INITIAL THERAPY WITH COMBINATION OF FIVE ANTIBIOTICS IN FEBRILE PATIENTS WITH LEUKÆMIA AND NEUTROPENIA

162 or possibly because of excessive breakdown or inactivation of pre-existing surfactant. Work by Nelson 14 indicated that surfactant concentration in fetal lung tissue might be reflected in the lecithin content of amniotic fluid. We have found a definite relationship between a low amniotic-fluid lecithin content and the subsequent development of neonatal R.D.S. When R.D.s. developed the immediate below pre-delivery amniotic-fluid lecithin had been 3-5 mg. per 100 ml.: by contrast, in the 12 " small for dates " or premature babies who breathed normally, the pre-delivery liquor lecithin levels were all 3-5 mg. per 100 ml. or more. We prefer to regard as critical lecithin concentrations between 3-0 and 4-0 mg. per 100 ml. A clinical problem, therefore, arises when delivery is contemplated but the amniotic-fluid lecithin proves to be just within this range, or below it. In such cases, postponing delivery, if at all possible, even for a few days, may make a vital difference to the infant’s chances of survival, especially if gestation is around 32-34 weeks, because a rapid increase in lecithin biosynthesis occurs at this time. The main theoretical disadvantage of measuring lecithin only is the possibility that excessively large or small amounts of amniotic fluid may produce misleading results. The lecithin/phospholipid ratio was, therefore, measured in each amniotic-fluid sample with the aim of avoiding such potential error, but no correlation could be demonstrated between this ratio and the subsequent development of neonatal R.D.S. In our experience so far, however, the prognostic reliability of the amniotic-fluid lecithin concentration has not been significantly influenced by apparently large or small volumes of amniotic fluid. Gluck et al. 15 have described a quick method for estimating the liquor lecithin/sphingomyelin ratio, which avoids the problems associated with abnormal volumes of amniotic fluid. Liquor extracts are chromatographed on thin layers of silica gel, and the phospholipids visualised by charring with sulphuric acid. Gluck et al. stated that the fetal lung may be considered mature and the infant free of the risk of R.D.s. when the lecithin/sphingomyelin ratio is 2/1 or greater. The attractions of this method are obvious, but in our limited experience we have sometimes found interpretation of the plates very difficult. Although the method we have reported is slower than that of Gluck et al. (7 hours compared with 2 hours), extraction of the lecithin from the amniotic fluid is reliable, end-point determination is precise, and in our hands the method has provided results of proved prognostic value in

immaturity,

neonatal R.D.s. On the evidence we have so far, the critical level for liquor lecithin taken 12-24 hours prior to delivery appears to be around 3-5 mg. per 100 ml. Below this, and especially below 2-5 mg., R.D.S. is liable to occur; above this, and provided no other complicating factors are present, neonatal respiration should be normal. Further experience with both methods is being obtained in our laboratories and will be reported in due course. We thank the medical and nursing staff of the Maternity Hospital, Cardiff, for the collection of amniotic-fluid samples and

anticipating

the Association of Commonwealth Universities for 1’-1"’B

c r_

u

a

scholarship

INITIAL THERAPY WITH COMBINATION OF FIVE ANTIBIOTICS IN FEBRILE PATIENTS WITH LEUKÆMIA AND

NEUTROPENIA M. H. N. TATTERSALL A. S. D. SPIERS J. H. DARRELL

Departments of Medicine and Bacteriology, and Medical Research Council Leukœmia Unit, Royal Postgraduate Medical School, London W.12

patients with leukæmia and blood dyscrasias overwhelming infection is a frequent cause of death. Twenty-seven episodes of presumed infection in such patients have been treated with an empirical combination of five antibiotics. The outcome was satisfactory in eight (53%) of the fifteen cases in which infection was confirmed by culture. In

Sum ary

Introduction

PATIENTS with leukaemia and neutropenia often have fever, and overwhelming infection is a frequent cause of death. 1,The patient often dies before the infecting organism can be identified bacteriologically. 3 Pseudomonas aeruginosa is the most frequent infecting organism,1,3although other gram-negative and, rarely, 4 may be involved. 1, These observations indicate the need for immediate treatment in the management of suspected infection in patients with leukasmia and neutropenia. Treatment should be with agents especially effective against gram-negative bacilli. The use of antibiotics,3,5-7 steroids,8gammaglobulin,9 and white-blood-cell transfusion 10 in these circumstances has met with varying success. We report here the results of a combination of five antibiotics used during a 15-month period as initial treatment of presumed infection in febrile neutropenic patients with leukaemia or other blood dyscrasias.

