Journal of Antimicrobial Chemotherapy (1991) 28, 117-129
Aztreonam therapy in children with febrile neutropenia: a randomized trial of aztreonam pins flucloxacillin versus piperacillin plus gentamicin
"Department of Paediatrics, St James's University Hospital, Leeds; ''Department of Microbiology, St James's University Hospital, Leeds, UK In a prospective, randomized trial in 100 febrile neutropenic children, aztreonam plus flucloxacillin was compared with piperacillin plus gentamicin. At the 72 h clinical assessment there was no statistically significant difference between the two groups. However, in microbiologically documented infections there was a higher response rate in the piperacillin/gentamicin group (57%) than in the aztreonam/ flucoxacillin group (41%). This was contributed to by the poorer Gram-positive cover of the aztreonam/flucloxacillin combination. In clinically documented infections and unexplained fevers the response rate of the two antibiotic regimens was identical. There were two deaths; one early death (in the piperacillin/gentamicin arm) and one late death. At the final assessment a successful outcome was obtained in the remaining patients. In the aztreonam/flucloxacillin group 75% of the episodes required modification compared with 59% in the piperacillin/gentamicin group.
Introduction Aztreonam is a monobactam antibiotic with in-vitro activity against most isolates of aerobic, Gram-negative bacilli (Stutman et al., 1984). It has no activity however, against Gram-positive or anaerobic organisms. The mechanism of action of the monobactams is similar to that of other /Mactam antibiotics but they are stable to a wide range of plasmid and chromosomally mediated /Mactamases (Friis et al., 1986). In children, aztreonam has been successfully used for the treatment of urinary tract infections (Kline, Kaplan & Mason, 1986), acute pulmonary exacerbations of cystic fibrosis (Bosso, Black & Matsen, 1987), deep soft tissue infections, septicaemia, pneumonia and peritonitis (Stutman et al., 1986). Its potential use in children with febrile neutropenia has been highlighted (Lebel & McCracken, 1988). Because of its lack of activity against Gram-positive organisms it is necessary to combine it with an appropriate antibiotic to provide satisfactory broad spectrum cover, when used to treat febrile episodes in neutropenic patients. Standard antibiotic regimens used in febrile neutropenic patients often combine an aminoglycoside with a broad spectrum /Mactam antibiotic. This remains a popular choice (Young, 1986) despite the advent of double /Mactam combinations (Fainstein et al., 1984; Winston et al., 1984) or single /Mactam regimens (Pizzo et al., 1986). The nephrotoxic and ototoxic side effects associated with aminoglycosides are of special Correspondence to: Dr D. Heney, Department of Paediatrics, St James's University Hospital, Leeds, LS9 7TF.UK. 0305-7453/91/070117+ 13 S02.00/0
117 © 1991 The British Society for Antimicrobial Chemotherapy
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D. Heney*, L J. Lewis', A. T. M. GboDeim', P. Chisholm*, and C. C. Bailey*
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Methods Eligibility criteria
All patients were being treated at the Paediatric Oncology Unit at St James's University Hospital. Patients aged between 1 month and 15 years who became febrile while neutropenic were eligible for the trial. Fever was defined as a temperature of > 38-5°C, or > 38°C on two occasions within a 12 h period. Neutropcnia was defined as an absolute neutrophil count of less than l-OxlO'/L. Written informed consent was obtained from a parent or legal guardian. Patients with a known hypersensitivity to any of the study antibiotics were excluded; as were patients who had received an antibiotic other than co-trimoxazole prophylaxis, in the previous seven days. No patient undergoing a bone marrow transplant was entered into the trial.
Study design One hundred consecutive eligible patients were entered into the trial. All patients had a history taken and a physical examination performed. A clinical evaluation of the severity of the sepsis was made by means of a scoring system developed within our unit (Table I). All patients had a single blood culture, taken either from a central venous line or peripherally, as well as samples of urine, faeces and throat swab sent for routine microbiology. All Gram-negative organisms and significant Gram-positive bacteria were fully identified by API procedures (API System S.A., La Balma Les Grottes, 38390 Montalieu Vercieu, France) and disc sensitivity testing was performed by Stokes' method (Stokes & Waterworth, 1972). Blood samples were sent for full blood count, electrolytes, creatinine and liver enzymes. Chest radiographs were performed in patients with respiratory symptoms. Patients were then randomly assigned to received either regimen A: aztreonam and flucloxacillin or regimen B: piperacillin and gentamicin. Once allocated to one of the two treatment groups the patients continued on that regimen for 72 h. Patients who had responded clinically at 72 h continued on the same regimen. Patients who showed no clear response at 72 h or whose condition had deteriorated were crossed over to the alternative treatment regimen which was continued until resolution of fever (see Figure 1 for study design). Co-trimoxazole prophylaxis was continued during the febrile episode.
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concern in neutropcnic children who may also be receiving a number of other toxic agents for treatment of their tumour. Aztreonam with its efficacy against Gram-negative organisms and its low toxicity should provide a useful, safer alternative in this population. The standard antibiotic combination used in our unit has been piperacillin and gentamicin, and it was therefore decided to compare this, in a randomized trial, with aztreonam and flucloxacillin. Despite the increasing incidence of Gram-positive infections it has been recommended that vancomycin should only be used as a second line antibiotic (Rubin et al., 1988). There is also evidence of an enhanced synergistic effect against Gram-positive organisms when aztreonam is combined with anti-staphylococcal antibiotics including cloxacillin (Bakhtiar & Selwyn, 1988).
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Table L Sepsis scoring system Cardiovascular - Normal pulse and blood pressure (bp) •» Tachycardia, normal bp = Increasing tacybcardia with evidence of peripheral shut-down - Tachycardia, peripheral shut-down, low bp, plasma support «* Circulatory support with pressor agents
(b) 1 2 3 4 5
Centra] nervous system = Normal/playing = Miserable/upset but conscious and awake - Drowsy but reusable and conscious = Drowsy/confused - Unconscious
(c) Gastrointestinal system 1 = Normal appetite/bowel motions 2 •= Poor appetite and/or slightly increased stool frequency, minimal vomiting, abdominal tenderness 3 •= Loss of appetite, markedly raised stool frequency, minimal vomiting, abdominal tenderness 4 = Appetite absent, vomiting + + , abdominal distension and pain 5 - Severe abdominal distension, absent bowel movement and sounds, marked abdominal pain and tenderness Note: the final tcore reflects the sum of the above three groups. The dosage of antibiotics used was: aztreonam SO mg/kg 6-hourly,
flucloxacillin
100 mg/kg/day 6-hourly, piperacillin 300 mg/kg/day 8-hourly and gentamicin 2 mg/kg 8-hourly. Aztreonam was reconstituted with sterile water and diluted with an infusion solution of either normal saline or a dextrose-saline solution, the final solution being at least lOOmL/g of aztreonam, and administered over 60 min. All antibiotics were administered as separate infusions. Gentamicin levels were monitored at 24 h and twice weekly subsequently, to maintain a peak level of 5-8 mg/L. All patients were closely monitored throughout the trial. The clinical sepsis score was recorded daily, or more frequently if there was any significant clinical change. Blood cultures were repeated when indicated. Blood counts and biochemistry were monitored every second day or more frequently if necessary. Treatment was continued for a minimum of 48 h after the patient became afebrile and for a minimum of seven days in those with microbiologically documented infections.
no response /
\ //
\
/N
Modification •jnphouricin B •cydovfr
Start
B
no response Flgmc 1. Outline of study design.
