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Ceftazidime as first-line therapy for fever in acute leukaemia
Journal of Infection (I985) I I , 2o5-2I 5
C e f t a z i d i m e as f i r s t - l i n e t h e r a p y f o r f e v e r in a c u t e l e u k a e m i a J. P. Donnelly, R. E. Marcus, J. M. Goldman, J. Cohen, A. M. Worsley, D. Catovsky, J. H. Darrell, S. V. Want, and D. A. G. Galton Medical Research Council Leukaemia Unit and the Department of Bacteriology, Royal Postgraduate Medical School, Ducane Road, London Wx2 o i l S Accepted for publication 3 December I984
Summary Fifty patients with acute non-lymphocytic leukaemia were treated by random allocation with either ceftazidime alone or a combination of piperacillin, netilmicin and cefotaxime for 65 febrile neutropenic episodes. Nineteen of 33 patient episodes (58%) responded to ceftazidime alone compared with 2i of 32 episodes (66 ~o) treated with the combination. There was one infective death in a patient given the combination; rates of documented superinfection were low. The treatment groups appeared identical in terms of patient demography, underlying disease and other risk factors, though patients with a clinical site of infection responded more slowly than those without. Bacteraemia per se did not appear to influence outcome. Bactericidal serum concentrations i> 8 x the minimum bactericidal concentration were predictive of a rapid response (within 4 days) to antibiotics. Furthermore, serum from patients treated with ceftazidime maintained adequate cidal activity against Pseudomonas aeruginosa for longer than that obtained from patients treated with the three-drug combination. Ceftazidime was shown to be a safe and effective alternative to the three-drug combination for the initial management of febrile neutropenic episodes in leukaemic patients.
Introduction Bacterial infection in neutropenic patients m a y run a fulminant course, and antimicrobial therapy m u s t be started before the cause has been established. 1 Antibiotic combinations are chosen to provide b r o a d - s p e c t r u m bactericidal activity against the most likely pathogens. 2 T h e empirical regimen used at H a m m e r s m i t h Hospital had evolved from a five-drug regimen in r9723 to a t h r e e - d r u g regimen in 1981 consisting ofpiperacillin, netilmicin and cefotaxime, t h o u g h formal trials had not been conducted. In the 2-year period immediately preceding the current trial, response rates had been 52 % and 44 % for complete and partial responses with treatment failing in 4 % o f patients. W e were concerned that this regimen was complex to administer, potentially toxic and costly. T h e third-generation cephalosporins offered the possibility of a singledrug regimen and, in particular, ceftazidime appeared to have the required specifications. T h i s c o m p o u n d has b r o a d - s p e c t r u m activity ,4 is bactericidal 5 Correspondence should be addressed to J. P. Donnelly, Department of Bacteriology, Royal Postgraduate Medical School, Ducane Road, London W I z oilS. oi63-4453/85/o6o2o5 + 11 $02.0o/o
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and stable to beta-lactamases. 6 If monotherapy is to replace combination therapy, however, the rates of success, adverse events, superinfection and emergent resistance must be similar or better. We, therefore, undertook a 2-year, prospective, randomised trial of our current regimen versus ceftazidime alone in order to evaluate its role in the initial management of fever in the neutropenic patient with leukaemia.
Patients and m e t h o d s
Patients with acute leukaemia, who were admitted for chemotherapy between February I982 and April I984, were entered into the trial after they had given their informed consent. O f these patients 6o % had acute myeloid leukaemia (AML); the remainder had either chronic granulocytic leukaemia (CGL) or acute lymphoblastic leukaemia (ALL). All were expected to become neutropenic (neutrophils < o'5 x IO9/1) for a variable duration. Patients already febrile on admission or who were already being treated for infection were excluded, as were patients with abnormal renal function (serum creatinine > I25 #mol/l) and those with known hypersensitivity to any of the trial drugs. All were treated in single rooms with reverse barrier nursing, and received oral amphotericin B and co-trimoxazole with or without colistin as antimicrobial prophylaxis. 7 As soon as an eligible patient became neutropenic he or she was allocated to receive empirical treatment by opening sealed envelopes within which cards indicating treatment had already been randomly distributed. Patients then received either ceftazidime (2 g) or a combination ofpiperacillin (4 g), netilmicin (I2O mg) and cefotaxime (2 g) as soon as they became febrile (temperature of more than 38 °C for more than 2 h) and after blood in two separate samples had been taken for culture. All drugs were given intravenously every 8 h. Patients re-admitted for second and subsequent courses of chemotherapy were re-randomised provided that they satisfied the above criteria and had had no therapeutic antibiotic treatment during the preceding 2 weeks. Blood was taken from patients who had given consent, and from whom samples could be obtained without difficulty at times o'5, I, 2, 4 and 8 h after the first dose of antibiotics. These were used to assay the bactericidal activity of the serum against control strains of Pseudornonas aeruginosa ( N C T C IO662), Klebsiella pneumoniae (K. edwardsii var. atlantae N C T C IO896: resistant to co-trimoxazole), a laboratory strain of Staphylococcus epidermidis and any pathogen isolated from the patient. Susceptibility to antibiotics was determined by means of a disc diffusion technique. Results were recorded as susceptible, indeterminate or resistant. Organisms were regarded as being susceptible to the three-drug regimen if they were susceptible to one or more of the constituents. Treatment was continued until the patient had been afebrile for more than 5 days or until the neutrophil count exceeded 0"5 × Io9/l. Therapy could be modified if, after 48 h of treatment, there was no marked improvement or the causative agent was resistant to the empirical regimen. Surveillance specimens of the throat, urine and stool were obtained on admission and at least once weekly thereafter. Haematological and biochemical profiles were obtained at least twice weekly.