gram-positive bacteria

The

Patients and Methods patients had leukaemia, lymphoma,

or aplastic primary diagnosis. Many were admitted to hospital urgently with signs of infection, but others had been in hospital for several days before fever and signs and symptoms suggesting infection developed. Patients were

anaemia

as a

Cohen, M. M., Weinbraub, D. M., Lilienfeld, A. M. Pediatrics, Springfield, 1960, 26, 40. 2. Dunn, P. M. Archs Dis. Childh. 1965, 40, 62. 3. Adams, F. H., Fujiwara, T., Emmanouilides, G., Scudder, A. J. Pediat. 1965, 66, 357. 4. Brumley, G. W., Hodson, W. A., Avery, M. E. Pediatrics, Springfield, 1967, 40, 13. 5. Adams, F. H., Fujiwara, T., Emmanouilides, G. C., Raiha, N. J. Pediat. 1970, 77, 833. 6. Gluck, L., Sribney, M., Kulovich, M. V. Pediat. Res. 1967, 1, 247. 7. Ross, B. B. Nature, 1963, 199, 1100. 8. Dubowitz, L. M. S., Dubowitz, V., Goldberg, C. J. Pediat. 1970, 77, 1. 9. Bligh, E. G., Dyer, W. J. Can. J. Biochem. Physiol. 1959, 37, 911. 10. Bottcher, C. J. F., van Gent, C. M., Pries, C. Analytica chim. Acta, 1961, 24, 203. 11. Fahmy, D. R. PH.D. thesis, University of Wales, 1969. 12. Tanner, J. M., Thomson, A. M. Archs Dis. Childh. 1970, 45, 566. 13. Reynolds, E. O. R., Jacobson, H. N., Motoyama, E. K., Kikkawa, Y., Craig, J. M., Orzalesi, M. M., Cook, C. D. Pediatrics, Springfield, 1965, 35, 382. 14. Nelson, G. H. Am. J. Obstet. Gynec. 1970, 105, 1072. 15. Gluck, L., Kulovich, M. V., Borer, R. C., Brenner, P. H., Anderson, G. G., Spellacy, W. N. ibid. 1971, 109, 440. 1.

163 TABLE II-OUTCOME

TABLE I-ANTIBIOTIC COMBINATIONS USED

70-100 ml. of sterile water, and infused over 10-15 minutes. Gentamicin and carbenicillin may be incompatible in vitro, 11l and the gentamicin was given as a separate 6-hourly injection into the tubing of the intravenous apparatus after completing each infusion of the other antibiotics. The dosages of gentamicin and cephalothin were reduced where indicated in patients with raised blood-urea concentrations,

i.v. intravenous.

p.o.=oral.

eligible for empirical combination antibiotic therapy if they were febrile (temperature 38-5°C or more) and had leukxmia andlor neutropenia (less than 500 neutrophils per 1.). Pyrexia without other symptoms or signs was frequently observed and investigated for up to 48 hours before therapy, but in seriously ill patients therapy was instituted immediately after bacteriological specimens had been obtained. Blood, urine, sputum, and stool were cultured, and swabs were taken routinely from nose, throat, and any skin ksions. In most cases a chest X-ray and routine hsematoiogicat and biochemical tests were also done. was set up, and the antibiotics administered as rapid infusions every 6 hours, the infusion being continued slowly with suitable fluids in the intervals. The antibiotics used are set out in table I. The parenteral drugs other than gentamicin were dissolved in

An intravenous infusion

were

but administration at 6-hourly intervals was continued.12 Changes in antibiotic therapy were made when the sensitivities of any isolated pathogen were available, but if no agent was cultured, the drugs were continued for at least 5 days. If no clinical improvement occurred within 48 hours, and infection still seemed clinically probable, amphotericin B (40 mg. per sq.m. per day) was added to the treatment schedule. Antibiotic-disc sensitivities were ascertained for all isolated organisms. Blood-counts, liver function, bloodurea, and electrolytes were monitored frequently. A positive bacteriological diagnosis was not established in all patients who received empirical combination antibiotic therapy, and for purposes of evaluation " infections " were classified into three groups, similar to those used by

