropenic patients: A prospective, randomized multi-clinical study. Scand J Infect Dis 1987; 52: 65-78. "Bodey GP, Alvares ME, Jones PG, Rolston KVI, Steelhammer L, Fainstein V. Imipenem-Cilastatin as initial therapy for febrile cancer patients. Antimicrob Agents Chemother 1986; 20: 211-4. 11 Young LS, Hindler J. Use of trimethoprim-sulfamethoxazole singly and in combination with other antibiotics in immunocompromised patients. Rev Infect Dis 1987; 9: 17781.
REFERENCES 'Bodey GP, Burkley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328-40. 'Pizzo PA. After empiric therapy: What to do until the granulocyte comes back? Rev Infect Dis 1987; 9: 214-9. ' Shimp££ S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Eng! J Med 1971 ; 284: 1061-5. ' The EORTC International Antimicrobial Therapy Project Group. Three antibiotic regimens in the treatment of infection in febrile gra nulocytopenic patients with cancer. J Infect Dis 1978; 137: 14-29. ' Klastersky J, Glauser MP, Schimpf£ SC, Zinner SH, Gaya H, European Organization for Research on Treatment of Cancer Antimicrobial Therapy Project Group. Prospective randomized comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenic patients. Antimicrob Agents Chemother 1986; 29: 263-70. 'Winston DJ, Ho WG, Young LS, Hewitt WL, Gale RP. Piperacillin plus amikacin therapy versus carbenicillin plus arnikacin therapy in febrile, granulocytopenic patients. Arch Intern Med 1982; 142: 1663-7.
" Braine HG, Stuart RK, Sara] R, Lierman PS. Parenteral trimethoprim-sulfamethoxazole and carbenicillin as empiric therapy for neutropenic patients with cancer. Rev Infect Dis 1982; 4: 586-92. "Bodey GP, Grose AWE, Keating MJ . Use of rrimerhoprim-sulfamethoxazole for treatment of infections in patients with cance.r. Rev Infect Dis 1982; 4: 579-85. "Stuart RK, Braine HG, Lierman PS , Saral R, Fuller DJ. Carbenicillin-trimethoprim/sulfamethoxazole versus carbenicillin-gentamicin as empiric therapy of infection in granulocytopenic patients: a prospective, randomized, double-blind study. Am J Med 1980; 86: 876-85. 11 Kahan M, Kropp H, SundelofJG, Birnbaum]. Thienamycin: development of imipenem-cilastatin. J Antimicrob Chemorher 1983 ; 12 Supp D: 1-35. " Rubin M, H athorn JW, Marshall D, Gress J, Steinberg S, Pizzo P. Gram-positive infections and the use of vancomycin in 55 0 episodes of fever and neutropenia. Ann Intern Med 1988; 108: 30-5. 19 Giinrher G, Bjorkholm M, Bjorklind A, Engervall P, Stiernstedt G . Septicemia in patients with hematological disorders and neutropenia. A retrospective study of causative agen ts and their resistance profile. Scand J Infect Dis 1991; 23: 589-98. 20 Bodey GP, Rolston K, Jones P, Alvares ME, Fainstein V, Steelhammer L. Imipenem/Cilastatin as secondary therapy for infections in cancer patients. J Antimicrob Chemother 1986; 18: 161-6.
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Trimethoprim-Sulfamethoxazole plus Amikacin as First-Line Therapy and Imipenem/Cilastatin as Second Empirical Therapy in Febrile Neutropenic Patients with Hematological Disorders P.A. Engervall, G.T. Stiernstedt, G.C. Günther & M.J. Björkholm To cite this article: P.A. Engervall, G.T. Stiernstedt, G.C. Günther & M.J. Björkholm (1992) Trimethoprim-Sulfamethoxazole plus Amikacin as First-Line Therapy and Imipenem/Cilastatin as Second Empirical Therapy in Febrile Neutropenic Patients with Hematological Disorders, Journal of Chemotherapy, 4:2, 99-106, DOI: 10.1080/1120009X.1992.11739148 To link to this article: http://dx.doi.org/10.1080/1120009X.1992.11739148
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Date: 20 March 2017, At: 03:41
Vol. 4 - n. 2 (99-106) - 1992
Journal of Chemotherapy
TrimethoprimSulfamethoxazole plus Amikacin as First-Line Therapy and lmipenem/Cilastatin as Second Empirical Therapy in Febrile Neutropenic Patients with Hematological Disorders
during TMP/SMZ +AMI therapy and (b) 18 episodes with a second fever episode during initially successful TMP/ SMZ +AMI therapy. The response rate for all 40 1/C treated episodes was 80%. One neutropenic patient in the whole series died from infectious complications within four weeks from institution of therapy. TMP/SMZ +AMI seems to be a safe and inexpensive «standard» antibiotic regimen in neutropenic patients. I/C appears to have good efficacy when used as secondary therapy after failure with TMP/SMZ +AMI. Key words: Imipenem/cilastatin, trimethoprim-sulfa· methoxazole, amikacin, neutropenia, leukemia, septicemia.