Ceftazidime in acute leukaemia
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T a b l e I Details of patients
Febrile episodes Patients Diagnosis AML other Age (years) mean range Sex male female Duration of neutropenia (days) mean range Days of neutropenia before the onset of fever mean range Duration of empirical therapy mean range
Ceftazidime
Piperacillin, netilmicin and cefotaxime
33 24
32 26
I6 8
14 I2
4I-6 i7-6o
37 i7-53
i6 8
i2 14
I4"7 6-34
I4'2 6-36
4"5 o- xI
4"7 o- 15
9"5 3-19
Io'4 3-21
Evaluation T h e o u t c o m e was classified as follows: (a) a r es p o ns e was defined as c o m p l e t e if t h e r e was resolution of t he fever and o f s y m p t o m s w i t h o u t modification o f t h e r a p y , (b) a response was defined as partial w h e n t r e a t m e n t had to be changed because o f i n c o m p l e t e resolution o f the signs and s y m p t o m s after 48 h, (c) failure was defined as d e t e r i o r a t i o n o f the patient's clinical condi t i on or d eath d u e to bacterial infection, or, if a bacterial cause had been identified, c o n t i n u e d isolation o f the pat hogen. I n f e c t i o n was p r e s u m e d unless a site o f infection was identified clinically (e.g. lung, rectal abscess) or microbiologically or both. Results were analysed by means o f t he c h i - s q u a r e d , analysis o f variance and M a n n - W h i t n e y tests.
Results Assessable patient episodes T h i r t y - t h r e e febrile episodes in 24 patients were t reat ed with ceftazidime and 32 episodes in 26 patients with the 3 - d r u g com bi nat i on. T h e r e was no significant difference in t he incidence o f u n d e r l y i n g diseases, age, sex ratio, or in the d u r a t i o n o f n e u t r o p e n i a b e f o r e the onset o f fever and o f t r e a t m e n t ( T a b l e I).
208
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Ceftazidime in acute leukaemia
Table III Causative agents of infection in relation to treatment regimen
Micro-organisms Staphylococcus epidermidis S. epidermidis plus Streptococcus mitis S. mitis S. aureus Coryneform Pseudomonas sp. P. aeruginosa plus P. maltophilia Enterobacteria Total
Ceftazidime
Piperacillin, netilmicin and cefotaxime
7 I
4 2
5 I -I --
3 -I 3* I
6 2x
4 18
* All were isolated from the blood except for one strain of P. aeruginosa. Aetiology o f infection
Infection was recorded in 28 (84 %) and 25 (78 %) episodes in the ceftazidime group and the three-drug group respectively (Table II). Clinically recognised infection of the oropharynx (erythema, plaques) or lung (chest sounds, X-ray) was recorded in 23 episodes, I3 in the ceftazidime group (39 %) and Io in the other group (31%). Infection of the alimentary tract (oesophagitis, anal fissure, ischio-rectal abscess) arose in the ceftazidime group 8 times (24 %) and in the alternative group five times (I 6 %). Infected lesions of the skin were diagnosed in two episodes (one a pustule on the face from which P. aeruginosa was cultured; the other on the forearm from which micro-organisms were not recovered). Both episodes were initially treated with the three-drug regimen. Microbiological data were recorded in 2I patient episodes treated with ceftazidime (64 %) and in I8 patient episodes given the combination (56 %). All but one were of bacteraemia. T h e causative agents and their relation to treatment regimen are shown in Table I I I. Although the ratio of Gram-positive to Gram-negative bacteria was higher in the ceftazidime group (2: I) compared with that in the other group (5:4) the difference was not significant. Response rates
Rates of complete response were similar for both ceftazidime (I9/33 = 58 %) and the three-drug regimen (21/32 -- 66%). Four patients failed to respond satisfactorily. Bacteraemia caused by a mixture of S. epidermidis and Streptococcus mitis persisted in one case of each. Both episodes were associated with clinical infection at the site of entry of a Hickman cannula; both resolved after the addition of vancomycin. Combined therapy also failed to eradicate a catheter-associated infection (CAI) caused by P. aeruginosa and P. maltophilia which resolved only after removal of the cannula. One patient died with S. mitis septicaemia after four doses of the three-drug regimen. T h e r e were I3 partial responders in the ceftazidime group compared with eight in the alternative
210
J. P. D O N N E L L Y E T A L .
Table IV Details of changes made to first-line therapy First-line therapy Ceftazidime
Piperacillin netilmicin and cefotaxime (PNC) .,
Patient number 003 o05 oi2 020 028 03° 043 o48t 079 088 089 o92t IO3 002 007 o27t 037 057 o65t o67t o98t
Supplementary antibiotics Penicillin G, piperacillin Amikacin, metronidazole Piperacillin, netilmicin Azlocillin, amikacin Vancomycin Piperacillin, amikacin Vancomycin PNC, amphotericin B Vancomycin Penicillin G Gentarnicin PNC Amikacin, metronidazole Metronidazole, amphotericin B Vancomycin Ceftazidime, amikacin, polymyxin B Metronidazole Vancomycin Ceftazidime Piperacillin, amikacin Ceftazidime, amphotericin B
Reason for change* S. mitis Clinical S. mitis P. aeruginosa S. epidermidis S. mitis Clinical Clinical S. epidermidis S. mitis Clinical Clinical Clinical Clinical S. epidermidis Clinical Clinical ' Coryneform' Clinical P. aeruginosa Clinical
* In bacteriologically documented infections, therapy was changed after the organism had been isolated but before susceptibility tests had been completed. t First-line therapy discontinued.
group. In every case, irrespective of the initial treatment, there was evident improvement and no pathogen persisted though fever had not resolved within the first 48 h. Therapy was changed empirically for 6 (46 % ) patients initially given ceftazidime and for 5 (63 %) patients given the combination. All other changes were made in response to bacteriological reports which confirmed bacteraemia but which were issued before susceptibility tests had been completed. Only one strain of S. epidermidis and one strain of S. mitis were subsequently ~shown to be resistant to the empirical regimen. Details of supplementary antibiotics are listed in Table IV. By the time infection had resolved, neutrophils had already recovered (counts of > 0"5 x io9/1) in I6 % of episodes treated with ceftazidime compared with I9 % treated with the combination of drugs. Pooled data
Analysis of variance, the t-test and the Mann-Whitney U test failed to show any significant difference in response times between the groups and between the different infection categories. Patients with fever and bacteraemia without accompanying clinical foci responded significantly faster than did the others (median 2 vs. 5 days: F = 0"0043). Similarly, patients with clinical sites of infection responded more slowly (median 5 days vs. 2"5 days: P = 0.086). N o such difference was observed between those who were bacteraemic and
Ceftazidime in acute leukaemia
2I I
T a b l e V Frequency of pre-treatment resistance of primary pathogens P e r c e n t a g e resistant to Micro-organisms Staphylococci Streptococci Enterobacteria Pseudomonas spp.