Schimpff et al. 3 : "

Documented infection ", where, in addition to signs of infection, proof was obtained from blood culture. " Probable infection ", where clinical signs and progress were consistent with an infection, but where cultures were negative. " Infection doubted ", where infection seemed improbable on review of clinical signs and progress. The result of antibiotic therapy was assessed by the progress of clinical signs and fever. In all cases of treatment failure, persistence of infection was presumed or proved on

TABLE III-CASE DETAILS

* w.B.c. = White-blood-cell count (per c.mm.). Not evaluated. Neut. = Neutrophil-count (per c.mm.). c.G.L.—A.i..= Chronic granulocytic leuttaetnia transformed to acute leukaemia. n.n.=Aplastic aneenua. A,M.t.=Acute myeloblastic teuka:mia. A.M.M.o.i.. = Acute myelocytic and monocytic leukaemia. C.L.L. =Chronic lymphocytic teuksemia. n.L.t.=Acute lymphocytic leukxmia.

164 the basis of culture of organisms (before or after death of Patients were the patient), and clinical deterioration. considered to have had a satisfactory response to antibiotic therapy if they became afebrile and all signs of infection disappeared, even if they died soon afterwards of the underlying leukaemia or lymphoma. Results

Table 11 shows the distribution of infections in the first twenty-seven patients treated with the combination of antibiotics. Of the fifteen patients with documented bacterial infection, eight (53%) had a satisfactory response. Six patients died with persisting signs of infection, and in one case no evaluation could be made because the patient died within 24 hours of admission to hospital and the start of antibiotic therapy. All patients with probable infections improved, and we feel confident on clinical grounds that infection was present. In only four of the twenty-seven patients (15%) treated with antibiotics was an infection subsequently judged improbable. In two of these, both adults with myeloblastic leukaemia, the clinical progress indicated that their fever was an index of disease activity rather than of infection. In the other two cases, no firm conclusions as to the cause of the fever were reached. Table ill summarises the clinical and laboratory data of the twenty-three documented and probable

infections. Of the fifteen documented

cases with infection, cultured from the blood in eleven aeruginosa In four of these eleven (73%). patients, another was also the cultured from organism blood, and in one case two further organisms were isolated. Of the seven patients with Ps. aeruginosa septiceemia alone, a successful outcome was achieved in six patients; the seventh patient died within 24 hours of admission to hospital and the start of antibiotic therapy. None of the four patients with a multiple-organism septicxmia survived, although in each case there was clinical improvement at first. In the patient with a threeorganism infection, all organisms were still present in blood cultured 48 hours after starting the antibiotic

Ps.

was

treatment.

Of the four patients with single-organism infections with species other than Pseudomonas, two with a Staphylococcus aureus and a Klebsiella septicmia recovered. A third with staphylococcal septicaemia died within 36 hours of admission to hospital. The fourth patient (no. 4) died of a widespread fungal infection 1 month after starting the antibiotics. For the last 10 days of his life signs of a chest infection from which no organism could be isolated increased steadily in the face of an antimicrobial barrage consisting of eleven parenteral agents, including streptomycin, amphotericin B, and pentamidine. At necropsy a fungus, Chaetomium aureum, was grown from the lung, and hyphas were seen in other organs. Recovery from a documented infection in these

patients was not entirely dependent on peripheralblood neutrophil-counts, and in only one patient (case 9) was there a striking improvement in the peripheral blood picture during the period of treatment. The factor most obviously related to treatment failure was

the presence of cultures.