INTRODUCTION
P.A. ENGERVALL * - G.T. STIERNSTEDT ** G.C. GUNTHER** - M.J . BJORKHOLM *
Summary ----------------------- -------One hundred and thirty-nine consecutive episodes of fever were evaluated in 55 patients with hematological disorders during persistent neutropenia. In 121 instances, pa· tients were given trimethoprim-sulfamethoxazole + amikacin (TMP/SMZ +AMI) as an initial antibiotic regimen with clini· cal success in 51% (i.e. antibiotic treatment was not changed within the first 7 days). lmipenem/cilastatin (1/C) therapy was instituted in: (a) 22 episodes with clinical failure and fever of unknown origin
* Division of Hematology and Immunology, Department of Medicine, Karolinska Hospital, Stockholm, Sweden . ** Department of Infectious Diseases, Danderyd Hospital, Danderyd, Sweden.
Requests for reprints and correspondence should be addressed to: Per Engervall, M.D., Division of Hematology and Immunology, Department of Medicine, S-104 01 Stockholm, Sweden . © Edizioni Riviste Sc.ientifiche - Firenze
Karolinska
Hospital,
Infection remains an important cause of morbidity and mortality in patients with hematological malignancies. Though many factors may contribute to the increased susceptibility to various infectious agents in this patient population, the most important predisposing factor is severity and duration of neutropenia 1 • 2 • Routine use of early empirical antibiotic therapy for newly febrile neutropenic patients has decreased infection-related morbidity and mortality in this population 3 • The isolation of grampositive pathogens has increased over the past years, with many of these strains, especially Staphylococcus epidermidis, being resistant or inadequately covered by most empirical regimens used today. Nevertheless, the devastating complications of gram-negative septicemia still remain the major concern. In most studies of empirical antibiotic therapy in neutropenic patients regimens containing both (3-lactam and aminoglycoside antibiotics have been used 3 " 9 • Monotherapy with ceftazidime or imipenem/ ISSN 1120-009X
100
P.A.
ENGERVALL - G.T. STIERNSTEDT - G.C. GUNTHER -
cilastatin (1/C) has also showed good efficacy in this clinical situation 1 0 " 12 • Within the Leukemia Group of Middle Sweden the most commonly used empirical antibiotic combination has been trimethoprim-sulfamethoxazole (TMP/SMZ) plus amikacin (AMI). The rationale for this choice is multifactorial: a) The regimen has a good antibacterial coverage, especially with regard to gram-negative organisms and the broad spectrum of TMP/SMZ also includes Listeria monocytogenes, Pneumocystis carinii, and Nocardia sp. 13 b) Earlier reports on TMP/SMZ in combination with an aminoglycoside or carbenicillin as early empirical therapy have shown its adequate efficacy 14 -16 . c) The combination preserves the anaerobic intestinal microflora. d) TMP/SMZ plus AMI are administered every 12 hours and the cost is low, even when taking into consideration the expenses for determination of AMI serum concentrations. During long-standing and recurrent periods of neutropenia, patients with hematological malignancy and acute leukemia in particular, often develop repeated infections and require therapy modification when a new fever episode occurs during continuous antibiotic treatment 2 • The choice of antibiotic regimen is often difficult in this clinical situation. 1/C monotherapy has a wide spectrum of antibacterial activity and is as effective as standard combinations of ~-lactam and aminoglycoside antibiotics in primary episodes of fever in neutropenic patients 11 • 12 • The risk of gram-positive superinfections increases with prolonged neutropenia 9 • 10 and gram-pos1t1ve isolates which are resistant to both aminoglycosides and ~-lactam antibiotics may emerge. 1/C is active against all streptococcal species and methicillinsusceptible staphylococci as well as anaerobes. Some activity in vitro to methicillin-resistant staphylococci is also reported 17 • Furthermore, there is no evidence of an increased mortality rate by delaying specific therapy against grampositive infections until the causative agent is isolated 11 • 1/C has recently been shown to have good efficacy as secondary therapy in neutropenic cancer patients with documented infections who have failed to respond to primary antibiotic therapy 19 • The toxicity of 1/C is
M.J.