N
CAZ
PIP
NET
CTM
PNC
COT
15 8 IO 6
47 25 o I7
80 o 80 x7
13 *oo Io 50
53 o 20 33
13 o o o
87 88 Ioo ioo
CAZ -- ceftazidime, PIP = piperacillin, NET = netilmicin, CTM = ceftoxime, PNC = piperacillin, netilmicin, cefotaxime, COT = co-trimoxazole. those w h o were not (median 4"I vs. 4"8 days: P = o'3148). T h u s a rapid response could be defined as one which took place within 4 days of therapy. Antibiotic resistance
Five infective episodes in the ceftazidime group and two in the t h r e e - d r u g group were caused b y bacteria resistant to drugs of empirical regimen. T r e a t m e n t was changed in three cases and one case respectively. O f all isolates, 92% w e r e resistant to co-trimoxazole and 9 of I5 ( 6 0 % ) strains of G r a m - n e g a t i v e bacilli were also resistant to piperacillin. Details of resistance are shown in T a b l e V. Serum cidal concentrations
S e r u m bactericidal concentrations were available from only 21 patient episodes treated with ceftazidime and from 20 patient episodes treated with the t h r e e - d r u g regimen. Positive blood cultures were obtained from r I (52 % ) and 7 (35 % ) respectively. All samples of s e r u m from b o t h treatment groups showed activity at a dilution/> r in 8 against K. pneumoniae for the first 4 h of treatment while none showed activity against the strain o f S. epidermidis after 30 min. After 2 h, 95 ~o of samples from ceftazidime-treated patients retained this activity (Fig. r) b u t only 3o ~o of samples from those treated with the t h r e e - d r u g regimen ( P < o.or). Data from b o t h treatment groups were c o m b i n e d to estimate the predictive value of the serum cidal test. T h u s a serum cidal dilution against K. pneumoniae or P. aeruginosa ~> I in 8 x h after the initial dose predicted a rapid response in 70 % of cases while killing at a dilution of < I in 8 predicted a slow response or failure of response in 88 % of cases. Adverse events
Breakthrough fever was observed in b o t h groups. Only two of ten episodes in patients given ceftazidime were recorded (Herpes simplex and clinical dacryocystitis). O n e patient treated with triple-drug therapy developed p u l m o n a r y aspergillosis. In another, the site of insertion of the intravenous catheter b e c a m e infected. Six episodes remained undiagnosed. All patients were successfully managed and none suffered any sequelae. T h e r e was no significant side-effect.
J.
212
P. DONNELLY
ET AL.
CO
=- i O 0
0--0~0
~ 80 ~5 ~
6O
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g ~ g_
20-
O u
oI
I
I
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4
I
I
8
Hours otter first _dose
Fig. I. S e r u m bactericidal activity against Pseudomonas aeruginosa. 0 : ceftazidime, 2i patients; (3 : three-drug regimen, 2o patients.
Discussion
We could not demonstrate any difference between the treatment groups in terms of types of infection, distribution and incidence of causative agents, rates of response, occurrence of breakthrough fevers or adverse reactions. We were encouraged by the favourable outcome of treatment. T h e r e was only one death in our series and this happened despite microbiologically appropriate therapy. T h r e e other failures were recognised early and were successfully reversed. Ceftazidime was supplemented more often than was the alternative regimen. T h e isolation of S. mitis from the blood suggested the need for a penicillin though the addition of an aminoglycoside was, in retrospect, unnecessary. Similarly, the isolation of coagulase-negative staphylococci was an indication to add vancomycin. Results of in vitro susceptibility tests, however, confirmed resistance in only two cases. Whether disc-diffusion tests are sufficiently predictive for Gram-positive cocci cannot be decided from the current study; this requires further investigation. Even if the incidence of pre-treatment resistance was actually higher than that observed, resistance per se did not appear to be a serious problem since bacteraemia seldom persisted. Nevertheless, the relatively high incidence of resistance to piperacillin among the enterobacteria underlines the importance of choosing empirical regimens carefully. T h e greater bactericidal activity against P. aeruginosa of serum from ceftazidime-treated patients is also encouraging, though the poor performance of the three-drug regimen is somewhat surprising. This may have been due to the lesser intrinsic activity of the combination or may have been the result of antagonism between the constituent drugs. Serum from patients given aminoglycosides in doses similar to that used in this study has been shown to have poor activity against P. aeruginosa. 8 Also the minimum bactericidal concentration (MBC) cefotaxime is not maintained beyond 2 h after a dose. 9 Piperacillin is intrinsically very active against susceptible strains of
Ceftazidime in acute leukaemia
213
P. aeruginosa but the serum concentration is likely to decline to below the MBC 4 h after the dose. 1° We investigated Io strains of P. aeruginosa for interactions between the three drugs but could demonstrate only indifference. Therefore the former explanation seems more likely. We acknowledge that our series is small and that the risk of falsely accepting the null hypothesis, i.e. both regimens have equal efficacy, is therefore in excess of 8o ~o. Nevertheless, our results are similar to those reported from other centres. In three trials ceftazidime was compared with dissimilar drugs (in two it was compared with cephalothin, gentamicin and carbenicillin 11.1~and in one with tobramycin and ticarcillin).l~ In two other trials, ceftazidime was compared with itself plus flucloxacillin in one 1~ and in the other with tobramycin. 