International Journal of Antimicrobial Agents 3 (1994) 245-250 245 © 1994 Elsevier Science BV 0924-8579194l$26.00

ANTAGE 00105

Current infectious complications and their management in acute leukemia and bone marrow transplantation

J. Peter Donne l ly and Ben E. De P a u w

Departments of Medical Microbiology and Haematology, University Hospital Nijmegen, Nijmegen, Netherlands"

(Accepted 1 October 1993)

Introduction

Most granulocytopenic patients develop fever within a few days of becoming neutropenic and therefore receive broad-spectrum antibiotics aimed primarily at preventing fulminant sepsis due to Gram-negative bacilli. However, in recent years there has been a marked shift in the patterns of infec- tion from Gram-negative rods to Gram-positive cocci with coagulase-negative staphylococci and 'viridans' streptococci now accounting for the ma- jority of bacteremias. Other Gram-positive bacteria are also encountered including Stomatococcus mu- cilaginosus [1], Bacillus species [2], Clostridium spe- cies [3] and coryneforms [4]. These changes might be explained by the greater use of prophylaxis were it not for the fact that they have also been observed in centers where antimicrobial prophylaxis is not used. The majority of cases of bacteremia due to the skin

Correspondence to. Dr. J.P. Donnelly, Department of Haema- tology, Internal Medicine, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, Netherlands.

commensal staphylococci and coryneforms as well as fungemia due to Candida parapsilosis appear re- lated to intraluminal colonisation of intravascular devices such as the Hickman catheter. On the other hand, skin and soft tissue infections associated with intravenous catheters are seldom related to organ- isms grown in the blood since only the outside of the catheter comes into contact with the tissues. Rather, these infections are the result of growth of organisms in the tissue-catheter interface. However, a minority of patients have no such devices yet are truly bacter- emic with these same organisms, in which case the port d'entree is probably the oral cavity as a result of oromucositis or even the gastrointestinal tract, just as was previously observed for Gram-negative bac- teria and Candida albicans.

Mucosit is and the oral and gastrointestinal mucosa

It is almost certain that damage to the mucosa, whether clinically apparent or not, accounts for the

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presence of oral viridans streptococci and also Sto- matococcus mucilaginosus. Both are normal com- mensals and both are relatively easily selected for by the fluoroquinolones due to their marginal suscepti- bility to these agents. Indeed, mucosal damage seems to be assuming greater importance due to the more intensive cytostatic regimens. Moreover, it is un- likely that the shorter duration of neutropenia that results from the use of the growth factors G or GM CSF will moderate mucositis. Rather, oral and gas- trointestinal toxicity will become the limiting factor for aggressive chemotherapy. Another inadvertent consequence of intensive chemotherapy is the greater use of H2-receptor antagonists that interrupt the gastric acid barrier which in turn leads to colonisation of the small and even large intestine with oral commensals many of which are resistant to the majority of agents currently available. This has also been highlighted recently as a major risk factor in the sepsis related to viridans streptococcal bacter- emia [5]. It is under these circumstances that prophy- lactic antibiotics probably exert their greatest effect by selecting organisms with marginal susceptibility which then are able to predominate at sites of mu- cosal damage from which they transmigrate into the bloodstream.

Bacteremia due to coagulase-negative staphylococci

There are major problems in assigning clinical sig- nificance to bacteremia due to these organisms since such cultures lack specificity and neither the morbid- ity nor the mortality has been determined with any accuracy nor have the risk factors for infection been definitively determined. Therefore some clinicians adopt permissive criteria for assigning significance to coagulase-negative staphylococci recovered from blood and assume every case to require treatment even with a single positive culture, with the result that as many as four of every five patients will be overtreated. On the other hand, a restrictive ap- proach will certainly spare most patients from un- necessary exposure to antibiotics but may result in a few cases of actual sepsis such as progressive celluli- tis, metastatic abscesses and perhaps endocarditis. The correct response lies somewhere in between

these extremes and therefore a practical compromise might be that bacteremia should be defined as being significant only when at least two consecutive ve- nous samples taken with a minimum interval of 30 min, or from two separate veins, yield the same strain of staphylococcus. Such a definition excludes most cases of contamination. However, it still does not address the issue of discriminating between colonisation and infection particularly in cases where there is an indwelling catheter. Various solu- tions have been proposed including using a tenfold difference in colony counts between blood cultured via the catheter and a similar sample taken contem- poraneously via a peripheral vein. Another ap- proach might be to take blood for culture every day in order to identify colonisation and, having done so, only to treat persistent bacteremia with the same strain of staphylococcus when it is associated with clinical sepsis, although to date there are no clear data.