BJORKHOLM
mostly limited to nausea/vomiting and skin rashes in a small proportion of patients 11 • 12 • Thus, 1/C may offer an alternative after TMP/ SMZ plus AMI have failed . The aim of this study was to document the efficacy of TMP/ SMZ plus AMI as a primary empirical antibiotic treatment in a consecutive series of fever episodes in neutropenic patients. Furthermore, the role of 1/C as secondary therapy after TMP/ SMZ plus AMI failure was studied. PATIENTS AND METHODS
This study was conducted on 139 consecutive episodes of fever in 55 patients with hematological disorders admitted to the Division of Hematology and Immunology, Karolinska Hospital during 1988/ 1990. There were 27 men and 28 women (median age 60 years, range 17-83 years) with the following diagnoses: acute nonlymphoblastic leukemia (n = 31), chronic myelogenous leukemia in b1ast crisis (n = 10), acute lymphoblastic leukemia/acute undifferentiated leukemia (n = 8), malignant lymphoma (n = 3), agranulocytosis (n = 1), severe aplastic anemia (n = 1) and myelomatosis (n = 1) . Six patients with leukemia and lymphoma underwent autologous bone marrow or blood stem cell transplantation. In 136 episodes neutropenia was induced by chemotherapy. Neutropenic (absolute neutrophil count < 0.5 X 10 9/l) patients were included if they developed a temperature of ~ 38.5 °C on one occasion or ~ 38.0 °C on two occasions during a 24h period with at least a 4h interval. Fever was not associated with the administration of known pyrogenic substances (blood transfusions, immunotherapeutic agents, etc). Only episodes in patients with neutropenia persisting for more than 4 days after start of antibiotic treatment were evaluated for response. A second episode of fever (n = 18, Figure 1) during the same neutropenic period was evaluated after a minimum of 7 days only if all signs of the first infection had disappeared. Furthermore, 3 consecutive days with a temperature below 3 7.5 °C was required. Fever episodes occurring in patients with prophylactic antibiotic therapy (n = 8) and episodes caused by documented viral or fungal infections (n = 5) were excluded.
TRIMETHOPRIM-SULFAMETHOXAZOLE PLUS AMIKACIN AS FIRST-LINE THERAPY AND IMIPENEM/CILASTATIN, ETC .
Furthermore, in 17 episodes during the study period TMP/SMZ plus AMI was not used as primary empirical therapy due to established allergy (n = 7), referral from other units within the hospital after institution of other antibiotic treatment (n = 3), or when anaerobic infection could be suspected (n = 7). None of these episodes (n = 17) will be discussed further (Figure 1).
Antimicrobial treatment All patients received TMP/SMZ plus AMI therapy when fever occurred (see definition . above). Primary empiric therapy was continued for at least 72 hours. Therapy was changed to I/C if the clinical status deteriorated in patients without documented infection or modified if susceptibility pattern in blood culture isolates revealed resistant bacteria. Persistence of fever per se did not motivate change of therapy. Empirical amphotericin B (Fungizone ®, Bristol-Myers Squibb) at a dose of 0.3 mg/kg was added when fungal infection could not be ruled out in a patient with profound neutropenia, persistence of fever and clinical deterioration. TMP/SMZ (Bactrim ®, Roche) was administered at a standard dose of 160 mg TMP plus 800 mg SMZ i.v.q. 12h. AMI (Biklin®, BristolMyers Squibb) was given at a dose of 7.5 mg/kg i.v.q. 12h. AMI dosage was adjusted, if necessary, to achieve serum concentrations of 15-35 mg/1 30 min after the end of a 30-min infusion and less than 8 mg/1 before the next scheduled dose. The 1/C (Tienam ®, Merck Sharp & Doh me) standard dose was 1 g i. v. over a period of 1h every 8h.
for the diagnosis of septicemia. Urinary tract infection was established when a patient had more than 10 5 colony forming units of a single organism per milliliter of urine. Cellulitis was defined as soft-tissue erythema, tenderness, induration or warmth, with or without microbia- . logical confirmation. Pulmonary infection was diagnosed by the occurrence of a new radiological infiltrate on chest x-ray within 72 hours from debut of fever, with or without positive cultures. Episodes were diagnosed as fever of unknown origin (FUO) if no site or isolate indicative of infection was found within 72 hours.