more

than

organism in blood

one

Complications of Treatment In only one patient was the appearance of a widespread macular rash together with a return of fever after 2 weeks of antibiotics thought to be due to antibiotic hypersensitivity. This patient (case 2) had disseminated histiocytosis as a primary diagnosis, and at first it was thought that the rash was due to skin metastases. However, the rash and fever disappeared and the patient improved after withdrawal of antibiotics. Other Complications Patients on high doses of semisynthetic penicillins are getting a substantial sodium load, 14 and weight gain and oedema were often observed during treatment. In a few patients the blood-urea rose, but only twice was the dosage of antibiotics reduced. No ototoxicity was encountered. An unexpected and frequent complication was hypokalaemia. In seventeen patients the serum-potassium fell below normal during the period of antibiotic In four patients with normal serumtreatment. levels before the start of antibiotics, the potassium serum-potassium fell to less than 2 meq. per litre. In one patient the serum-potassium fell to 1 meq. per litre, and this was accompanied by severe weakness and a series of grand-mal convulsions. Changes consistent with hypokalaemia were present on an electrocardiographic tracing, and large potassium supplements improved the weakness and the electrocardiogram. Whether the fits were related to the low potassium, or were a direct consequence of the large doses of penicillins, is not clear. The mechanism of the hypokalsemia has been investigated and will be

reported elsewhere. 14 Discussion

Fever is

common

in

patients

not always due to infection. commonest cause of death in

with leukaemia, but is Infections remain the

leukaemia, despite the fact that very effective antibiotics have become available in recent years 15 ; and many deaths classified as due to haemorrhage are accompanied and precipitated

by concurrent infection.1 Gram-negative bacteria, especially Ps. ceruginosa, are very common causes of infection in patients with cancer, blood dyscrasias, and leukaemia, and death may be very rapid if septicxmia develops. Physicians have been reluctant to treat all febrile episodes in leuksemic patients with antibiotics because of the well-established therapeutic principle until one knows what one is with infections in leukoemic patients, treating. However, the patient may die before the invading organism has been positively identified.Radioisotopic methods for rapidly establishing the presence of bacteraemia are being investigated,16 but this work is at a relatively early stage and its clinical value remains to be proved. The nitroblue-tetrazolium (N.B.T.) test 17 seems to be a reliable index of bacterial infection in haematologicatly normal subjects, and preliminary results suggest 19 that it may be similarly valuable in patients with leukaemia. However, the N.B.T. test is difficult when

that

one

should

not treat

165

.

’

FEVER

neutropenia is severe, and even a positive result does not help in the choice of antibiotic. A reasonable

REGIMEN

approach to the management of infections in leukaemia is to use a standardised antibiotic regimen empirically as soon as fever is noted, and to modify the treatment in accordance with bacteriological findings and clinical response.

mortality for Ps. ceruginosa septicarmia in patients with malignancy has been reported as 70-90 %, and about half have died before bacteriological identification and commencement of antibiotic therapy. 3,
poiymyxin B,carbenicillin and gentadicing and gentamicin and cephalothin/ and with these treatments better survival-rates have been reported. Our" fever regimen " was designed to be effective against the most common pathogens likely to infect patients with immune suppression, cancer, or leukxmia. The antibiotics chosen

provide good cover against gram-posi-

Sensitivities of pathogenic bacteria to the antibiotic combinations used.

The four-antibiotic combination significant penicillin allersv.

tive organisms, and, more important, are active against Pseudomonas, Klebsiella, Escherichia, and other gram-negative bacteria. The initial fever regimen (table I) was abandoned when the frequency of Ps. aeruginosa infections showed the necessity of weighting treatment heavily towards this organism by incorporating both carbenicillin and gentamicin from the onset of therapy. The second regimen (table I and figure) also incorporates clindamycin, which, apart from its antistaphylococcal activity, is also a potent agent against Bacteroides fragilis. The simultaneous administration of five agents is certainly not in accord with the usual principles of antibiotic therapy. However, we are dealing with a situation where infection is liable to be fulminant, and the range of possible pathogens is exceptionally wide, demanding an unusually extensive antibiotic cover. Positive bacteriological diagnosis enabled prompt curtailment of the superfluous antibiotics in those cases where a diagnosis could be established. Unusual infections may develop in leukamuc patients - indeed one patient in this series died from a fungal infection by an agent previously only known to produce a disease in lupins and other plants. However, the more common agents have been responsible for most of the overwhelming infections in this series. The results of the trial are encouraging, and of the eleven patients with a single-organism septicxmia a good result (cure) was achieved in eight (73%); these eleven patients include two who died within 48 hours of becoming ill and starting on the fever regimen. The re;ults are less encouraging for multiple-organism infections; none of the four patients survived. There "as, however, some prolongation of survival over that reported by Bodey et a1.,20 whose patients had a median survival from the time of multiple-organism creture of 3 days. Our four patients had a median survival of 8 days. Two of the patients with multipleorganism septicaemia were also given transfusions of granulocytes obtained from patients with chronic granulocytic leuksmia, using an Aminco cell separator.