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(a) 1 2 3 4 5
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Diagnostic criteria and evaluation
Modification of the initial treatment regimen In addition to the possible 72 h cross-over to the alternative antibiotic regimen, a number of other modifications were allowed. Amphotericin B was added if patients remained febrile and neutropenic after five days of antibiotic therapy, or if there was clinical or microbiological evidence of an invasive fungal infection. Acyclovir was added if there was clinical or culture-confirmed evidence of a herpes infection. Metronidazole was administered in patients developing marked gastrointestinal symptoms, including abdominal pain or diarrhoea. Where positive cultures revealed an organism resistant to the initial study antibiotic, the appropriate modification indicated by the sensitivities was made. Patients who failed to respond after receiving both antibiotic regimens or whose clinical condition was deteriorating rapidly were considered for a rescue regimen consisting of ceftazidime and vancomycin.
Evaluation of response Patients were evaluated for their clinical and microbiological response. An evaluation was performed at two distinct time points. The first was at 72 h after starting treatment to assess the response to the initial antibiotic regimen. The second was a final overall evaluation to assess not only the efficacy of the randomly assigned regimen, but also the incidence and outcome of secondary infections and the need for modifications to the treatment.
72 h clinical evaluation A successful clinical response comprised the following: (i) complete resolution, when all signs and symptoms related to the initial infection resolved; (ii) partial resolution, if there was moderate or marked reduction of the signs and symptoms. A failure of clinical response comprised the following: (i) clinical failure with no, or only slight, reduction of signs and symptoms of infection; (ii) death due to uncontrolled infection. Indeterminate response occurred if no evaluation was possible for any reason, including treatment with the study regimens for less than 72 h.
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Initial febrile episodes were categorized into the following groups: (1) microbiologically documented infection in patients with a fever and a positive blood culture or with signs and symptoms of localized infection with definitive microbiological identification. This does not include isolates from skin, stool or mouth unless clinically relevant; (2) clinically documented infection in patients with signs and symptoms indicating a clinical site of infection (e.g. pneumonia or soft tissue infection) but with negative microbiological cultures; (3) unexplained fever in patients presenting with a fever but without a site of infection and with negative microbiological cultures. (This corresponds to 'possible infection' as defined by the EORTC group (1979) and to 'fevers of undetermined origin' as defined by Pizzo et al. (1986).)
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Overall assessment At the final overall assessment patients were classified into one of three categories (Pizzo et al., 1986). Success without modification referred to patients who successfully recovered without the need for modification of the initial randomly assigned regimen. Success with modification referred to patients who recovered successfully but who required modification of their initial regimen. The third category comprised patients who had died due to presumed or documented infection.
The microbiological evaluation included an assessment both of primary treatment failures and the sensitivity or resistance of the microbial isolates. The elimination or persistence of infection as well as the occurrence of superinfcctions was also documented. Toxicity Renal toxicity was defined as a two-fold increase in serum creatinine and hepatic toxicity as a two-fold increase in serum aspartate aminotransferase, alaninc aminotransferase or total bilirubin. The occurrence of rashes and phlebitis was also documented. A chi-squared test with Yates continuity correction, was used to compare differences in proportions between groups. The Fischer's exact test was used to compare proportions involving fewer than 20 patients in either group.
Results Characteristics of the study population During an eight month period, 100 episodes of fever and neutropenia occurred in 59 patients entered into the trial. Only one eligible patient refused randomization. Three entries into the trial were excluded from the final analysis for the following reasons: antibiotics received in preceding seven days (two cases) and above the age limit (one case). The clinical characteristics of the patients in both treatment groups are shown in Table II. Both groups are comparable for age, sex, underlying diagnosis, disease activity and clinical sepsis score. The degree of neutropenia was similar for the two study groups with the majority of patients (74%) having an absolute neutrophil count of less than 0-1 x 109/L. Clinical and microbiological evaluation before antibiotic therapy An assessment of diagnostic categories was made at 72 h when microbiological results were available. Forty-five febrile episodes were microbiologically documented (46% of total), with 37 episodes associated with a bacteraemia. There were 48 episodes of unexplained fever (49%). Both treatment groups were comparable (see Table UJ). Table IV lists the positive cultures obtained before antibiotics were started. The number of Gram-negative organisms in each treatment group was small, and the
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Microbiological evaluation
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Table IL Clinical characteristics of patients Piperacillin/ gentamicin
50 2
50
48 36 6-2 11-15 24 24
1 49 37 6-3 1-5-15 28 21
26 3 3 15 1
25 6 2 16 0
16 25 7 0-092
27
16 6 0097
37 (77%) 45 (94%) 22
35 (71%) 45 (92%) 20
5-4
5-4 8
7
ALL, Acute lymphoblajtic leukaemia; AML, acute myeloblastic leukaemia, NHL, non-Hodgkin's lymphoma.
majority 71%) of organisms were Gram-positive with staphylococcal infections predominating. Central venous catheters Twenty-two patients with central venous catheters had 42 episodes of febrile neutropenia, of which 15 were associated with a positive blood culture on day one. Six of the fifteen cultures were staphylococcal (40%). This compares with 38 patients without central lines who had 55 febrile episodes. Twenty-three of these had a positive blood culture of which thirteen were staphylococcal (56%). There was no significant difference between either treatment group. Patients with central lines therefore did not have an increased incidence of positive blood cultures, nor of staphylococcal infections. Clinical evaluation at 72 h assessment
The early evaluation was made at 72 h (Table V). Patients with clinically documented infections and unexplained fevers had an identical response rate in both treatment groups, with 69% of episodes responding successfully to the initial treatment. There were no deaths in this group. Patients with microbiologically documented infections
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Total number of episodes Withdrawals Number of episodes in trial Number of patients Age of patients: mean (years) range Females Males Diagnosis (per episode) ALL AML NHL solid tumour other Stage of disease new (within one month of diagnosis) remission relapse with active disease Initial neutrophil count (mean) x 10yL Initial neutrophil count Number of episodes with: less than 0-1 x 10*/L less than 0-5 x 10*/L Central line present Clinical severity score: before starting antibiotics number of episodes with score > 8
Aztreonam/ flucloxacillin
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Aztreoaam in febrile, neatropenk children
Table m . Diagnosis at 72 h evaluation Aztreonam/ flucioxacillin
Piperacillin/ gentamicin
22 18 1 0
23 19 0
2
0 1 3 2 1 0 23 48
0 0 1 25 49
who were treated with piperacillin/gentamicin had a higher response rate (57%) compared with aztreonam/flucloxacilnn (41%); P = 0-36 (95% confidence interval for difference between the proportions is —11% to 47%). A single early death at 48 h occurred in the piperacillin/gentamicin group as a result of overwhelming endotoxic shock with Escherichia coli, sensitive to piperacillin and aztreonam, cultured from blood samples. Table IV shows the clinical response to individual pathogens at 72 h. Seven out of ten Gram-negative infections failed to respond clinically at 72 h. Of the staphylococcal infections, in the aztreonam/flucloxacillin group five out of eight (including one multiresistant coagulase-negative staphylococcus (CNS)) failed to respond; while in the Table IV. Clinical response of specific pathogens at 72 h Aztreonam/flucloxacillin clinical response (%) episodes Total Gram-positive organisms S. aureus CNS* E. faecalis Others Total Gram-negative organisms E. coli Pseudomonas spp. Salmonella sp. Serratia sp. Haemophihu influenzae Fungal—Candida Viral—Rota virus
14 5 3 2 4 5 3 0 1 0 1 1 2
7(50) 2(40) 1(33) 0(0) 4(100) 1(20) 1(33) 0(0) 0(0) 0(0) 1(50)
Piperacillin/gentamicin clinical episodes response (%) 17 3 8 1 5 5 2 2 0 1 0 0 1
11(65) 1(33) 5* (63) 1(100) 4(80) 2(40) 0(0) 1(50) — 1(100) — — 1(100)
•CNS, Coagulise-negative ttaphylococcus. *One CNS was part of a polymkrobia] infection with S. sanguii and Corynebacterhan sp.