Criteria for response to therapy All episodes were evaluated for response 7 days after institution of antibiotic therapy. Three categories were defined : A) disappearance of fever and signs of infection within 4 days and lasting for more than 3 days B) no change of antibiotic therapy within 7 days (i.e. persistence of fever with the patient remaining in stable clinical condition) C) change of antibiotic therapy within 7 days or death due to infection.
RESULTS
One hundred and thirty-nine febrile episodes were recorded in the 55 patients (Figure 1). In 125 episodes (90 % ) neutropenia was sev169 epi sodes of fever -> ->
Bacteriological procedures Before institution of empirical antibiotic therapy, specimens for culture were collected from urine, throat, sputum (if possible) and other appropriate sites. At least three blood cultures were performed. The same procedure was repeated if fever persisted or a new episode of fever developed during therapy.
Diagnostic criteria for documented infections The isolation of the same bacterial strain from at least two blood cultures was required
101
8 eplaodes during prophylaxis 5 episodes caused by virus or fungi 17 episodes not treated with amlkacln plus trlmethoprlm sulfamethoxazo l e
,j,
139 eva luable episodes 121 ep i sodes treated with -> 18 ep isodes of "new fever" amlkacln plus trlm ethoduring amlkacln plus trl prl m -s u If a met oxazo l e methoprlm-sulfametoxazole treated with lmlpenemlcllastalln 22 ep isodes with clinical failure during am lka cln plus trlmethoprlm-sulfametoxazole treated with lmlpenemlc llastalln
Figure 1 - Schematic view of the fever episodes recorded in this study.
P.A.
102
ENGERVALL . G.T. SnERNsTEoT •
ere, reaching absolute nadir neutrophil counts < 0.1 X 10 9/l. The mean time from neutropenia (< 0.5 X 10 9/1} to institution of antibiotic treatment was 4.7 days (range 1-16 days). One hundred and twenty-one of the 139 episodes (87%) were primary, i.e. occurring in patients not receiving antibiotic treatment. In 22 of those 121 episodes secondary empirical therapy was also evaluated. Eighteen out of 139 episodes (13%) occurred as a second event of fever during the same neutropenic period in patients receiving TMP/SMZ plus AMI treatment.
c.c.
The clinical outcome of 121 primary fever episodes treated with TMP/SMZ plus AMI is presented in Table 1. Change or modification of treatment (response C) was required in 59/121 instances (49%). In 33/59 fever episodes (56%) the reason for change of primary TMP/SMZ plus AMI was persistence of high fever and clinical deterioration. All of these episodes were classified as FUO except four (two episodes with urinary tract infection and two episodes with pulmonary infection). In another 5/59 instances blood cultures were positive with isolates sensitive to therapy, but persistence of high fever with lack of clinical improvement motivated a change of
TABLE 1 - Response to primary and secondary empirical antibiotic therapy.
Type of therapy and clinical situation TMP/SMZ-AMib in primary fever episodes I/Cc in primary clinical TMP/SMZ-AMI therapy failures I/C in new fever episodes during TMP/SMZ-AMI therapy
Type of response" n.
n .(%)
A
121
22
B
C
42(35) 20(16) 59(49)
17(77)
0
5(23)
M.J.
BJoRKHoLM
TABLE 2 · Response to trimethoprim-sulfamethoxazole plus amikacin therapy in primary fever episodes (N = 121) with regard to documented infection or fever of unknown origin.