1~ T h e individual sample sizes ranged from 44 to 349 patients and were thus too small to reduce the type II errors to within acceptable limits. Cochran's method of analysis, however, allows these data and that of the current study to be pooled. TM This results in a sample size of 9x8 which is closer to that required (n = I I82). T h u s there was no significant difference (X2 = 5"865 :P > o. I) between response rates for ceftazidime (average 74% :range 43-84) and those for alternative treatment (average 78% :range 56-9o). Also the data were homogeneous (X2 = 3"75:P > o.I). Nevertheless, large multi-centre or multi-independent trials are needed for confirmation. Some general points emerged during the study which have a direct bearing on the management of the febrile, neutropenic patient. Patients in whom there was a demonstrable site of infection appeared to take longer to respond to empirical therapy than did patients with either bacteraemia alone or presumed infection. In these circumstances, disseminated infection may require drugs in addition to those of the empirical regimen, that either penetrate better or accelerate killing of the bacteria. This is almost certainly true of proven infection caused by bacteria with diminished susceptibility to the empirical regimen or none. Gram-positive bacteria clearly come into this category, as do fungi and other non-bacterial micro-organisms. Slow responders and those with breakthrough fevers present a more intractable problem, particularly if a cause is not identified. T h e variety of regimens used during this study serves only to emphasise the need for a specific study of possible therapeutic strategies, which may include early empirical use of amphotericin B. 17 It also appears that 48 h is too early to assess the efficacy of therapy and that 72-96 h is more appropriate. Should the patient's condition worsen, and this seems unlikely, a ureidopenicillin, aminoglycoside or vancomycin may be added with relative safety. I f those patients that are likely to either fail or respond slowly could be better defined, rapid responders could be spared from receiving unnecessary antibiotics. A bactericidal serum dilution of >~ I in 8 corresponded with a rapid response. Such results are available for likely pathogens 48 h after the onset of fever. This type of test may prove to be a better predictor of outcome than conventional tests, an observation which is consistent with previous reports, s, 18Knowledge of the serum bactericidal activity against likely pathogens may be all that is required in most instances, though this suggestion needs to be confirmed. Patients in our series were essentially ' g o o d ' risks, since all had received prophylactic antibiotics and their gut flora were considerably reduced. Man-
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a g e m e n t o f a p a t i e n t w h o is a d m i t t e d a l r e a d y i n f e c t e d a n d n e u t r o p e n i c , e.g. w i t h r e l a p s e d A M L o r C G L in b l a s t crisis, m a y h a v e a h i g h e r f a i l u r e r a t e if m o n o t h e r a p y is u s e d . T h e r e f o r e , u n t i l sufficient d a t a o n this g r o u p o f p a t i e n t s are available they should be treated conventionally. W e c o n c l u d e t h a t c e f t a z i d i m e is a p p r o p r i a t e initial t h e r a p y f o r f e v e r in t h o s e p a t i e n t s w h o b e c o m e n e u t r o p e n i c f o l l o w i n g r e m i s s i o n or i n d u c t i o n t h e r a p y , at least u n t i l l a b o r a t o r y c o n f i r m a t i o n o f t h e c a u s e is f o r t h c o m i n g o r u n t i l n e u t r o p h i l r e g e n e r a t i o n is i m m i n e n t . (J. P. Donnelly was supported by the Medical Research Council and J. Cohen by the Wellcome Trust. T h e authors thank the nursing staff of Sir John Dacie W a r d and H a m m e r s m i t h Hospital for their care of the patients and their co-operation in this study, Glaxo G r o u p Research for material support and Wai F a m for secretarial assistance.) References
I. The EORTC International Project Group. Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer, ff lnfect Dis I978; I37: I4-29. 2. Klastersky J. Management of infection in granuiocytopenic patients, ff Antirnicrob Chernother I983; IZ: IO2-IO4. 3- Tattersall MHN, Spiers ASD, Darrell JH. Initial therapy with combination of five antibiotics in febrile patients with leukaemia and neutropenia. Lancet r972; ii: I62-I66. 4. Bint AJ, Yeoman P, Kilburn P, Anderson R, Stansfield E. In-vitro activity of ceftazidime compared with that of other cephalosporins, ff Antirnicrob Chernother I981; 8: suppl. 47-5 I. 5. Simpson IN, Plested SJ, Harper PB. Investigation of the betalactamase stability of ceftazidime and eight other cephalosporin antibiotics, ff Antimicrob Chernother I984; x3: suppl. A 9-22. 6. Neu HC. In-vitro activity ofceftazidime, a beta-lactamase stable cephalosporin, ff Antirnicrob Chemother i98I; 8: suppl. I3I-I34. 7. Starke ID, Donnelly JP, Catovsky D et al. Co-trimoxazole alone for the prevention of bacterial infection in patients with acute leukaemia. Lancet I982; i: 5--6. 8. Donnelly JP. Serum bactericidal levels in leukaemic patients treated with either netilmicin or tobramycin in combination with mezlocillin and cefotaxime. In: Richardson RG, Ed. Netilmicin--a recent advance in arninoglycoside therapy. London: Royal Society of Medicine, I982; 37-43. 9- Esmieu F, Guibert J, Rosenkilde HC, Ho I, Le Go A. Pharmacokinetics of cefotaxime in normal human volunteers, ff Antirnicrob Chernother I98o; 6: suppl. A 83-92. Io. Welling PG, Craig WA, Bundtzen RW, Kwok FW, Gerber AU, Madsen PO. Pharmacokinetics of piperacillin in subjects with various degrees of renal function. Antirnicrob Agent Chemother r 983 ; z3: 881-887. I r. Ramphal R, Kramer BS, Rand KH, Weiner RS, Shands JW. Early results of a comparative trial of ceftazidime versus cephalothin, carbenicillin and gentamicin in the treatment of febrile granulocytopenic patients. J Antirnicrob Chernother I983; IZ: suppl. A 81-88. I2. Pizzo PA, Thaeur M, Heimenz Jet al. Monotherapy versus combination antibiotics for the initial empiric management of febrile granulocytopenic cancer patients. Abstracts of the 24th lnterscience Conference on Antimicrobial Agents and Chemotherapy I984; No. 38o. I3. Reilly JT, Bradda M, Bellingham AJ, Hart CA, Bennet C. Ceftazidime compared to tobrarnycin and ticarcillin in immunocompromised haematological patients, ff Antimicrob Chernother r983 ; 12: suppl. A 89-92. I4. De Pauw BE, De Witte T, Bothof T, Williams KJ. A randomised study of ceftazidime versus ceftazidime plus flucloxacillin in febrile neutropenic patients. Abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy r984; No. 376. I5. Fanstein V, Bodey, GP and Eking L e t al. A randomised study of ceftazidime compared to ceftazidime and tobramycin for the treatment of infections in cancer patients. J Antimicrob Chemother I983; Iz: suppl. A IOI-IIO.
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16. Polk BF. Antibiotic prophylaxis to prevent mixed bacterial infection. J Antimicrob Chemother I98I; suppl. D II5-IZ9. 17. Pizzo PA, Robichaud KJ, Gill FA, Witesby FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. AmJ Med 1982; 72: IOI - I I I. I8. Standiford HC, Johnston DE, Schimpff SC. Role of antimicrobial synergism in infected granulocytopenic patients. Eur J Clin Oncol I98I: 2: lOO7-1OlO.