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Microbiologically documented infection bacteraemia urinary tract infection respiratory gastrointestinal soft tissue pharynx Ginically documented infection soft tissue eye respiratory Unexplained fever Total
0 22
0
13
6 3 13
9 (41%)
Clinical sepsis score: mean (95% confidence interval) 5-8 (5-2-6-5) Oh 5 0 (4-3-5-6) 72 h
Successful clinical response: complete partial Failure of clinical response: clinical failure death Indeterminate Total episodes: 50 (4-6-5-4) 4 0 (3-5-4-4)
18 (69%) 11 7 7 7 0 1 26
Aztreonam/flucloxacillin unexplained fever microbiologically and clinically documented documented infection
4
8 8
4
9
5-6 (4-8-6-4) 4-3 (3-6-50)
5-3 (4-8-5-8) 3-7 (3-3-4-1)
0 0 26
14
9 8 1 1 23
18 (69%)
13 (57%)
Piperacillin/gentamicin unexplained fever microbiologically and clinically documented documented infection
Table V. Clinical response at 72 h evaluation
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piperacillin/gentamicin group five out of eleven failed (with three multi-resistant CNS). There were two Enterococcus faecalis infections in the aztreonam/flucloxacillin group that were resistant to aztreonam and flucloxacillin but sensitive to piperacillin. If the fungal and viral infections are excluded, the clinical response of the enterococcal and staphylococcal infections comprises the main difference between the two treatment groups.
Febrile episodes that failed to respond clinically at 72 h were crossed over to the opposite treatment group and assessed again 48 h later. Seventeen patients in the aztreonam/flucloxacillin group were switched to piperacillin/gentamicin, and of these five required no further modification. Twelve patients in the piperacillin/gentamicin group were switched to aztreonam/flucloxacillin and five required no further modification. Although the response rate is higher for patients crossed over to aztreonam/ flucloxacillin than for those crossed to piperacillin/gentamicin, for the majority (75%), a cross-over did not result in the resolution of fever within the next 48 h. For patients who were crossed-over, a resolution of fever occurred in association with a rising neutrophil count in 81% of cases. Eight patients (three in the aztreonam/flucloxacillin group and five in the piperacillin/gentamicin group) who failed clinically at 72 h were given a rescue regimen instead of being crossed over. These were all microbiologically documented infections and included seven CNS infections where vancomycin was preferred. Breakthrough bacteraemia and secondary fevers Seventeen patients developed a secondary fever after resolution of the initial fever, but while still neutropenic. In the aztreonam/flucloxacillin group there were nine patients with three positive cultures Streptococcus sanguis, E. faecalis and AspergUlus spp.) and eight patients in the piperacillin/gentamicin group with four positive cultures (S. morbillorum, S. pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa). The aspergillus infection resulted in a single late death, which occurred on day 20 in a patient with relapsed B cell acute lymphoblastic leukaemia (ALL) who failed to respond to antifungal therapy. Three patients also developed breakthrough bacteraemias during their initial febrile illness. Two patients were in the aztreonam/flucloxacillin group, with E. faecalis and Bacteroides fragilis cultured, and one patient in the piperacillin/gentamicin group with S. aureus cultured. Overall evaluation There were two deaths in the trial; one an early death and one a late death. In the remaining patients a successful outcome was obtained. For most of these patients a modification was required, and details are shown in Table VI and Figure 2. In the aztreonam/flucloxacillin group 75% of the episodes required modification, compared with 59% in the piperacillin/gentamicin group (P = 014; 95% confidence interval for differences between proportions is —2% to 34%). For patients crossed over to aztreonam/flucloxacillin, 7/12 (58%) required a further modification, compared to 12/17 (70%) crossed to piperacillin/gentamicin.
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Assessment of treatment cross-over
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AZTREONAM/ FLUCLOXACILLJN
Indeterminate : 1
Success : 27
Additional Modification
Start
12(1 draft)
12
Success : 31
PIPERACILLJN/ GENTAMICIN
Indeterminate : 1
Figure 2. Flow diagram of study to indicate outcome for groups of patients. Numbers of patients requiring modifications are indicated within the box labelled 'modifications'. Numben of patients reaching the end of the study without further modification are given in the circles at the right hand side of the figure.
Toxidty The overall incidence of toxicity was low. Aztreonam was used in a total of 59 febrile episodes either initially or following a cross-over and the only toxicity seen was in one patient who developed phlebitis. The use of a slower infusion rate and adequate diluent prevented any recurrence. No patient on aztreonam developed liver or renal toxicity. Table VI. Overall assessment and modifications Aztreonam/ flucloxatillin
Piperacillin/ gentamicin
48 5-4 7-8 10-4 6-8 1 11 (23%) 36 (75%)
49 4-8 6-7 9-6 71 1 19 (38%) 29 (59%)
17 9 12 25 1
12 11 7 15 2
Evaluable episodes Mean duration of initial fever (days) Mean time to final defervescence (days) Mean duration of all antibiotics (days) Mean duration neutropenia < 0-5 x 10*/L (days) Deaths Success without modification Success with modification Modifications': crossover vancomycin amphotcridn B metronidazole acyclovir •Note: individual patients will have had more than one modification.