Type of response (n.)" Total A B C Documented infection Septicemia Urinary tract with septicemia Pulmonary with septicemia Cellulitis Total Fever of unknown origin
TMP/SMZ plus AMI therapy in 121 primary fever episodes
GuNTHER •
8 3
4 1
3
21 2 1
33 6 1
2 1
6 1
14
6
3 30
50
28
14
29
71
3
• Criteria for response to therapy: A) disappearance of fever and signs of infection within 4 days and lasting more than 3 days; B) no change of antibiotic therapy within 7 days; C) change of antibiotic treatment or death due to infection.
treatment. In 2/59 episodes the patients rapidly developed a septic shock and therapy was changed before results of blood culture were obtained. Both patients survived and the causative agents were Streptococcus milleri and Escherichia coli. In 16/59 episodes blood culture findings per se motivated change of therapy, though five of the 16 isolates were sensitive to both TMP/SMZ and AMI. In all these five episodes gram-positive bacteria were found and TMP/SMZ was changed to benzylpenicillin or cloxacillin. In the remaining 3/59 episodes treatment against anaerobic bacteria was added due to cellulitis. Documented infection was seen in 50 of 121 (40%) episodes empirically treated with TMP/SMZ plus AMI. The response rate (type A and B responses) was 40% in episodes with documented infections and 59% in episodes with FUO (Table 2). Forty isolates were found in 35 episodes with septicemia. Three isolates were resistant both to AMI and TMP/SMZ and 25 isolates were sensitive both to AMI and TMP/SMZ. The clinical outcome is depicted in
Table 3. 18
9(50)
6(33)
3(17)
• Criteria for response to therapy: A) disappearance of fever and signs of infection within 4 days and lasting more than 3 days; B) no change of antibiotic therapy within 7 days; C) change of antibiotic treatment or death due to infection. b Trimethoprim-sulfamethoxazole plus amikacin. c Imipenem/cilastatin.
I/C therapy in 22 evaluable episodes with FUO and clinical failure during TMP/SMZ plus AMI therapy I/C monotherapy was instituted in 24/29 episodes classified as FUO with persistence of
103
TRIMETHOPRIM-SULFAMETHOXAZOLE PLUS AMIKACIN AS FIRST-LINE THERAPY AND IMIPENEM/CILASTATIN, ETC .
. TABLE 3 - Response to "!"!~thoprim-sulfamethoxazole plus amlkacin therapy in septic fever episodes with regard to bl00 d l tsolates (n = 40) and suscepttbtltty. cu ture
Antibiotics• Resistant(R)/Susceptible(S) Type of responseb
TMP/SMZ +AMI R to Both A
B
c
AMI
TMP/SMZ
s
A
B
TMP/SMZ +AMI S to Both
s
c
A
3 1
1
B
c
A
B
c
Isolates S. epidermidis S. mitis
2 2
1
S. aureus
Other gram-positive cocci
4 2
E. coli
2
K. pneumoniae
3
Other gram-negative rods
1
3
6 1
1
\Criteria/or ~b_po~se to therapy: !"l dis appearance of fever and signs of infection within 4 days and lasting more than 3 da s· B) no oh a~tl tot tc therapy wtthm 7 days ; C) change of antibiotic treatment or death due to infection y ' nmet opnm-su1famethoxazole + amikacin. ·
~ Ta~ge
high fever and clinical deterioration (response C) during TMP/SMZ plus AMI therapy (Figure 1, Table 1). In two episodes neutrophil count was restituted within 4 days and consequently response was not evaluated. Median duration of therapy before change to I/C was 4 days (range 3-7). I/C therapy was successful (type A and B responses) in 17/22 episodes (77%; Table 1). I/C therapy was modified (response C) in four episodes due to either persistence of high fever and poor clinical status (n = 3) or skin rash (n = 1). One patient expired after three doses of I/C (see below). In six of the 17 episodes with a successful outcome (type A and B responses) concomitant amphotericin B was instituted. In three of the six episodes antifungal therapy was started before I/C. In 5/29 episodes with FUO and clinical failure during TMP/SMZ plus AMI therapy I/C therapy was not started due to: allergy to I/C (n = 1), positive blood cultures during initial therapy (n = 2), suspicion of P. carinii infection (n = 1) and, in one episode, a patient with a refractory leukemia who received oral antibiotics on an outpatient basis. Evaluation after 72 hours of I/C therapy revealed four documented infections, one septicemia and three cases with pneumonia. The clinical outcome of these episodes was: A (n = 2) and C (n = 2). In the remaining 18 episodes with FUO the results were: A (n = 15) and C (n = 3).