C e f t a z i d i m e as f i r s t - l i n e t h e r a p y f o r f e v e r in a c u t e l e u k a e m i a J. P. Donnelly, R. E. Marcus, J. M. Goldman, J. Cohen, A. M. Worsley, D. Catovsky, J. H. Darrell, S. V. Want, and D. A. G. Galton Medical Research Council Leukaemia Unit and the Department of Bacteriology, Royal Postgraduate Medical School, Ducane Road, London Wx2 o i l S Accepted for publication 3 December I984
Summary Fifty patients with acute non-lymphocytic leukaemia were treated by random allocation with either ceftazidime alone or a combination of piperacillin, netilmicin and cefotaxime for 65 febrile neutropenic episodes. Nineteen of 33 patient episodes (58%) responded to ceftazidime alone compared with 2i of 32 episodes (66 ~o) treated with the combination. There was one infective death in a patient given the combination; rates of documented superinfection were low. The treatment groups appeared identical in terms of patient demography, underlying disease and other risk factors, though patients with a clinical site of infection responded more slowly than those without. Bacteraemia per se did not appear to influence outcome. Bactericidal serum concentrations i> 8 x the minimum bactericidal concentration were predictive of a rapid response (within 4 days) to antibiotics. Furthermore, serum from patients treated with ceftazidime maintained adequate cidal activity against Pseudomonas aeruginosa for longer than that obtained from patients treated with the three-drug combination. Ceftazidime was shown to be a safe and effective alternative to the three-drug combination for the initial management of febrile neutropenic episodes in leukaemic patients.
Introduction Bacterial infection in neutropenic patients m a y run a fulminant course, and antimicrobial therapy m u s t be started before the cause has been established. 1 Antibiotic combinations are chosen to provide b r o a d - s p e c t r u m bactericidal activity against the most likely pathogens. 2 T h e empirical regimen used at H a m m e r s m i t h Hospital had evolved from a five-drug regimen in r9723 to a t h r e e - d r u g regimen in 1981 consisting ofpiperacillin, netilmicin and cefotaxime, t h o u g h formal trials had not been conducted. In the 2-year period immediately preceding the current trial, response rates had been 52 % and 44 % for complete and partial responses with treatment failing in 4 % o f patients. W e were concerned that this regimen was complex to administer, potentially toxic and costly. T h e third-generation cephalosporins offered the possibility of a singledrug regimen and, in particular, ceftazidime appeared to have the required specifications. T h i s c o m p o u n d has b r o a d - s p e c t r u m activity ,4 is bactericidal 5 Correspondence should be addressed to J. P. Donnelly, Department of Bacteriology, Royal Postgraduate Medical School, Ducane Road, London W I z oilS. oi63-4453/85/o6o2o5 + 11 $02.0o/o
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and stable to beta-lactamases. 6 If monotherapy is to replace combination therapy, however, the rates of success, adverse events, superinfection and emergent resistance must be similar or better. We, therefore, undertook a 2-year, prospective, randomised trial of our current regimen versus ceftazidime alone in order to evaluate its role in the initial management of fever in the neutropenic patient with leukaemia.
Patients and m e t h o d s
Patients with acute leukaemia, who were admitted for chemotherapy between February I982 and April I984, were entered into the trial after they had given their informed consent. O f these patients 6o % had acute myeloid leukaemia (AML); the remainder had either chronic granulocytic leukaemia (CGL) or acute lymphoblastic leukaemia (ALL). All were expected to become neutropenic (neutrophils < o'5 x IO9/1) for a variable duration. Patients already febrile on admission or who were already being treated for infection were excluded, as were patients with abnormal renal function (serum creatinine > I25 #mol/l) and those with known hypersensitivity to any of the trial drugs. All were treated in single rooms with reverse barrier nursing, and received oral amphotericin B and co-trimoxazole with or without colistin as antimicrobial prophylaxis. 7 As soon as an eligible patient became neutropenic he or she was allocated to receive empirical treatment by opening sealed envelopes within which cards indicating treatment had already been randomly distributed. Patients then received either ceftazidime (2 g) or a combination ofpiperacillin (4 g), netilmicin (I2O mg) and cefotaxime (2 g) as soon as they became febrile (temperature of more than 38 °C for more than 2 h) and after blood in two separate samples had been taken for culture. All drugs were given intravenously every 8 h. Patients re-admitted for second and subsequent courses of chemotherapy were re-randomised provided that they satisfied the above criteria and had had no therapeutic antibiotic treatment during the preceding 2 weeks. Blood was taken from patients who had given consent, and from whom samples could be obtained without difficulty at times o'5, I, 2, 4 and 8 h after the first dose of antibiotics. These were used to assay the bactericidal activity of the serum against control strains of Pseudornonas aeruginosa ( N C T C IO662), Klebsiella pneumoniae (K. edwardsii var. atlantae N C T C IO896: resistant to co-trimoxazole), a laboratory strain of Staphylococcus epidermidis and any pathogen isolated from the patient. Susceptibility to antibiotics was determined by means of a disc diffusion technique. Results were recorded as susceptible, indeterminate or resistant. Organisms were regarded as being susceptible to the three-drug regimen if they were susceptible to one or more of the constituents. Treatment was continued until the patient had been afebrile for more than 5 days or until the neutrophil count exceeded 0"5 × Io9/l. Therapy could be modified if, after 48 h of treatment, there was no marked improvement or the causative agent was resistant to the empirical regimen. Surveillance specimens of the throat, urine and stool were obtained on admission and at least once weekly thereafter. Haematological and biochemical profiles were obtained at least twice weekly.
Ceftazidime in acute leukaemia
207
T a b l e I Details of patients
Febrile episodes Patients Diagnosis AML other Age (years) mean range Sex male female Duration of neutropenia (days) mean range Days of neutropenia before the onset of fever mean range Duration of empirical therapy mean range
Ceftazidime
Piperacillin, netilmicin and cefotaxime
33 24
32 26
I6 8
14 I2
4I-6 i7-6o
37 i7-53
i6 8
i2 14
I4"7 6-34
I4'2 6-36
4"5 o- xI
4"7 o- 15
9"5 3-19
Io'4 3-21
Evaluation T h e o u t c o m e was classified as follows: (a) a r es p o ns e was defined as c o m p l e t e if t h e r e was resolution of t he fever and o f s y m p t o m s w i t h o u t modification o f t h e r a p y , (b) a response was defined as partial w h e n t r e a t m e n t had to be changed because o f i n c o m p l e t e resolution o f the signs and s y m p t o m s after 48 h, (c) failure was defined as d e t e r i o r a t i o n o f the patient's clinical condi t i on or d eath d u e to bacterial infection, or, if a bacterial cause had been identified, c o n t i n u e d isolation o f the pat hogen. I n f e c t i o n was p r e s u m e d unless a site o f infection was identified clinically (e.g. lung, rectal abscess) or microbiologically or both. Results were analysed by means o f t he c h i - s q u a r e d , analysis o f variance and M a n n - W h i t n e y tests.