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Of the other antibiotics used, five episodes of renal toxicity were documented. Three were in patients receiving gentamicin and two receiving amphotericin B. Three patients developed a rash; two in relation to flucloxacillin and one following piperacillin. Discussion Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on November 25, 2014
Aztreonam has been used in adult cancer patients with neutropenia in combination with vancomycin and also with vancomycin plus amikacin (Jones et al., 1986). Comparisons of these and other trials is difficult because of different definitions of response and diagnostic categories. We agree with Pizzo et al. (1986), that patients need to be assessed at two time points; an early assessment to examine the true empiric effect of a chosen antibiotic and also a final overall assessment to examine breakthrough infections, secondary fevers and the effect of any cross-over within the trial. In this study, at the 72 h assessment, patients with unexplained fevers and clinically documented infections showed a similar clinical response rate for both aztreonam/ flucloxacillin (69%) and piperacUlin/gentamicin (69%). In patients with microbiologically documented infections there were only a small number of Gram-negative organisms and for these there was a similar response rate in both treatment groups. The clinical response rate for all Gram-negative infections was poor with only three out of ten showing a satisfactory response at 72 h. However there was no microbiological evidence of persisting infection in these patients apart from the single acute death. This highlights the difficulty in controlling the symptoms of Gram-negative infections in the early stages of the infection and the associated mortality. For the Gram-positive organisms aztreonam/flucloxaciUin was successful in seven of fourteen infections (50%) and piperacillin/gentamicin in eleven of seventeen infections (65%), possibly reflecting the poorer Gram-positive cover of the aztrconam/flucloxacillin combination. All patients with Gram-positive infections nevertheless recovered successfully with further antibiotic therapy. Gram-positive organisms represented 71% of all positive cultures at the start of therapy and demonstrates the growing importance of these infections and their tendency to create morbidity rather than mortality (Rubin et al., 1988). The overall assessment performed at completion of therapy examined a number of aspects. We included a cross-over in our trial at 72 h for patients who were assessed as having failed clinically. The cross-over, however, did not appear to alter the course of the fever. Of the patients who were crossed over the majority (75%) did not respond to the alternative antibiotic regimen within the next 48 h, but subsequently showed a reduction in fever usually in association with a rising neutrophil count. Both treatment groups showed comparable response rates. Breakthrough infections and secondary fevers were also similar in both treatment groups and again a preponderance of Gram-positive organisms was seen in those with positive cultures. Patients with febrile neutropenia often have prolonged and complex patterns of fever. As can be seen from Figure 2, modifications continued to occur whether initial therapy was successful or not. The increased number of modifications in the aztreonam/flucloxacillin group was only partly contributed to by the need for additional Gram-positive cover. The reason for the increased use of amphotericin B and metronidazole in this group is not clear. An examination of individual modifications is complex, and a much larger study would be required for statistical analysis. The clinical sepsis score proved easy to use. It provided a further indicator for
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Acknowledgements We wish to thank Squibb for the provision of aztreonam supplies and for their support. We also wish to thank the staff of Ward 15, St James's Hospital, for their dedicated care of the patients and their help in collection of specimens. References Bakhtiar, M. & Selwyn, S. (1988). Combination of aztreonam with anti-staphlococcal antibiotics. Journal of Antimicrobial Chemotherapy 22, 773-4. Bosso, J. A., Black, P. G. & Matsen, J. M. (1987). Efficacy of aztreonam in pulmonary exacerbations of cystic fibrosis. Pediatric Infectious Disease Journal 6, 393-7. EORTC International Antimicrobial Therapy Project Group (1978). Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. Journal of Infectious Diseases 137, 14-29. Fainstein, V., Bodey, G. P., Bolivar, R., Elting, L., McCredie, K. B. & Keating, M. J. (1984). Moxalactam plus ticarcillin or tobramycin for treatment of febrile episodes in neutropenic cancer patients. Archives of Internal Medicine 144, 1766-70. Friis, H., Prag, J., Togsverd, E. & Benson, M. W. (1986). Beta-lactamase stability and in vitro activity of aztreonam, with a comparison to 9 other beta-lactam antibiotics and gentamicin. Chemotherapy {Basel) 32, 329-35. Jones, P. G., Rolston, K. V., Fainstein, V., Elting, L., Walters, R. S. & Bodey, G. P. (1986). Aztreonam therapy in neutropenic patients with cancer. American Journal of Medicine 81, 243-8. Kline, M. W., Kaplan, S. L. & Mason, E. O. (1986). Aztreonam therapy of Gram-negauve infections predominantly of the urinary tract in children. Current Therapeutic Research 39, 625-31. Lebel, M. H. & McCracken, G. H. (1988). Aztreonam: review of the clinical experience and potential uses in pediatrics. Pediatric Infectious Disease Journal 7, 331-9.
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assessment of both severity of illness and response to treatment. The difference in mean scores between the two treatment groups at 72 h correlated well with the differences seen in clinical response. We feel a standard scoring system would prove of value when comparing results from different trials. Previous studies have shown aztreonam to be well tolerated in paediatric patients with a 2-1% incidence of clinical adverse reactions including rash, phlebitis, diarrhoea and altered taste sensation (Lebel & McCracken, 1988). The main biochemical abnormality noted has been an elevation of hepatic enzymes. In this study the incidence of side effects related to aztreonam was low with only a single episode of phlebitis. No hepatic or renal toxicity was seen. Three patients developed gentamicin-related renal toxicity, an incidence of 5%. Cytotoxic chemotherapy may itself produce renal and ototoxic side effects, which are particularly important in children where permanent damage creates numerous long term problems. It is therefore necessary to search for antibiotics with low toxicity that provide an alternative to the aminoglycosides. In summary the initial, empiric use of aztreonam/flucloxacilhn proved comparable to our standard combination of piperadllin/gentamicin with a reduction in toxic side effects. Its main limitation is in providing adequate Gram-positive cover. Although differences do exist between the two study groups, the fact that most patients had a successful outcome at completion of therapy, suggests that an overall, comprehensive strategy for managing infective complications in immunocompromised patients is more important than small differences between empirical therapeutic regimens.
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(Received 12 September 1990; revised version accepted 26 February 1991)
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Pizzo, P. A., Hathorn, J. W., Hiemenz, J., Browne, M., Commcrs, J., Cotton, D. et al. (1986). A randomized trial comparing ceflazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. New England Journal of Medicine 315, 552-8. Rubin, M., Hathorn, J. W., Marshal, D., Gross, J., Steinberg, S. M. & Pizzo, P. A. (1988). Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia. Annals of Internal Medicine 108, 30-5. Stokes, E. J. & Waterworth, P. M. (1972). Antibiotic Sensitivity Tests by Diffusion Methods. Association of Clinical Pathologists Broadsheet No. 55 (revised). Stutman, H. R., Chartrand, S. A., Tolentino, T., Friedhoff, L. & Marks, M. I. (1986). Aztreonam therapy for serious Gram-negative infections in children. American Journal of Diseases of Children 140, 1147-51. Stutman, H. F., Welch, D. F., Scribner, R. K. & Marks, M. I. (1984). In vitro antimicrobial activity of aztreonam alone and in combination against bacterial isolates from pediatric patients. Antimicrobial Agents and Chemotherapy 25, 212-5. Winston, D. J., Barnes, R. C, Ho, W. G., Young, L. S., Champlin, R. E. & Gale, R. P. (1984). Moxalactam plus piperacilh'n versus moxalactam plus amikacin in febrile granulocytopcnic patients. American Journal of Medicine 77, 442-50. Young, L. S. (1986). Empirical antimicrobial therapy in the neutropenic host. New England Journal of Medicine 315, 580-1.