Bacteremia due to oral 'viridans' streptococci

Bacteremia due to viridans streptococci, particu- larly Streptococcus mitis, has been associated with what has been termed the 'alpha-strep sepsis syn- drome' [5] which is characterized by a sudden onset of more than 39.5°C, chills and flushing with hypo- tension, desquamating rash of the palms and soles of the feet, adult respiratory distress syndrome (ARDS) and acute renal failure. However, these or- ganisms may not be directly involved since both ARDS and shock have also been associated with high doses of cytarabine without any bacteriological involvement. Moreover, the incidence of bacteremia due to these bacteria appears strongly dependant upon the nature of cytostatic chemotherapy. Thus, in our hospital, almost two of every three allogeneic bone marrow transplant (BMT) recipients condi- tioned with idarubicin developed viridans strepto- coccal bacteremia whereas only one tenth this num- ber did so in the absence of this cytostatic. In con- trast, 35% of our leukemic patients given high- dose cytarabine developed bacteremia, compared with 6% in those given a lower dose and 4% in patients given other cytostatics. Despite the extremely high bacteremic rate, none of the allogeneic BMT recipi-

ents treated with idarubicin developed sepsis or ARDS, and bacteremia occurred after oromucositis had developed but before it had reached its peak. Moreover, treatment with clindamycin and cef- tazidime failed to alter the clinical course of oromu- cositis which was accompanied by fever and elevated C-reactive protein. In contrast, ARDS developed in 10% of patients with viridans streptococcal bactere- mia following high-dose cytarabine and oromucosi- tis was not a consistent finding.

It was also of interest that the ratio ofS. sanguis to S. mitis was 2 to 1 in the BMT recipients while in other patients it was completely reversed, as had been reported by McWhinney and colleagues [6]. Fi- nally, although a potential r61e has been suggested for herpes simplex, there was not a single case in which viral replication or infection was demon- strated in our BMT patients since all patients were given acyclovir beginning 4 week before transplant and continued for a further 4 weeks. As yet, there has not been any systematic investigation of herpes sim- plex infection in nontransplant leukemic patients but clinically apparent infection seldom occurs al- though acyclovir prophylaxis is not given. It would

TABLE 1

Viridans streptococcal bacteremia in leukemic patients

Syndrome

Plain bacteremia Bacteremiawith sepsis

Patient group allo BMT remission induc- tion

Cytostatic idarubicin high-dose cytarabine

Chlorhexidine all none mouthwash Acyclovir all none H2-receptor antagonists infrequent frequent Ratio ofmitis:sanguis 1"2 2:1 Oromucosit is severe mild or absent Initial temperature > 39.5°C > 39.5°C Sepsis none ~ 30% A R D S none ~ 10% Penicillin to reduce

bacteremia effective effective sepsis no difference possibly effective

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therefore appear that there are two distinct syn- dromes associated with bacteremia due to viridans streptococci - plain bacteremia which is a sign of extensive, severe mucositis rather than infection and a septic-like syndrome which might be the direct re- sult of disseminated streptococcal infection, toxicity due to high-dose cytarabine or a combination of both (Table 1).

This syndrome may progress to ARDS or shock and might be precipitated by a breach in the gastric barrier. However, it is hard to explain such a syn- drome in terms of the streptococci alone since they do not possess toxins and appear poor inducers of tumour necrosis factor (TNF) and other biomodula- tors involved in inducing shock. It may be that over- whelming colonisation of the alimentary tract might lead to extremely large numbers of bacteria transmi- grating into the blood stream and major organs, or that enough cell-wall antigen is released to trigger off the metabolic chaos associated with shock and the sepsis syndrome. Alternatively, certain strains of S. mitis may elaborate so-called 'super-antigens'. Whatever the explanation, prophylaxis with penicil- lins only prevents bacteremia in BMT patients al- though it may limit both this and the sepsis observed in other patients.