I/C therapy in 18 episodes of a second fever during initially successful TMP/SMZ plus AMI therapy Eighteen episodes appeared during initially successful TMP/SMZ plus AMI therapy (Figure 1). Although three of the 18 episodes were cl~ssified as documented when primary antibiotic therapy was started, no signs of the initial infection were present when the new fever episode started. I/C monotherapy was instituted after 9 days (median, range 7-22) of TMP/SMZ plus. AMI tre~tment. The clinical response to I/C 1s shown m Table 1. Modification of antibiotic therapy was required (response C) in three of 18 new fever episodes due to persistence of high fever and clinical deterioration. In six of the 15 episodes with successful outcome (type A and B responses) concomitant amphotericin B was instituted. In two of the six episodes antifungal therapy was started more than 48 hours before I/C. Evaluation after 72 hours of I/C therapy reve.aled four .documented infections: one septicemia, one unnary tract infection and two cases of pneumonia. The therapeutic results for these episodes were: A (n = 2) and B (n = 2). For the remaining 14 episodes with FUO, the clinical outcome was: A (n = 7), B (n = 4) and C (n = 3) .
I/C therapy in 18 plus 22 episodes (see above) after TMP/SMZ plus AMI therapy The overall response rate to I/C (type A and B responses) after primary and secondary failure
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ENGERVALL - G.T. STIERNsTEoT - G.c . GuNTHER -
with TMP/SMZ plus AMI was 32/40 (80%). In 12 of these 32 episodes concomitant parenteral amphotericin B therapy was instituted. For documented infections the corresponding response (type A and B) was six out of eight.
Side eHects TMP/SMZ plus AMI therapy was not associated with any life-threatening side effects. No allergic events resulting in change of therapy occurred. There were no serious side effects during 1/C therapy. One patient experienced a rash which motivated a change in therapy. Some patients experienced nausea during 1/C infusion but this was reduced with an extended infusion time.
Deaths Five patients died from tumor progression and another four died from other causes after maximal 4 weeks of neutropenia ( < 0.5 X 10 9/l; Table 4). Their median age was 77 years and only one of them died from infectious complications. This was a female patient with a mixed S. epidermidis septicemia (two different strains) who died within 24h after institution of 1/C. She had previously received TMP/SMZ plus AMI for five days.
Blood culture isolates Blood culture isolates for the 121 primary episodes are listed in Table 3. In 35/121 (29%) septicemia was documented and there was an
M.J.
BJoRKHoLM
even distribution between gram-positive and gram-negative organisms. Five mixed septicemias were observed. There was only one isolate of a Pseudomonas sp. Gram-positive bacteria were found in eight out of nine blood culture isolates obtained during antibiotic therapy (clinical failure or new fever episodes, n=74). DISCUSSION
The need for empirical antibiotic therapy for febrile, neutropenic patients evolved from the observation that delaying treatment until a pathogen had been isolated often led to rapid clinical deterioration, especially if a gram-negative organism was the causative agent 3 • In our study, using no antibiotic prophylaxis, 50% of positive primary blood culture isolates were gram-negative. No patient with a documented gram-negative septicemia who received TMP/SMZ plus AMI died. Although there has been a shift in pathogens isolated from immunocompromised patients from gram-negative to gram-positive organisms, adequate gram-negative coverage is still essential for any initial empirical antibiotic regimen as concluded from the results of this study. TMP/SMZ plus AMI has a broad gramnegative coverage and the Leukemia Group of Middle Sweden has used this antibiotic combination as empirical antibiotic treatment for several years. There were only three of 20 gramnegative isolates that were resistant to either AMI or TMP/SMZ, and no isolate was resistant
9 TABLE 4 - Clinical and bacteriological data in patients who died after maximal 4 weeks of neutropenia ( < 0.5 X 10 1) not due to tumor progression.
Cause of death (days after start of fever episode)
Diagnosis
Age
Antibiotic treatment at time of death
Septicemia isolate
ANLL"
62
Imipenem/cilastatin
S. epidermidis (two isolates)
ANLL AULb
77
Imipenem/cilastatin
Negative
Heart failure (14)
66
Imipenem/cilastatin
Not done
Toxicity related to cytostat-
ANLL
80
Amikacin/trimethoprim-
Negative
Septicemia (6)
ics (18) -sulfamethoxazole • Acute non-lymphoblastic leukemia. b Acute undifferentiated leukemia.
