Journal oflnfecuon (1982) 5, 61-65

T h e v a l u e o f ora l n o n - a b s o r b e d a n t i b i o t i c s in a c u t e m y e l o i d l e u k a e m i a

Melanie Will iams*, A. K. Burne t t t and G. A. McDona ld t

Departments of Bacteriology* and tHaematology, Royal Infirmary, Glasgow G4 oSF

Summary To assess the value of oral non-absorbed antibiotics (FRACON), we compared the results of their administration with standard care in granulocytopenic patients with acute myeloid leukaemia. The 23 patients received identical cytotoxic regimens and similar supportive measures. No statistically significant differences were observed in the median number of days when the patients were neutropenic or the number of these days when the patients were pyrexial. Similarly, the number of patients with bacteraemic episodes, and the number of patients achieving complete remission, in the two groups were not statistically different. However, FRACON improved significantly the I2-week and the median overall survival.

Introduction

T h e remission rate in acute myeloid leukaemia (AML) has improved as more intensive myelosuppressive t reatments have been introduced. The consequent reduct ion in bone-marrow reserves, resulting in neutropenia, predisposes these patients to infection, 1-3 which is a major cause of death. 1,4.5 Even if a patient survives an episode of infection, the scheduled anti-leukaemic chem- otherapy may have to be interrupted. Prevention of infection will directly reduce mortal i ty and morbidi ty. In addition, because cytotoxic t reatment can continue as planned, the remission rate and survival should be improved.

We report the results of a controlled s tudy to determine the value of oral non-absorbed antibiotics as compared with standard care in granulocytopenic patients with A M L .

Methods Study population and design

Between January I974 and December t976, newly admit ted adult patients with A M L were eligible for participation in this study. Patients who received granulocyte transfusions were excluded. Between April, I975 and December I976, patients with neutropenia (less than I × Io 9 neutrophils per litre of serum) received oral non-absorbed antibiotics a n d ' clean food '. The oral non-absorbed antibiotic regimen (FRA CON) consisted of framycetin sulphate 5oo mg (tablets) six-hourly, colistin sulphate I 5 x io 6 units (tablets) six-hourly, nystat in o'5 x io 6 units (tablets) six-hourly and nystat in 0"5 × Io 6 units (syrup) six-hourly. 6 'Clean food ' was prepared in individual portions. These patients represented the F R A C O N group. Between January I974 and April I975,

* Present address : Department of Microbiology, St James' Hospital, Sarsfeld Road, Balham, London, SWI2 8HW.

oi63-4453/82/o4oo6I + 05 $02.00/0 © 1982 The British Society for the Study of Infection

6 2 M. W I L L I A M S , A. K. B U R N E T T A N D G. A. M c D O N A L D

Table I. The median number of days on which the patients were neutropenic according to the administration of F R A C O N

N e u t r o p h i l coun t U value (per litre) Cont ro l F R A C O N (test ing lower value) P

< I X IO 9 53"5 50 47"5 N.S . < 0' 5 x IO 9 50"5 40 40 N .S . < 0 '2 X 109 29'5 24 47 N .S .

N .S . = not significant .

neutropenic patients received neither F R A C O N nor 'c lean food ' . T h e y were retrospect ively matched for factors regarded as of prognost ic importance (age, sex, present ing blast and granulocyte counts) and were classified as the ' control ' group.

All the patients received identical chemotherapeut ic regimens ( B A R T ' S I I I : daunorubic in Ioo mg per metre 2 on day one and cytosine arabinoside ioo mg per metre 2 for five days, at f ive-day intervals). The patients were treated by the same personnel in the same three-bed units. Suppor t ive measures, including red-cell and platelet transfusions, and antimicrobial therapy were similar in both groups. Antimicrobial therapy for suspected, or identified, infection was not influenced by s tudy-group status. Careful clinical and microbiological surveillance was per formed regularly. Blood cultures, and cultures f rom other probable sites of infection, were rout inely per formed in all patients with fever or other signs of infection. The patients were fol lowed up until death.

Def in i t ion o f in fec t ion

Bacteraemia was defined as the finding of one or more blood cultures that were positive for an organism considered to represent a pathogen. A 'pyrexial day ' occurred when at least two consecutive body tempera ture recordings (at two hour intervals) exceeded 38 °C during a 24-hour period. Pyrexial episodes that seemed to be clinically related to the transfusion of b lood components were excluded.

Stat i s t ica l procedures

Convent ional methods of analysis were used. The median values in Tables I and II were compared by the M a n n - W h i t n e y test and the significance of the differences were de termined with the lower of the two values obtained. 7 Chi -squared analysis, using two by two cont ingency tables, was used to test the values in Tab le I I I . Yates correction was applied, s

Results

There were I I patients in the F R A C O N group and I2 patients, matched for age, sex and presenting blast and neutrophi l counts , in the control group. The same chemotherapeut ic regimen was given to all the patients and a similar

Non-absorbed antibiotics in leukaemia 63

Tab le II The median number of days when the patients were both neutropenic and pyrexial in relation to the administration of F R A C O N

Neutrophil count U value (per litre) Control FRACON (testing lower value) P

< I X I O 9 3 4 I I 4 9 ' 5 N . S .

< 0 . 5 x I O 9 3 5 3 0 58 N . S .

< 0 . 2 x I O 9 3 4 " 5 I 6 4 2 N . S .