Aztreonam therapy in children with febrile neutropenia: a randomized trial of aztreonam pins flucloxacillin versus piperacillin plus gentamicin
"Department of Paediatrics, St James's University Hospital, Leeds; ''Department of Microbiology, St James's University Hospital, Leeds, UK In a prospective, randomized trial in 100 febrile neutropenic children, aztreonam plus flucloxacillin was compared with piperacillin plus gentamicin. At the 72 h clinical assessment there was no statistically significant difference between the two groups. However, in microbiologically documented infections there was a higher response rate in the piperacillin/gentamicin group (57%) than in the aztreonam/ flucoxacillin group (41%). This was contributed to by the poorer Gram-positive cover of the aztreonam/flucloxacillin combination. In clinically documented infections and unexplained fevers the response rate of the two antibiotic regimens was identical. There were two deaths; one early death (in the piperacillin/gentamicin arm) and one late death. At the final assessment a successful outcome was obtained in the remaining patients. In the aztreonam/flucloxacillin group 75% of the episodes required modification compared with 59% in the piperacillin/gentamicin group.
Introduction Aztreonam is a monobactam antibiotic with in-vitro activity against most isolates of aerobic, Gram-negative bacilli (Stutman et al., 1984). It has no activity however, against Gram-positive or anaerobic organisms. The mechanism of action of the monobactams is similar to that of other /Mactam antibiotics but they are stable to a wide range of plasmid and chromosomally mediated /Mactamases (Friis et al., 1986). In children, aztreonam has been successfully used for the treatment of urinary tract infections (Kline, Kaplan & Mason, 1986), acute pulmonary exacerbations of cystic fibrosis (Bosso, Black & Matsen, 1987), deep soft tissue infections, septicaemia, pneumonia and peritonitis (Stutman et al., 1986). Its potential use in children with febrile neutropenia has been highlighted (Lebel & McCracken, 1988). Because of its lack of activity against Gram-positive organisms it is necessary to combine it with an appropriate antibiotic to provide satisfactory broad spectrum cover, when used to treat febrile episodes in neutropenic patients. Standard antibiotic regimens used in febrile neutropenic patients often combine an aminoglycoside with a broad spectrum /Mactam antibiotic. This remains a popular choice (Young, 1986) despite the advent of double /Mactam combinations (Fainstein et al., 1984; Winston et al., 1984) or single /Mactam regimens (Pizzo et al., 1986). The nephrotoxic and ototoxic side effects associated with aminoglycosides are of special Correspondence to: Dr D. Heney, Department of Paediatrics, St James's University Hospital, Leeds, LS9 7TF.UK. 0305-7453/91/070117+ 13 S02.00/0
117 © 1991 The British Society for Antimicrobial Chemotherapy
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D. Heney*, L J. Lewis', A. T. M. GboDeim', P. Chisholm*, and C. C. Bailey*
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Methods Eligibility criteria
All patients were being treated at the Paediatric Oncology Unit at St James's University Hospital. Patients aged between 1 month and 15 years who became febrile while neutropenic were eligible for the trial. Fever was defined as a temperature of > 38-5°C, or > 38°C on two occasions within a 12 h period. Neutropcnia was defined as an absolute neutrophil count of less than l-OxlO'/L. Written informed consent was obtained from a parent or legal guardian. Patients with a known hypersensitivity to any of the study antibiotics were excluded; as were patients who had received an antibiotic other than co-trimoxazole prophylaxis, in the previous seven days. No patient undergoing a bone marrow transplant was entered into the trial.
Study design One hundred consecutive eligible patients were entered into the trial. All patients had a history taken and a physical examination performed. A clinical evaluation of the severity of the sepsis was made by means of a scoring system developed within our unit (Table I). All patients had a single blood culture, taken either from a central venous line or peripherally, as well as samples of urine, faeces and throat swab sent for routine microbiology. All Gram-negative organisms and significant Gram-positive bacteria were fully identified by API procedures (API System S.A., La Balma Les Grottes, 38390 Montalieu Vercieu, France) and disc sensitivity testing was performed by Stokes' method (Stokes & Waterworth, 1972). Blood samples were sent for full blood count, electrolytes, creatinine and liver enzymes. Chest radiographs were performed in patients with respiratory symptoms. Patients were then randomly assigned to received either regimen A: aztreonam and flucloxacillin or regimen B: piperacillin and gentamicin. Once allocated to one of the two treatment groups the patients continued on that regimen for 72 h. Patients who had responded clinically at 72 h continued on the same regimen. Patients who showed no clear response at 72 h or whose condition had deteriorated were crossed over to the alternative treatment regimen which was continued until resolution of fever (see Figure 1 for study design). Co-trimoxazole prophylaxis was continued during the febrile episode.
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concern in neutropcnic children who may also be receiving a number of other toxic agents for treatment of their tumour. Aztreonam with its efficacy against Gram-negative organisms and its low toxicity should provide a useful, safer alternative in this population. The standard antibiotic combination used in our unit has been piperacillin and gentamicin, and it was therefore decided to compare this, in a randomized trial, with aztreonam and flucloxacillin. Despite the increasing incidence of Gram-positive infections it has been recommended that vancomycin should only be used as a second line antibiotic (Rubin et al., 1988). There is also evidence of an enhanced synergistic effect against Gram-positive organisms when aztreonam is combined with anti-staphylococcal antibiotics including cloxacillin (Bakhtiar & Selwyn, 1988).
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Table L Sepsis scoring system Cardiovascular - Normal pulse and blood pressure (bp) •» Tachycardia, normal bp = Increasing tacybcardia with evidence of peripheral shut-down - Tachycardia, peripheral shut-down, low bp, plasma support «* Circulatory support with pressor agents
(b) 1 2 3 4 5
Centra] nervous system = Normal/playing = Miserable/upset but conscious and awake - Drowsy but reusable and conscious = Drowsy/confused - Unconscious
(c) Gastrointestinal system 1 = Normal appetite/bowel motions 2 •= Poor appetite and/or slightly increased stool frequency, minimal vomiting, abdominal tenderness 3 •= Loss of appetite, markedly raised stool frequency, minimal vomiting, abdominal tenderness 4 = Appetite absent, vomiting + + , abdominal distension and pain 5 - Severe abdominal distension, absent bowel movement and sounds, marked abdominal pain and tenderness Note: the final tcore reflects the sum of the above three groups. The dosage of antibiotics used was: aztreonam SO mg/kg 6-hourly,
flucloxacillin
100 mg/kg/day 6-hourly, piperacillin 300 mg/kg/day 8-hourly and gentamicin 2 mg/kg 8-hourly. Aztreonam was reconstituted with sterile water and diluted with an infusion solution of either normal saline or a dextrose-saline solution, the final solution being at least lOOmL/g of aztreonam, and administered over 60 min. All antibiotics were administered as separate infusions. Gentamicin levels were monitored at 24 h and twice weekly subsequently, to maintain a peak level of 5-8 mg/L. All patients were closely monitored throughout the trial. The clinical sepsis score was recorded daily, or more frequently if there was any significant clinical change. Blood cultures were repeated when indicated. Blood counts and biochemistry were monitored every second day or more frequently if necessary. Treatment was continued for a minimum of 48 h after the patient became afebrile and for a minimum of seven days in those with microbiologically documented infections.
no response /
\ //
\
/N
Modification •jnphouricin B •cydovfr
Start
B
no response Flgmc 1. Outline of study design.