Myocardial infarction (5)
TRJMETHOPRIM·SULFAMETHOXAZOLE PLUS AMIKACIN AS FIRST-UNE THERAPY AND IMIPENEM/CILAST ATIN , ETC .
to both antibiotics. E. coli dominated among gram-negative blood culture isolates. Although 11/12 strains isolated were sensitive to both TMP/SMZ and AMI, therapy was changed (response C) in six episodes (Table 3). In two episodes mixed septicemia was present with Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In another episode the patient developed a septic shock and therapy was changed before results of blood cultures were available. E. coli bacteremia did not persist during TMP/SMZ and AMI therapy in any of the six episodes. It might be argued that the antibacterial coverage of this regimen against P. aeruginosa is fully dependent on its sensitivity to AMI. In this study only one P. aeruginosa was isolated and this strain was sensitive to AMI. The low incidence of Pseudomonas infection is in good agreement with previous results from other leukemia units in Sweden 19 • Gram-positive isolates were found at presentation in 19/1 21 primary fever episodes (one mixed septicemia). Although therapy was changed in 17 of those episodes, only three isolates were resistant to both primary antibiotics. No mortality was recorded. The overall response rate for TMP/SMZ plus AMI was 51% and for documented infections 40%. This is in the lower range as compared to reports using other antibiotic combinations 5 • 8 • 9 • 11 • It is, however, difficult to compare our results with other studies. In our study many elderly and severely ill patients were included and the criteria for response were very strict. Furthermore, therapy was modified in some episodes of gram-positive septicemia even if isolates were sensitive to both TMP/SMZ and AMI. From a clinical point of view survival during the neutropenic period is the most relevant endpoint for evaluating different antibiotic regimens . If data are presented emphasizing survival according to Pizzo et al., 10 successful outcome (within one month or to restitution of neutropenia) was achieved in 99.2% of the episodes. Success without modification (antifungal therapy included) was seen in 41/121 (34%). Thus, in a majority of episodes therapy had to be modified. In episodes classified as documented infections at evaluation after 72 hours, sue-
105
cess without modifications was obtained in 17/50 (34%). This finding is equivalent to the outcome in the study of Pizzo et al. 10 where the corresponding response rates were 30% for ceftazidime and 31% for the combination of gentamicin, cephalothin and carbenicillin, respecti~ vely. Only one patient died due to infection in this series of patients with profound neutropenia and a median (and mean) age of 60 years. Furthermore, there were no severe toxic/allergic reactions observed in patients treated with TMP/SMZ. The authors are fully aware of the limitations associated with a non-randomized study. This is, however, a first report on a primary empirical antibiotic therapy used by leukemia units within the Leukemia Group of Middle Sweden during the last decade . In centers with a low incidence of Pseudomonas sp., TMP/SMZ plus AMI seems to be an efficacious, safe and inexpensive «standard» antibiotic regimen in neutropenic patients with febrile episodes. The results have motivated a prospective randomized phase III trial comparing TMP/SMZ plus AMI with ceftazidime monotherapy. This study also demonstrated favorable therapeutic results with 1/C as secondary empiric therapy in patients with primary or secondary failures on TMP/SMZ plus AMI treatment. The response rate of 80% is similar to the 68% reported by Bodey et al. 20 in 1/C treated secondary fever episodes. However, in that study only episodes with a documented infection were evaluated and in 20% of the patients the neutrophil count exceeded 1.0 X 10 9/l. In contrast, all patients in this study had persistent neutropenia and only patients with clinical failure and FUO were included. The corresponding response rate in this series for 1/C monotherapy in episodes classified as documented infection after 72 hours was 75%, but there were only eight episodes evaluated. The fact that TMP/SMZ plus AMI therapy failed as primary therapy in 41% of the episodes with FUO may contribute to the high response rate for 1/C as secondary empirical therapy . Furthermore, it cannot be fully excluded that antifungal therapy contributed to the clinical response in a few of the 16 episodes where amphotericin B was administered concomitantly, although fungal infections were not
P.A.
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ENGERVALL
documented. In patients with clinical failure or in whom a new fever episode developed during initially successful empirical therapy, gram-positive bacteria were isolated from eight of nine positive blood cultures with 5. epidermidis dominating. This finding supports the notion that grampositive septicemias dominate late in the neutropenic period and mainly in patients previously exposed to antibiotic therapy. I/C therapy was discontinued due to the appearance of skin rashes in one patient and a few patients experienced nausea during I/C administration. However, there were no serious life threatening side effects in patients treated with I/C therapy. Although this series includes a limited number of episodes, I/C monotherapy appears to be an adequate candidate for «second-line» treatment in this clinical setting. Moreover, this schematic approach to the treatment of infections in neutropenic patients does not seem to be associated with an increased infectious related mortality.