Table I I I The frequency of bacteriologically proven episodes of bacteraemia and the outcome of leukaemia according to the administration of F R A C O N

Control FRACON

Number % Number % X ~ P

Number of patients I 2 - - I I - - - - - -

Number of patients with 6 (50) I (9) 2.8I N.S. episodes of bacterae/na

Number of patients surviving 6 (5 O) I I ( I O O ) 5 " 0 7 < 0 " 0 5

I 2 weeks Number of patients achieving 5 (42) 8 (73) I'I7 N.S. complete remission

degree of neutropenia was p roduced in bo th groups of patients (Table I). T h e median n u m b e r of these 'a t r isk ' neutropenic days on which the patients were pyrexial, was less in the F R A C O N group than in the Control group. However , a l though this seemed true at all levels of neutropenia , the difference was not statistically significant (Table II). Fewer patients in the F R A C O N group developed bacteraemia (Table I I I ) , bu t this difference too was not statistically significant. In the control group six patients had eight episodes of bacter- aemia; the organisms isolated from the b lood cultures were Escherichia coli (four), pseudomonas species (two), klebsiella species (one) and a strain of f l-haemolytic s t reptococcus which did not belong to Lancefield Group A (one). Only one pat ient in the F R A C O N group had an episode of bacteraemia, when Staphylococcus aureus was isolated from blood cultures and from extensive cellulitis of the face present at the t ime of the patient 's admission. Three patients (25 per cent) in the control group developed anorectal infection bu t none was observed in the patients who received F R A C O N . Fewer courses of antibiotics were required by patients in the F R A C O N group compared with those in the control group. This represented a considerable financial saving which offset the considerable cost of F R A C O N . All the patients tolerated F R A C O N , al though a few had to be encouraged to comply with the regimen.

T h e patients in the F R A C O N group all survived I2 weeks (Table I I I , Fig. I). This was significantly longer (P < 0"05) than in the control group, in which six patients died before the twelf th week. Bacteraemia cont r ibuted to the death of five of these control patients. The complete remission rate also was

64 M. W I L L I A M S , A. K. B U R N E T T A N D G. A. M c D O N A L D

~ L1 ~ A -- , CON

~ , 5 0 Control!

25 '-, ~ ~' I B I / /

I I I i I I , ~ / / I n 0 I0 20 30 40 50 60 7 120

,Time (weeks)

Fig. I. T h e survival curves for acute myeloid leukaemia according to the adminis t ra t ion of F R A C O N .

increased in the FRACON groups (Table III). The median overall survival in the FRACON group was 26 weeks compared to I2"5 weeks in the control group and this difference was statistically significant [U = I3"5 (testing lower value), P < o.ooI] (Fig. I).

D i s c u s s i o n

In z98o, Newman and Sweet 9 surveyed I43 cancer-treatment centres in the United States to ascertain what protective measures were being taken in caring for neutropenic patients with AML. Fifteen per cent of these institutions were using' bowel sterilisation' by means of non-absorbed oral antibiotics. Newman and Sweet 9 concluded that none of the isolation or sterilisation techniques being used significantly improved the remission-rate or survival. In the present study, the remission rate was not significantly improved, but survival was significantly prolonged by the use of FRACON.

In the present study every member of the FRACON group survived I2 weeks compared with only 5o per cent of the control group. Furthermore, the median overall survival was 26 weeks in the FRACON group compared with I Z'5 weeks in the control group. These differences were statistically significant. The patients were treated identically, except for the administration of FRACON and during the period studied there were no changes that might have altered outcome, such as changes in personnel or empirical antibiotic policy.

Infection in neutropenic patients may be difficult to diagnose both clinically and in the laboratory. 1° For this reason, in the present study, only episodes of bacteraemia and perianal sepsis were documented as proven infection. Six of i2 patients in the control group had episodes of bacteraemia, compared with one of the 11 patients who received FRACON. It would be incorrect to include successive episodes occurring in the same patient because, clearly, the outcome of each episode depends on the outcome of the previous episode. 11 The absence of perianal sepsis in the FRACON group concurs with the findings of Storring e t a l . 6 and is especially important because anorectal infections are life-threat- ening in neutropenic patients.

Although fever does not always indicate infection, when a neutropenic

Non-absorbed antibiotics in leukaemia 65

pa t i en t b e c o m e s py rex ia l , a dec is ion m u s t be m a d e as to w h e t h e r or no t an t ib io t ics shou ld be s ta r ted , and w h e t h e r or no t cy to tox ic t h e r a p y shou ld be de layed . T h e r e f o r e , in the p r e s e n t s tudy , the t r e n d o b s e r v e d towards fewer py rex ia l n e u t r o p e n i c days was benef ic ia l to the a t t endan t s and to the pa t ien t . Less sys temic an t ib io t ics were r e q u i r e d w h i c h saved m o n e y .

O u r s t udy d e m o n s t r a t e d tha t F R A C O N signif icant ly i m p r o v e d i 2 - w e e k and m e d i a n overa l l surv iva l in pa t ien t s u n d e r g o i n g ident ica l an t i - l eukaemic t r e a t m e n t for A M L . T h e pa t i en t s were e n t e r e d in the M . R . C . S ix th A c u t e M y e l o i d L e u k a e m i a trial . W e sugges t tha t the poss ib le benef i t o f s u p p o r t i v e measu re s , such as oral n o n - a b s o r b e d ant ib io t ics , sh o u ld be taken into a c c o u n t w h e n the resul ts o f an t i - l eukaemic cy to tox i c r eg imens are be ing analysed.

(We thank Mr A. McLelland, Depar tment of Biochemistry, Royal Infirmary, Glasgow, for assistance with the statistical analysis.)

R e f e r e n c e s

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3. Keating MJ, Pennington DG. Prophylaxis against septicaemia in acute leukaemia: the use of oral framycetin. M e d J Aust I973; ii: 213-2I 7.

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7- Sokal RR, Rohlf FJ. Biometry. San Francisco: WH Freeman and Company, I969: 391-395.

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