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(a) 1 2 3 4 5
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Diagnostic criteria and evaluation
Modification of the initial treatment regimen In addition to the possible 72 h cross-over to the alternative antibiotic regimen, a number of other modifications were allowed. Amphotericin B was added if patients remained febrile and neutropenic after five days of antibiotic therapy, or if there was clinical or microbiological evidence of an invasive fungal infection. Acyclovir was added if there was clinical or culture-confirmed evidence of a herpes infection. Metronidazole was administered in patients developing marked gastrointestinal symptoms, including abdominal pain or diarrhoea. Where positive cultures revealed an organism resistant to the initial study antibiotic, the appropriate modification indicated by the sensitivities was made. Patients who failed to respond after receiving both antibiotic regimens or whose clinical condition was deteriorating rapidly were considered for a rescue regimen consisting of ceftazidime and vancomycin.
Evaluation of response Patients were evaluated for their clinical and microbiological response. An evaluation was performed at two distinct time points. The first was at 72 h after starting treatment to assess the response to the initial antibiotic regimen. The second was a final overall evaluation to assess not only the efficacy of the randomly assigned regimen, but also the incidence and outcome of secondary infections and the need for modifications to the treatment.
72 h clinical evaluation A successful clinical response comprised the following: (i) complete resolution, when all signs and symptoms related to the initial infection resolved; (ii) partial resolution, if there was moderate or marked reduction of the signs and symptoms. A failure of clinical response comprised the following: (i) clinical failure with no, or only slight, reduction of signs and symptoms of infection; (ii) death due to uncontrolled infection. Indeterminate response occurred if no evaluation was possible for any reason, including treatment with the study regimens for less than 72 h.
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Initial febrile episodes were categorized into the following groups: (1) microbiologically documented infection in patients with a fever and a positive blood culture or with signs and symptoms of localized infection with definitive microbiological identification. This does not include isolates from skin, stool or mouth unless clinically relevant; (2) clinically documented infection in patients with signs and symptoms indicating a clinical site of infection (e.g. pneumonia or soft tissue infection) but with negative microbiological cultures; (3) unexplained fever in patients presenting with a fever but without a site of infection and with negative microbiological cultures. (This corresponds to 'possible infection' as defined by the EORTC group (1979) and to 'fevers of undetermined origin' as defined by Pizzo et al. (1986).)
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Overall assessment At the final overall assessment patients were classified into one of three categories (Pizzo et al., 1986). Success without modification referred to patients who successfully recovered without the need for modification of the initial randomly assigned regimen. Success with modification referred to patients who recovered successfully but who required modification of their initial regimen. The third category comprised patients who had died due to presumed or documented infection.
The microbiological evaluation included an assessment both of primary treatment failures and the sensitivity or resistance of the microbial isolates. The elimination or persistence of infection as well as the occurrence of superinfcctions was also documented. Toxicity Renal toxicity was defined as a two-fold increase in serum creatinine and hepatic toxicity as a two-fold increase in serum aspartate aminotransferase, alaninc aminotransferase or total bilirubin. The occurrence of rashes and phlebitis was also documented. A chi-squared test with Yates continuity correction, was used to compare differences in proportions between groups. The Fischer's exact test was used to compare proportions involving fewer than 20 patients in either group.
Results Characteristics of the study population During an eight month period, 100 episodes of fever and neutropenia occurred in 59 patients entered into the trial. Only one eligible patient refused randomization. Three entries into the trial were excluded from the final analysis for the following reasons: antibiotics received in preceding seven days (two cases) and above the age limit (one case). The clinical characteristics of the patients in both treatment groups are shown in Table II. Both groups are comparable for age, sex, underlying diagnosis, disease activity and clinical sepsis score. The degree of neutropenia was similar for the two study groups with the majority of patients (74%) having an absolute neutrophil count of less than 0-1 x 109/L. Clinical and microbiological evaluation before antibiotic therapy An assessment of diagnostic categories was made at 72 h when microbiological results were available. Forty-five febrile episodes were microbiologically documented (46% of total), with 37 episodes associated with a bacteraemia. There were 48 episodes of unexplained fever (49%). Both treatment groups were comparable (see Table UJ). Table IV lists the positive cultures obtained before antibiotics were started. The number of Gram-negative organisms in each treatment group was small, and the
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Microbiological evaluation
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Table IL Clinical characteristics of patients Piperacillin/ gentamicin
50 2
50
48 36 6-2 11-15 24 24
1 49 37 6-3 1-5-15 28 21
26 3 3 15 1
25 6 2 16 0
16 25 7 0-092
27
16 6 0097
37 (77%) 45 (94%) 22
35 (71%) 45 (92%) 20
5-4
5-4 8
7
ALL, Acute lymphoblajtic leukaemia; AML, acute myeloblastic leukaemia, NHL, non-Hodgkin's lymphoma.
majority 71%) of organisms were Gram-positive with staphylococcal infections predominating. Central venous catheters Twenty-two patients with central venous catheters had 42 episodes of febrile neutropenia, of which 15 were associated with a positive blood culture on day one. Six of the fifteen cultures were staphylococcal (40%). This compares with 38 patients without central lines who had 55 febrile episodes. Twenty-three of these had a positive blood culture of which thirteen were staphylococcal (56%). There was no significant difference between either treatment group. Patients with central lines therefore did not have an increased incidence of positive blood cultures, nor of staphylococcal infections. Clinical evaluation at 72 h assessment
The early evaluation was made at 72 h (Table V). Patients with clinically documented infections and unexplained fevers had an identical response rate in both treatment groups, with 69% of episodes responding successfully to the initial treatment. There were no deaths in this group. Patients with microbiologically documented infections
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Total number of episodes Withdrawals Number of episodes in trial Number of patients Age of patients: mean (years) range Females Males Diagnosis (per episode) ALL AML NHL solid tumour other Stage of disease new (within one month of diagnosis) remission relapse with active disease Initial neutrophil count (mean) x 10yL Initial neutrophil count Number of episodes with: less than 0-1 x 10*/L less than 0-5 x 10*/L Central line present Clinical severity score: before starting antibiotics number of episodes with score > 8
Aztreonam/ flucloxacillin
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Aztreoaam in febrile, neatropenk children
Table m . Diagnosis at 72 h evaluation Aztreonam/ flucioxacillin
Piperacillin/ gentamicin
22 18 1 0
23 19 0
2
0 1 3 2 1 0 23 48
0 0 1 25 49
who were treated with piperacillin/gentamicin had a higher response rate (57%) compared with aztreonam/flucloxacilnn (41%); P = 0-36 (95% confidence interval for difference between the proportions is —11% to 47%). A single early death at 48 h occurred in the piperacillin/gentamicin group as a result of overwhelming endotoxic shock with Escherichia coli, sensitive to piperacillin and aztreonam, cultured from blood samples. Table IV shows the clinical response to individual pathogens at 72 h. Seven out of ten Gram-negative infections failed to respond clinically at 72 h. Of the staphylococcal infections, in the aztreonam/flucloxacillin group five out of eight (including one multiresistant coagulase-negative staphylococcus (CNS)) failed to respond; while in the Table IV. Clinical response of specific pathogens at 72 h Aztreonam/flucloxacillin clinical response (%) episodes Total Gram-positive organisms S. aureus CNS* E. faecalis Others Total Gram-negative organisms E. coli Pseudomonas spp. Salmonella sp. Serratia sp. Haemophihu influenzae Fungal—Candida Viral—Rota virus
14 5 3 2 4 5 3 0 1 0 1 1 2
7(50) 2(40) 1(33) 0(0) 4(100) 1(20) 1(33) 0(0) 0(0) 0(0) 1(50)
Piperacillin/gentamicin clinical episodes response (%) 17 3 8 1 5 5 2 2 0 1 0 0 1
11(65) 1(33) 5* (63) 1(100) 4(80) 2(40) 0(0) 1(50) — 1(100) — — 1(100)
•CNS, Coagulise-negative ttaphylococcus. *One CNS was part of a polymkrobia] infection with S. sanguii and Corynebacterhan sp.