Results Assessable patient episodes T h i r t y - t h r e e febrile episodes in 24 patients were t reat ed with ceftazidime and 32 episodes in 26 patients with the 3 - d r u g com bi nat i on. T h e r e was no significant difference in t he incidence o f u n d e r l y i n g diseases, age, sex ratio, or in the d u r a t i o n o f n e u t r o p e n i a b e f o r e the onset o f fever and o f t r e a t m e n t ( T a b l e I).
208
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Ceftazidime in acute leukaemia
Table III Causative agents of infection in relation to treatment regimen
Micro-organisms Staphylococcus epidermidis S. epidermidis plus Streptococcus mitis S. mitis S. aureus Coryneform Pseudomonas sp. P. aeruginosa plus P. maltophilia Enterobacteria Total
Ceftazidime
Piperacillin, netilmicin and cefotaxime
7 I
4 2
5 I -I --
3 -I 3* I
6 2x
4 18
* All were isolated from the blood except for one strain of P. aeruginosa. Aetiology o f infection
Infection was recorded in 28 (84 %) and 25 (78 %) episodes in the ceftazidime group and the three-drug group respectively (Table II). Clinically recognised infection of the oropharynx (erythema, plaques) or lung (chest sounds, X-ray) was recorded in 23 episodes, I3 in the ceftazidime group (39 %) and Io in the other group (31%). Infection of the alimentary tract (oesophagitis, anal fissure, ischio-rectal abscess) arose in the ceftazidime group 8 times (24 %) and in the alternative group five times (I 6 %). Infected lesions of the skin were diagnosed in two episodes (one a pustule on the face from which P. aeruginosa was cultured; the other on the forearm from which micro-organisms were not recovered). Both episodes were initially treated with the three-drug regimen. Microbiological data were recorded in 2I patient episodes treated with ceftazidime (64 %) and in I8 patient episodes given the combination (56 %). All but one were of bacteraemia. T h e causative agents and their relation to treatment regimen are shown in Table I I I. Although the ratio of Gram-positive to Gram-negative bacteria was higher in the ceftazidime group (2: I) compared with that in the other group (5:4) the difference was not significant. Response rates
Rates of complete response were similar for both ceftazidime (I9/33 = 58 %) and the three-drug regimen (21/32 -- 66%). Four patients failed to respond satisfactorily. Bacteraemia caused by a mixture of S. epidermidis and Streptococcus mitis persisted in one case of each. Both episodes were associated with clinical infection at the site of entry of a Hickman cannula; both resolved after the addition of vancomycin. Combined therapy also failed to eradicate a catheter-associated infection (CAI) caused by P. aeruginosa and P. maltophilia which resolved only after removal of the cannula. One patient died with S. mitis septicaemia after four doses of the three-drug regimen. T h e r e were I3 partial responders in the ceftazidime group compared with eight in the alternative
210
J. P. D O N N E L L Y E T A L .
Table IV Details of changes made to first-line therapy First-line therapy Ceftazidime
Piperacillin netilmicin and cefotaxime (PNC) .,
Patient number 003 o05 oi2 020 028 03° 043 o48t 079 088 089 o92t IO3 002 007 o27t 037 057 o65t o67t o98t
Supplementary antibiotics Penicillin G, piperacillin Amikacin, metronidazole Piperacillin, netilmicin Azlocillin, amikacin Vancomycin Piperacillin, amikacin Vancomycin PNC, amphotericin B Vancomycin Penicillin G Gentarnicin PNC Amikacin, metronidazole Metronidazole, amphotericin B Vancomycin Ceftazidime, amikacin, polymyxin B Metronidazole Vancomycin Ceftazidime Piperacillin, amikacin Ceftazidime, amphotericin B
Reason for change* S. mitis Clinical S. mitis P. aeruginosa S. epidermidis S. mitis Clinical Clinical S. epidermidis S. mitis Clinical Clinical Clinical Clinical S. epidermidis Clinical Clinical ' Coryneform' Clinical P. aeruginosa Clinical
* In bacteriologically documented infections, therapy was changed after the organism had been isolated but before susceptibility tests had been completed. t First-line therapy discontinued.
group. In every case, irrespective of the initial treatment, there was evident improvement and no pathogen persisted though fever had not resolved within the first 48 h. Therapy was changed empirically for 6 (46 % ) patients initially given ceftazidime and for 5 (63 %) patients given the combination. All other changes were made in response to bacteriological reports which confirmed bacteraemia but which were issued before susceptibility tests had been completed. Only one strain of S. epidermidis and one strain of S. mitis were subsequently ~shown to be resistant to the empirical regimen. Details of supplementary antibiotics are listed in Table IV. By the time infection had resolved, neutrophils had already recovered (counts of > 0"5 x io9/1) in I6 % of episodes treated with ceftazidime compared with I9 % treated with the combination of drugs. Pooled data
Analysis of variance, the t-test and the Mann-Whitney U test failed to show any significant difference in response times between the groups and between the different infection categories. Patients with fever and bacteraemia without accompanying clinical foci responded significantly faster than did the others (median 2 vs. 5 days: F = 0"0043). Similarly, patients with clinical sites of infection responded more slowly (median 5 days vs. 2"5 days: P = 0.086). N o such difference was observed between those who were bacteraemic and
Ceftazidime in acute leukaemia
2I I
T a b l e V Frequency of pre-treatment resistance of primary pathogens P e r c e n t a g e resistant to Micro-organisms Staphylococci Streptococci Enterobacteria Pseudomonas spp.