In neither

on

the

right of the figure

case was

there

a

was

only used in cases of

clear clinical

improvement,

or rise in the peripheral-blood neutrophil-count. From our experience in treating these patients, several points can be made. In this type of patient the typical signs of infection are often absent-e.g. clinical chest signs are unimpressive (no inflammatory response), and sputum is non-purulent (no neutrophils). When fever or rigors occur in these patients, it is reasonable to assume infection exists (documented in fifteen out of twenty-seven and presumed retrospectively in eight more). Ps. œruginosa septiceemia is almost bound to develop if routine skin, sputum, or stool cultures have yielded the organism. The presence of superficial skin lesions yielding Pseudomonas is an indication for systemic therapy directed against this organism. Prophylaxis is likely to be the better treatment: attempts to prevent patients at risk from contracting an infection are more likely to be effective than treatment of a serious established infection in a patient with impaired host defences. Clinical and bacteriological investigation of patient isolation and prophylactic sterilisation of the skin and the gastrointestinal tract 21 are proceeding. The relative infrequency of staphylococcal septicaemia in our patients, together with the good antistaphylococcal activity of cephalothin, clindamycin, and gentamicin, has prompted us to delete methicillin from the latest version of the fever regimen. Clinical evaluation of this four-antibiotic combination continues. REFERENCES

Hersh, E. M., Bodey, G. P., Nies, B. A., Freireich, E. J. J. Am. med. Ass. 1965, 193, 105. 2. Bodey, G. P., Buckley, M., Sathe, Y. S., Freireich. E. J. Ann. intern., Med. 1966, 64, 328. 3. Schimpff, S., Satterlee, W., Young, V. M., Serpick, A. New Engl. J. Med. 1971, 284, 1061. 4. Freid, M. A., Vosti, K. L. Archs intern. Med. 1968, 121, 418. 5. Bodey, G. P., Rodrigues, V., Luce, J. K. Am. J. med. Sci. 1969, 257, 1.

408. 6. Klastersky, J., Cappel, R., Debusscher, L., Daneau, D., Chemotherapy, 1971, 16, 269.

Swings, G.

166

ASSOCIATION OF FIBRINOGEN-FIBRINRELATED ANTIGEN (F.R.-ANTIGEN) WITH POSTOPERATIVE DEEP-VEIN THROMBOSIS AND SYSTEMIC COMPLICATIONS E. H. WOOD C. R. M. PRENTICE G. P. MCNICOL* Division

and

of Surgery University Department of Medicine, Royal Infirmary, Glasgow C.4

Postoperative deep-vein thrombosis, diagnosed by the 125I-fibrinogen scanwas found in 74% of patients following technique, ning Summary

surgery for fractured neck of femur. The concentration

of

serum-fibrinogen-fibrin-related antigen (F.R.-antigen) was measured serially in the group of patients and was correlated with the presence or absence of deepvein thrombosis. The patients with positive 125Ifibrinogen scans had significantly higher postoperative F.R.-antigen levels than those without this complication. When the patients with positive scans were analysed further it was found that the highest F.R.-antigen levels were associated with systemic complications such as sepsis, congestive failure, or metastatic disease rather than with deep-vein thrombosis alone. It is suggested that in the presence of systemic complications F.R.-antigen is produced not only by fibrinolytic digestion of intravascular fibrin but also as a result of diffuse cellular damage. Introduction

RECENTLY, the diagnosis of postoperative deep-vein thrombosis has been improved by the use of objective methods such as 125I-fibrinogen scanning. 1,2 This technique, which appears to provide a reliable estimate of deep-vein thrombosis when correlated with venography,3,4 indicates that there is a much higher incidence of deep-vein thrombosis in the hospital population than can be detected clinically.5 Although it appears that many of these thrombi clear spontaneously, with-

causing clinical complications, the mechanism by they are removed is not understood. In particular, more information is required about the part played by the fibrinolytic enzyme system in this out

which

*

7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21.