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Microbiologically documented infection bacteraemia urinary tract infection respiratory gastrointestinal soft tissue pharynx Ginically documented infection soft tissue eye respiratory Unexplained fever Total
0 22
0
13
6 3 13
9 (41%)
Clinical sepsis score: mean (95% confidence interval) 5-8 (5-2-6-5) Oh 5 0 (4-3-5-6) 72 h
Successful clinical response: complete partial Failure of clinical response: clinical failure death Indeterminate Total episodes: 50 (4-6-5-4) 4 0 (3-5-4-4)
18 (69%) 11 7 7 7 0 1 26
Aztreonam/flucloxacillin unexplained fever microbiologically and clinically documented documented infection
4
8 8
4
9
5-6 (4-8-6-4) 4-3 (3-6-50)
5-3 (4-8-5-8) 3-7 (3-3-4-1)
0 0 26
14
9 8 1 1 23
18 (69%)
13 (57%)
Piperacillin/gentamicin unexplained fever microbiologically and clinically documented documented infection
Table V. Clinical response at 72 h evaluation
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piperacillin/gentamicin group five out of eleven failed (with three multi-resistant CNS). There were two Enterococcus faecalis infections in the aztreonam/flucloxacillin group that were resistant to aztreonam and flucloxacillin but sensitive to piperacillin. If the fungal and viral infections are excluded, the clinical response of the enterococcal and staphylococcal infections comprises the main difference between the two treatment groups.
Febrile episodes that failed to respond clinically at 72 h were crossed over to the opposite treatment group and assessed again 48 h later. Seventeen patients in the aztreonam/flucloxacillin group were switched to piperacillin/gentamicin, and of these five required no further modification. Twelve patients in the piperacillin/gentamicin group were switched to aztreonam/flucloxacillin and five required no further modification. Although the response rate is higher for patients crossed over to aztreonam/ flucloxacillin than for those crossed to piperacillin/gentamicin, for the majority (75%), a cross-over did not result in the resolution of fever within the next 48 h. For patients who were crossed-over, a resolution of fever occurred in association with a rising neutrophil count in 81% of cases. Eight patients (three in the aztreonam/flucloxacillin group and five in the piperacillin/gentamicin group) who failed clinically at 72 h were given a rescue regimen instead of being crossed over. These were all microbiologically documented infections and included seven CNS infections where vancomycin was preferred. Breakthrough bacteraemia and secondary fevers Seventeen patients developed a secondary fever after resolution of the initial fever, but while still neutropenic. In the aztreonam/flucloxacillin group there were nine patients with three positive cultures Streptococcus sanguis, E. faecalis and AspergUlus spp.) and eight patients in the piperacillin/gentamicin group with four positive cultures (S. morbillorum, S. pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa). The aspergillus infection resulted in a single late death, which occurred on day 20 in a patient with relapsed B cell acute lymphoblastic leukaemia (ALL) who failed to respond to antifungal therapy. Three patients also developed breakthrough bacteraemias during their initial febrile illness. Two patients were in the aztreonam/flucloxacillin group, with E. faecalis and Bacteroides fragilis cultured, and one patient in the piperacillin/gentamicin group with S. aureus cultured. Overall evaluation There were two deaths in the trial; one an early death and one a late death. In the remaining patients a successful outcome was obtained. For most of these patients a modification was required, and details are shown in Table VI and Figure 2. In the aztreonam/flucloxacillin group 75% of the episodes required modification, compared with 59% in the piperacillin/gentamicin group (P = 014; 95% confidence interval for differences between proportions is —2% to 34%). For patients crossed over to aztreonam/flucloxacillin, 7/12 (58%) required a further modification, compared to 12/17 (70%) crossed to piperacillin/gentamicin.
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Assessment of treatment cross-over
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AZTREONAM/ FLUCLOXACILLJN
Indeterminate : 1
Success : 27
Additional Modification
Start
12(1 draft)
12
Success : 31
PIPERACILLJN/ GENTAMICIN
Indeterminate : 1
Figure 2. Flow diagram of study to indicate outcome for groups of patients. Numbers of patients requiring modifications are indicated within the box labelled 'modifications'. Numben of patients reaching the end of the study without further modification are given in the circles at the right hand side of the figure.
Toxidty The overall incidence of toxicity was low. Aztreonam was used in a total of 59 febrile episodes either initially or following a cross-over and the only toxicity seen was in one patient who developed phlebitis. The use of a slower infusion rate and adequate diluent prevented any recurrence. No patient on aztreonam developed liver or renal toxicity. Table VI. Overall assessment and modifications Aztreonam/ flucloxatillin
Piperacillin/ gentamicin
48 5-4 7-8 10-4 6-8 1 11 (23%) 36 (75%)
49 4-8 6-7 9-6 71 1 19 (38%) 29 (59%)
17 9 12 25 1
12 11 7 15 2
Evaluable episodes Mean duration of initial fever (days) Mean time to final defervescence (days) Mean duration of all antibiotics (days) Mean duration neutropenia < 0-5 x 10*/L (days) Deaths Success without modification Success with modification Modifications': crossover vancomycin amphotcridn B metronidazole acyclovir •Note: individual patients will have had more than one modification.