N
CAZ
PIP
NET
CTM
PNC
COT
15 8 IO 6
47 25 o I7
80 o 80 x7
13 *oo Io 50
53 o 20 33
13 o o o
87 88 Ioo ioo
CAZ -- ceftazidime, PIP = piperacillin, NET = netilmicin, CTM = ceftoxime, PNC = piperacillin, netilmicin, cefotaxime, COT = co-trimoxazole. those w h o were not (median 4"I vs. 4"8 days: P = o'3148). T h u s a rapid response could be defined as one which took place within 4 days of therapy. Antibiotic resistance
Five infective episodes in the ceftazidime group and two in the t h r e e - d r u g group were caused b y bacteria resistant to drugs of empirical regimen. T r e a t m e n t was changed in three cases and one case respectively. O f all isolates, 92% w e r e resistant to co-trimoxazole and 9 of I5 ( 6 0 % ) strains of G r a m - n e g a t i v e bacilli were also resistant to piperacillin. Details of resistance are shown in T a b l e V. Serum cidal concentrations
S e r u m bactericidal concentrations were available from only 21 patient episodes treated with ceftazidime and from 20 patient episodes treated with the t h r e e - d r u g regimen. Positive blood cultures were obtained from r I (52 % ) and 7 (35 % ) respectively. All samples of s e r u m from b o t h treatment groups showed activity at a dilution/> r in 8 against K. pneumoniae for the first 4 h of treatment while none showed activity against the strain o f S. epidermidis after 30 min. After 2 h, 95 ~o of samples from ceftazidime-treated patients retained this activity (Fig. r) b u t only 3o ~o of samples from those treated with the t h r e e - d r u g regimen ( P < o.or). Data from b o t h treatment groups were c o m b i n e d to estimate the predictive value of the serum cidal test. T h u s a serum cidal dilution against K. pneumoniae or P. aeruginosa ~> I in 8 x h after the initial dose predicted a rapid response in 70 % of cases while killing at a dilution of < I in 8 predicted a slow response or failure of response in 88 % of cases. Adverse events
Breakthrough fever was observed in b o t h groups. Only two of ten episodes in patients given ceftazidime were recorded (Herpes simplex and clinical dacryocystitis). O n e patient treated with triple-drug therapy developed p u l m o n a r y aspergillosis. In another, the site of insertion of the intravenous catheter b e c a m e infected. Six episodes remained undiagnosed. All patients were successfully managed and none suffered any sequelae. T h e r e was no significant side-effect.
J.
212
P. DONNELLY
ET AL.
CO
=- i O 0
0--0~0
~ 80 ~5 ~
6O
~, 40 -& E ~6
g ~ g_
20-
O u
oI
I
I
m/~ i
I
2
4
I
I
8
Hours otter first _dose
Fig. I. S e r u m bactericidal activity against Pseudomonas aeruginosa. 0 : ceftazidime, 2i patients; (3 : three-drug regimen, 2o patients.
Discussion
We could not demonstrate any difference between the treatment groups in terms of types of infection, distribution and incidence of causative agents, rates of response, occurrence of breakthrough fevers or adverse reactions. We were encouraged by the favourable outcome of treatment. T h e r e was only one death in our series and this happened despite microbiologically appropriate therapy. T h r e e other failures were recognised early and were successfully reversed. Ceftazidime was supplemented more often than was the alternative regimen. T h e isolation of S. mitis from the blood suggested the need for a penicillin though the addition of an aminoglycoside was, in retrospect, unnecessary. Similarly, the isolation of coagulase-negative staphylococci was an indication to add vancomycin. Results of in vitro susceptibility tests, however, confirmed resistance in only two cases. Whether disc-diffusion tests are sufficiently predictive for Gram-positive cocci cannot be decided from the current study; this requires further investigation. Even if the incidence of pre-treatment resistance was actually higher than that observed, resistance per se did not appear to be a serious problem since bacteraemia seldom persisted. Nevertheless, the relatively high incidence of resistance to piperacillin among the enterobacteria underlines the importance of choosing empirical regimens carefully. T h e greater bactericidal activity against P. aeruginosa of serum from ceftazidime-treated patients is also encouraging, though the poor performance of the three-drug regimen is somewhat surprising. This may have been due to the lesser intrinsic activity of the combination or may have been the result of antagonism between the constituent drugs. Serum from patients given aminoglycosides in doses similar to that used in this study has been shown to have poor activity against P. aeruginosa. 8 Also the minimum bactericidal concentration (MBC) cefotaxime is not maintained beyond 2 h after a dose. 9 Piperacillin is intrinsically very active against susceptible strains of
Ceftazidime in acute leukaemia
213
P. aeruginosa but the serum concentration is likely to decline to below the MBC 4 h after the dose. 1° We investigated Io strains of P. aeruginosa for interactions between the three drugs but could demonstrate only indifference. Therefore the former explanation seems more likely. We acknowledge that our series is small and that the risk of falsely accepting the null hypothesis, i.e. both regimens have equal efficacy, is therefore in excess of 8o ~o. Nevertheless, our results are similar to those reported from other centres. In three trials ceftazidime was compared with dissimilar drugs (in two it was compared with cephalothin, gentamicin and carbenicillin 11.1~and in one with tobramycin and ticarcillin).l~ In two other trials, ceftazidime was compared with itself plus flucloxacillin in one 1~ and in the other with tobramycin. 1~ T h e individual sample sizes ranged from 44 to 349 patients and were thus too small to reduce the type II errors to within acceptable limits. Cochran's method of analysis, however, allows these data and that of the current study to be pooled. TM This results in a sample size of 9x8 which is closer to that required (n = I I82). T h u s there was no significant difference (X2 = 5"865 :P > o. I) between response rates for ceftazidime (average 74% :range 43-84) and those for alternative treatment (average 78% :range 56-9o). Also the data were homogeneous (X2 = 3"75:P > o.I). Nevertheless, large multi-centre or multi-independent trials are needed for confirmation. Some general points emerged during the study which have a direct bearing on the management of the febrile, neutropenic patient. Patients in whom there was a demonstrable site of infection appeared to take longer to respond to empirical therapy than did patients with either bacteraemia alone or presumed infection. In these circumstances, disseminated infection may require drugs in addition to those of the empirical regimen, that either penetrate better or accelerate killing of the bacteria. This is almost certainly true of proven infection caused by bacteria with diminished susceptibility to the empirical regimen or none. Gram-positive bacteria clearly come into this category, as do fungi and other non-bacterial micro-organisms. Slow responders and those with breakthrough fevers present a more intractable problem, particularly if a cause is not identified. T h e variety of regimens used during this study serves only to emphasise the need for a specific study of possible therapeutic strategies, which may include early empirical use of amphotericin B. 17 It also appears that 48 h is too early to assess the efficacy of therapy and that 72-96 h is more appropriate. Should the patient's condition worsen, and this seems unlikely, a ureidopenicillin, aminoglycoside or vancomycin may be added with relative safety. I f those patients that are likely to either fail or respond slowly could be better defined, rapid responders could be spared from receiving unnecessary antibiotics. A bactericidal serum dilution of >~ I in 8 corresponded with a rapid response. Such results are available for likely pathogens 48 h after the onset of fever. This type of test may prove to be a better predictor of outcome than conventional tests, an observation which is consistent with previous reports, s, 18Knowledge of the serum bactericidal activity against likely pathogens may be all that is required in most instances, though this suggestion needs to be confirmed. Patients in our series were essentially ' g o o d ' risks, since all had received prophylactic antibiotics and their gut flora were considerably reduced. Man-
2I 4
J . P . D O N N E L L Y liT A L .