Present address:

Department of Medicine, University of Leeds.

Ehresmann, U., Freick, H. Therapiewoche, 1970, 20, 2919. Shubin, H., Weil, M. H. J. Am. med. Ass. 1963, 185, 850. Bodey, G. P. ibid. 1964, 190, 1099. Eyre, H. J., Goldstein, I. M., Perry, S., Graw, R. G. Blood, 1970, 36, 432. McLaughlin, J. E., Reeves, D. S. Lancet, 1971, i, 261. McLenry, M. C., Gavan, T. L., Gifford, R. W., Gounkink, N. A., Van Ommen, R. A., Town, M. A., Wagner, J. G. Ann. intern. Med. 1971, 74, 192. Hoffman, T. J. A., Bullock, W. E. ibid. 1970, 73, 165. Tattersall, M. H. N., Battersby, G., Spiers, A. S. D. Unpublished. Bodey, G. P., Hart, J., Freireich, E., Frei, E. Cancer, 1968, 22, 1018. Gaya, H. Personal communication. Lancet, 1971, ii, 909. Catovsky. Unpublished. DuPont, H. L., Spink, W. W. Medicine, Baltimore, 1969, 48, 307. Bodey, G. P., Nies, B. A., Freireich, E. J. Archs intern. Med. 1965, 116, 266. Preisler, H. D., Goldstein, I. M., Henderson, E. S. Cancer, 1970, 26, 1076.

process. Measurement of non-clottable derivatives of fibrinogen or fibrin may indicate the degree of fibrin digestion by plasmin, or other proteolytic enzymes, in patients with thrombotic disorders. As these serum derivatives are measured immunologically by antifibrinogen antiserum we are following the suggestion of Merskey et al.that they should be termed fibrino-

gen-fibrin-related antigen (F.R.-antigen); formerly they were known as fibrinolytic degradation products (F.D.r.). There may be elevation of serum-F.R.-antigen in conditions associated with the deposition of fibrin such as disseminated intravascular coagulation, deepvein thrombosis, and pulmonary embolism,’,’ and it is assumed that these are produced in part by secondary fibrinolytic activity. In an attempt to assess the role of the fibrinolytic enzyme system in the resolution of postoperative deep-vein thrombosis, and the value of F.R.-antigen as a diagnostic aid, we have estimated the incidence of thrombosis by the 125I-fibrinogen scanning technique in orthopaedic patients undergoing surgery for fractured neck of femur and have correlated this with measurement of serial F.R.-antigen concentrations. Methods Patients 27 patients (20 females, 7 males) were studied as an unselected group, admitted as emergencies with fractured neck of femur who underwent surgical correction by pinning or insertion of an Austin-Moore prosthesis. Their mean age was 76 (range 54-86) years.

Detection of Deep-vein Thrombosis This was carried out by the 125I-labelled-fibrinogen technique.3,4 The thyroid gland was blocked by 60 mg. potassium iodide given orally before the intravenous injection of 100 .Gi of 125I-fibrinogen (Radiochemical Centre, Amersham) and daily for five days thereafter. The limbs were scanned using a portable Isotope Localisation Monitor (Pitman model 235) on alternate postoperative days for two weeks.9 A difference of 20% in the counts between on opposite limbs on two consecutive occasions was taken as evidence of deep-vein thrombosis. In practice, this difference in counts between the limbs was greatly exceeded in all cases except 1, in which positive scans were recorded. The diagnosis of deep-vein thrombosis was confirmed by ascending venography in 5 patients with positive 125I-fibrinogen scans, but owing to the difbculty of moving these postoperative patients venography was not undertaken routinely. A complete preoperative clinical examination of the patients was carried out. To detect deep-vein thrombosis they were subsequently examined daily for the presence of leg swelling, oedema, calf tenderness, dilated superficial veins, positive Homan’s sign, and raised leg temperature. As far as possible these examinations were made by an observer who did not know

equivalent points

TABLE I-CLINICAL MATERIAL