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Of the other antibiotics used, five episodes of renal toxicity were documented. Three were in patients receiving gentamicin and two receiving amphotericin B. Three patients developed a rash; two in relation to flucloxacillin and one following piperacillin. Discussion Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on November 25, 2014
Aztreonam has been used in adult cancer patients with neutropenia in combination with vancomycin and also with vancomycin plus amikacin (Jones et al., 1986). Comparisons of these and other trials is difficult because of different definitions of response and diagnostic categories. We agree with Pizzo et al. (1986), that patients need to be assessed at two time points; an early assessment to examine the true empiric effect of a chosen antibiotic and also a final overall assessment to examine breakthrough infections, secondary fevers and the effect of any cross-over within the trial. In this study, at the 72 h assessment, patients with unexplained fevers and clinically documented infections showed a similar clinical response rate for both aztreonam/ flucloxacillin (69%) and piperacUlin/gentamicin (69%). In patients with microbiologically documented infections there were only a small number of Gram-negative organisms and for these there was a similar response rate in both treatment groups. The clinical response rate for all Gram-negative infections was poor with only three out of ten showing a satisfactory response at 72 h. However there was no microbiological evidence of persisting infection in these patients apart from the single acute death. This highlights the difficulty in controlling the symptoms of Gram-negative infections in the early stages of the infection and the associated mortality. For the Gram-positive organisms aztreonam/flucloxaciUin was successful in seven of fourteen infections (50%) and piperacillin/gentamicin in eleven of seventeen infections (65%), possibly reflecting the poorer Gram-positive cover of the aztrconam/flucloxacillin combination. All patients with Gram-positive infections nevertheless recovered successfully with further antibiotic therapy. Gram-positive organisms represented 71% of all positive cultures at the start of therapy and demonstrates the growing importance of these infections and their tendency to create morbidity rather than mortality (Rubin et al., 1988). The overall assessment performed at completion of therapy examined a number of aspects. We included a cross-over in our trial at 72 h for patients who were assessed as having failed clinically. The cross-over, however, did not appear to alter the course of the fever. Of the patients who were crossed over the majority (75%) did not respond to the alternative antibiotic regimen within the next 48 h, but subsequently showed a reduction in fever usually in association with a rising neutrophil count. Both treatment groups showed comparable response rates. Breakthrough infections and secondary fevers were also similar in both treatment groups and again a preponderance of Gram-positive organisms was seen in those with positive cultures. Patients with febrile neutropenia often have prolonged and complex patterns of fever. As can be seen from Figure 2, modifications continued to occur whether initial therapy was successful or not. The increased number of modifications in the aztreonam/flucloxacillin group was only partly contributed to by the need for additional Gram-positive cover. The reason for the increased use of amphotericin B and metronidazole in this group is not clear. An examination of individual modifications is complex, and a much larger study would be required for statistical analysis. The clinical sepsis score proved easy to use. It provided a further indicator for
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Acknowledgements We wish to thank Squibb for the provision of aztreonam supplies and for their support. We also wish to thank the staff of Ward 15, St James's Hospital, for their dedicated care of the patients and their help in collection of specimens. References Bakhtiar, M. & Selwyn, S. (1988). Combination of aztreonam with anti-staphlococcal antibiotics. Journal of Antimicrobial Chemotherapy 22, 773-4. Bosso, J. A., Black, P. G. & Matsen, J. M. (1987). Efficacy of aztreonam in pulmonary exacerbations of cystic fibrosis. Pediatric Infectious Disease Journal 6, 393-7. EORTC International Antimicrobial Therapy Project Group (1978). Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. Journal of Infectious Diseases 137, 14-29. Fainstein, V., Bodey, G. P., Bolivar, R., Elting, L., McCredie, K. B. & Keating, M. J. (1984). Moxalactam plus ticarcillin or tobramycin for treatment of febrile episodes in neutropenic cancer patients. Archives of Internal Medicine 144, 1766-70. Friis, H., Prag, J., Togsverd, E. & Benson, M. W. (1986). Beta-lactamase stability and in vitro activity of aztreonam, with a comparison to 9 other beta-lactam antibiotics and gentamicin. Chemotherapy {Basel) 32, 329-35. Jones, P. G., Rolston, K. V., Fainstein, V., Elting, L., Walters, R. S. & Bodey, G. P. (1986). Aztreonam therapy in neutropenic patients with cancer. American Journal of Medicine 81, 243-8. Kline, M. W., Kaplan, S. L. & Mason, E. O. (1986). Aztreonam therapy of Gram-negauve infections predominantly of the urinary tract in children. Current Therapeutic Research 39, 625-31. Lebel, M. H. & McCracken, G. H. (1988). Aztreonam: review of the clinical experience and potential uses in pediatrics. Pediatric Infectious Disease Journal 7, 331-9.
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assessment of both severity of illness and response to treatment. The difference in mean scores between the two treatment groups at 72 h correlated well with the differences seen in clinical response. We feel a standard scoring system would prove of value when comparing results from different trials. Previous studies have shown aztreonam to be well tolerated in paediatric patients with a 2-1% incidence of clinical adverse reactions including rash, phlebitis, diarrhoea and altered taste sensation (Lebel & McCracken, 1988). The main biochemical abnormality noted has been an elevation of hepatic enzymes. In this study the incidence of side effects related to aztreonam was low with only a single episode of phlebitis. No hepatic or renal toxicity was seen. Three patients developed gentamicin-related renal toxicity, an incidence of 5%. Cytotoxic chemotherapy may itself produce renal and ototoxic side effects, which are particularly important in children where permanent damage creates numerous long term problems. It is therefore necessary to search for antibiotics with low toxicity that provide an alternative to the aminoglycosides. In summary the initial, empiric use of aztreonam/flucloxacilhn proved comparable to our standard combination of piperadllin/gentamicin with a reduction in toxic side effects. Its main limitation is in providing adequate Gram-positive cover. Although differences do exist between the two study groups, the fact that most patients had a successful outcome at completion of therapy, suggests that an overall, comprehensive strategy for managing infective complications in immunocompromised patients is more important than small differences between empirical therapeutic regimens.
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(Received 12 September 1990; revised version accepted 26 February 1991)
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Pizzo, P. A., Hathorn, J. W., Hiemenz, J., Browne, M., Commcrs, J., Cotton, D. et al. (1986). A randomized trial comparing ceflazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. New England Journal of Medicine 315, 552-8. Rubin, M., Hathorn, J. W., Marshal, D., Gross, J., Steinberg, S. M. & Pizzo, P. A. (1988). Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia. Annals of Internal Medicine 108, 30-5. Stokes, E. J. & Waterworth, P. M. (1972). Antibiotic Sensitivity Tests by Diffusion Methods. Association of Clinical Pathologists Broadsheet No. 55 (revised). Stutman, H. R., Chartrand, S. A., Tolentino, T., Friedhoff, L. & Marks, M. I. (1986). Aztreonam therapy for serious Gram-negative infections in children. American Journal of Diseases of Children 140, 1147-51. Stutman, H. F., Welch, D. F., Scribner, R. K. & Marks, M. I. (1984). In vitro antimicrobial activity of aztreonam alone and in combination against bacterial isolates from pediatric patients. Antimicrobial Agents and Chemotherapy 25, 212-5. Winston, D. J., Barnes, R. C, Ho, W. G., Young, L. S., Champlin, R. E. & Gale, R. P. (1984). Moxalactam plus piperacilh'n versus moxalactam plus amikacin in febrile granulocytopcnic patients. American Journal of Medicine 77, 442-50. Young, L. S. (1986). Empirical antimicrobial therapy in the neutropenic host. New England Journal of Medicine 315, 580-1.