a g e m e n t o f a p a t i e n t w h o is a d m i t t e d a l r e a d y i n f e c t e d a n d n e u t r o p e n i c , e.g. w i t h r e l a p s e d A M L o r C G L in b l a s t crisis, m a y h a v e a h i g h e r f a i l u r e r a t e if m o n o t h e r a p y is u s e d . T h e r e f o r e , u n t i l sufficient d a t a o n this g r o u p o f p a t i e n t s are available they should be treated conventionally. W e c o n c l u d e t h a t c e f t a z i d i m e is a p p r o p r i a t e initial t h e r a p y f o r f e v e r in t h o s e p a t i e n t s w h o b e c o m e n e u t r o p e n i c f o l l o w i n g r e m i s s i o n or i n d u c t i o n t h e r a p y , at least u n t i l l a b o r a t o r y c o n f i r m a t i o n o f t h e c a u s e is f o r t h c o m i n g o r u n t i l n e u t r o p h i l r e g e n e r a t i o n is i m m i n e n t . (J. P. Donnelly was supported by the Medical Research Council and J. Cohen by the Wellcome Trust. T h e authors thank the nursing staff of Sir John Dacie W a r d and H a m m e r s m i t h Hospital for their care of the patients and their co-operation in this study, Glaxo G r o u p Research for material support and Wai F a m for secretarial assistance.) References
I. The EORTC International Project Group. Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer, ff lnfect Dis I978; I37: I4-29. 2. Klastersky J. Management of infection in granuiocytopenic patients, ff Antirnicrob Chernother I983; IZ: IO2-IO4. 3- Tattersall MHN, Spiers ASD, Darrell JH. Initial therapy with combination of five antibiotics in febrile patients with leukaemia and neutropenia. Lancet r972; ii: I62-I66. 4. Bint AJ, Yeoman P, Kilburn P, Anderson R, Stansfield E. In-vitro activity of ceftazidime compared with that of other cephalosporins, ff Antirnicrob Chernother I981; 8: suppl. 47-5 I. 5. Simpson IN, Plested SJ, Harper PB. Investigation of the betalactamase stability of ceftazidime and eight other cephalosporin antibiotics, ff Antimicrob Chernother I984; x3: suppl. A 9-22. 6. Neu HC. In-vitro activity ofceftazidime, a beta-lactamase stable cephalosporin, ff Antirnicrob Chemother i98I; 8: suppl. I3I-I34. 7. Starke ID, Donnelly JP, Catovsky D et al. Co-trimoxazole alone for the prevention of bacterial infection in patients with acute leukaemia. Lancet I982; i: 5--6. 8. Donnelly JP. Serum bactericidal levels in leukaemic patients treated with either netilmicin or tobramycin in combination with mezlocillin and cefotaxime. In: Richardson RG, Ed. Netilmicin--a recent advance in arninoglycoside therapy. London: Royal Society of Medicine, I982; 37-43. 9- Esmieu F, Guibert J, Rosenkilde HC, Ho I, Le Go A. Pharmacokinetics of cefotaxime in normal human volunteers, ff Antirnicrob Chernother I98o; 6: suppl. A 83-92. Io. Welling PG, Craig WA, Bundtzen RW, Kwok FW, Gerber AU, Madsen PO. Pharmacokinetics of piperacillin in subjects with various degrees of renal function. Antirnicrob Agent Chemother r 983 ; z3: 881-887. I r. Ramphal R, Kramer BS, Rand KH, Weiner RS, Shands JW. Early results of a comparative trial of ceftazidime versus cephalothin, carbenicillin and gentamicin in the treatment of febrile granulocytopenic patients. J Antirnicrob Chernother I983; IZ: suppl. A 81-88. I2. Pizzo PA, Thaeur M, Heimenz Jet al. Monotherapy versus combination antibiotics for the initial empiric management of febrile granulocytopenic cancer patients. Abstracts of the 24th lnterscience Conference on Antimicrobial Agents and Chemotherapy I984; No. 38o. I3. Reilly JT, Bradda M, Bellingham AJ, Hart CA, Bennet C. Ceftazidime compared to tobrarnycin and ticarcillin in immunocompromised haematological patients, ff Antimicrob Chernother r983 ; 12: suppl. A 89-92. I4. De Pauw BE, De Witte T, Bothof T, Williams KJ. A randomised study of ceftazidime versus ceftazidime plus flucloxacillin in febrile neutropenic patients. Abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy r984; No. 376. I5. Fanstein V, Bodey, GP and Eking L e t al. A randomised study of ceftazidime compared to ceftazidime and tobramycin for the treatment of infections in cancer patients. J Antimicrob Chemother I983; Iz: suppl. A IOI-IIO.
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16. Polk BF. Antibiotic prophylaxis to prevent mixed bacterial infection. J Antimicrob Chemother I98I; suppl. D II5-IZ9. 17. Pizzo PA, Robichaud KJ, Gill FA, Witesby FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. AmJ Med 1982; 72: IOI - I I I. I8. Standiford HC, Johnston DE, Schimpff SC. Role of antimicrobial synergism in infected granulocytopenic patients. Eur J Clin Oncol I98I: 2: lOO7-1OlO.