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'Winston DJ, Barnes RC, Ho WG, Young LS, Champlin RE, Gale RP. Moxalactam plus piperacillin versus moxalactam plus amikacin in febrile granulocytopenic patients. Am J Med 1984; 77 : 442-50. 1 The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer. Combination of arnikacin and carbenicillin with or without cefazolin as empirical treatment of febrile neutropenic patients . J Clin Oncol 1983; 1: 597-603. • The EORTC International Antimicrobial Therapy Project Group. Ceftazidirne combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. N Eng!J Med 1987; 317: 1692-8. 0 ' Pizzo PA, Hathorn JW, Hiemenz J, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Eng! J Med 1986; 315 : 552-8. " Norrby SR, Vandercam B, Louie T, et al. Imipenem/ Cilastatin versus amikacin plus piperacillin in the treatment of infections in neutropenic patients: A prospective, randomized multi-clinical study. Scand J Infect Dis 1987; 52: 65-78. "Bodey GP, Alvares ME, Jones PG, Rolston KVI, Steelhammer L, Fainstein V. Imipenem-Cilastatin as initial therapy for febrile cancer patients. Antimicrob Agents Chemother 1986; 20: 211-4. 11 Young LS, Hindler J. Use of trimethoprim-sulfamethoxazole singly and in combination with other antibiotics in immunocompromised patients. Rev Infect Dis 1987; 9: 17781.
REFERENCES 'Bodey GP, Burkley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328-40. 'Pizzo PA. After empiric therapy: What to do until the granulocyte comes back? Rev Infect Dis 1987; 9: 214-9. ' Shimp££ S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Eng! J Med 1971 ; 284: 1061-5. ' The EORTC International Antimicrobial Therapy Project Group. Three antibiotic regimens in the treatment of infection in febrile gra nulocytopenic patients with cancer. J Infect Dis 1978; 137: 14-29. ' Klastersky J, Glauser MP, Schimpf£ SC, Zinner SH, Gaya H, European Organization for Research on Treatment of Cancer Antimicrobial Therapy Project Group. Prospective randomized comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenic patients. Antimicrob Agents Chemother 1986; 29: 263-70. 'Winston DJ, Ho WG, Young LS, Hewitt WL, Gale RP. Piperacillin plus amikacin therapy versus carbenicillin plus arnikacin therapy in febrile, granulocytopenic patients. Arch Intern Med 1982; 142: 1663-7.
" Braine HG, Stuart RK, Sara] R, Lierman PS. Parenteral trimethoprim-sulfamethoxazole and carbenicillin as empiric therapy for neutropenic patients with cancer. Rev Infect Dis 1982; 4: 586-92. "Bodey GP, Grose AWE, Keating MJ . Use of rrimerhoprim-sulfamethoxazole for treatment of infections in patients with cance.r. Rev Infect Dis 1982; 4: 579-85. "Stuart RK, Braine HG, Lierman PS , Saral R, Fuller DJ. Carbenicillin-trimethoprim/sulfamethoxazole versus carbenicillin-gentamicin as empiric therapy of infection in granulocytopenic patients: a prospective, randomized, double-blind study. Am J Med 1980; 86: 876-85. 11 Kahan M, Kropp H, SundelofJG, Birnbaum]. Thienamycin: development of imipenem-cilastatin. J Antimicrob Chemorher 1983 ; 12 Supp D: 1-35. " Rubin M, H athorn JW, Marshall D, Gress J, Steinberg S, Pizzo P. Gram-positive infections and the use of vancomycin in 55 0 episodes of fever and neutropenia. Ann Intern Med 1988; 108: 30-5. 19 Giinrher G, Bjorkholm M, Bjorklind A, Engervall P, Stiernstedt G . Septicemia in patients with hematological disorders and neutropenia. A retrospective study of causative agen ts and their resistance profile. Scand J Infect Dis 1991; 23: 589-98. 20 Bodey GP, Rolston K, Jones P, Alvares ME, Fainstein V, Steelhammer L. Imipenem/Cilastatin as secondary therapy for infections in cancer patients. J Antimicrob Chemother 1986; 18: 161-6.