Less frequent causes o f bacteremia

Among the less frequent causes of bacteremia at- tention has been drawn to both Gram-positive and Gram-negative bacteria. For instance, bacteremia due to Enterobacter cloacae and Citrobacter freundii appears to be associated with inadequate therapy [2, 7, 8]. Of the two organisms, E. cloacae is the more dangerous since some strains possess a chromo- somally-mediated gene for [3-1actamase which can be de-repressed by cephalosporins such as ceftazidime. Thus, if a patient is colonized and treated with this antibiotic there is a risk of both inducing resistance and giving selective advantage to these bacteria thereby increasing the risk of bacteremia and rapidly fulminant sepsis. Prophylaxis with cotrimoxazole and colistin might be indicated since the organism is usually susceptible. Similarly, treatment with car- bapenems such as imipenem or meropenem might select for Xanthomonas maltophilia in the upper res-

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piratory tract and even the skin [9]. If this occurs at the exit site of an indwelling catheter, infection might then ensue. Attention has also been drawn to an- other saprophytic bacterium Achromobacter xy- losoxidans, which is a soil inhabitant but can also colonize intravascular devices and the mucosal sur- faces. Neutropenia is not a risk factor and the organ- ism is usually susceptible to cotrimoxazole, anti- pseudomonal ~3-1actams but resistant to quinolones, aminoglycosides and other [3-1actams [10].

Stomatococcus mucilaginosus is a normal mouth commensal in some 5% of the population. Interest has been recently aroused since the organism has been isolated from cases with endocarditis as well as leukemic patients [1]. The bacterium has some of the features of micrococci, staphylococci and even streptococci which makes laboratory diagnosis more difficult. It also appears easily selected by prior exposure to fluoroquinolones since it is only margin- ally susceptible. Although there has been one case report suggesting that bacteremia due to stomato- coccus resulted in death, there were other equally plausible explanations and the organism was only isolated from a single culture [11]. Moreover, there appeared to be little evidence of sepsis in any of the other seven cases reported while oromucositis ap- peared to be a risk factor. Nor was it entirely clear whether or not treatment with a glycopeptide was necessary in addition to basic empiric therapy.

Bacteremia due to Bacillus species may indicate either colonisation of a catheter or the gastrointesti- nal tract [12]. Strains usually belong to the cereus group and may be ingested with grains such as rice. Isolates are often resistant to 13-1actam antibiotics and aminoglycosides. While recovery from single blood cultures suggests contamination, treatment with a glycopeptide is advisable when these bacteria are recovered from more than two consecutive sam- ples especially when it coincides with colonisation of the gut as does persistent or recurrent bacteremia. Any intravascular catheter suspected of being colo- nized should be removed.

In contrast, bacteremia due to clostridia may indi- cate a lesion in the lower bowel. In particular, Clos- tridium septicum can produce spontaneous gangrene which may progress rapidly culminating in fatal tox- emia [3]. The organism can produce abscesses in solid organs, the retroperitoneum, and the extremi-

ties. Asymptomatic bacteremia should prompt a search for abscesses including the liver. Treatment should include either a glycopeptide or penicillin G and any necrotic tissue must be removed. Prolonged and even lifelong prophylactic oral penicillin G might be necessary to prevent further recurrences.

Infection due to Candida spp.

Candida albicans remains the most frequent cause of yeast infection which is preceded by high-level colonisation of the gastrointestinal tract. Mucocuta- neous candidiasis is the most common manifestation of infection but there are, as yet, no reliable estimates of the frequency. The disease is effectively treated with as little as 50 mg/day of fluconazole with signs and symptoms resolving within 7 10 days. However, accurate diagnosis is confounded by the similarity of some types of oromucositis with early oral thrush and the relative ease with which the yeast is isolated from oral secretions. Since there is no reliable test for definitive diagnosis, infection is as easily over as under diagnosed unless care is taken to examine the macroscopic character of lesions as well as histology to establish the presence of both blastospores and pseudomycelia. There is also difficulty in distin- guishing oesophagitis due to this yeast from that caused by herpes simplex and it may be that infection due to this virus may be necessary for candidiasis to become established. However, once a lesion devel- ops, the risk of dissemination increases with a com- mensurate rise in the likelihood of organ infection. Repeated cycles of chemotherapy-induced mucosal damage and neutropenia probably precipitate pro- gressive dissemination with intermissions of quies- cence. Indeed, the occurrence of hepatosplenic can- didiasis suggests such an evolution since the disease usually becomes manifest clinically after neutrophil recovery. Persistent fever is usually the only indica- tion until granulocyte counts recover whereupon liver involvement is detected by elevated levels of al- kaline phosphatase. 'Bulls eye' lesions are usually detected on ECHO or CT scan but biopsy may not yield any viable yeasts especially if the patient has received either amphotericin B or fluconazole, both of which are effective at appropriate dosages.

Other candida are assuming greater importance.

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Infection with Candida parapsilosis is invariably as- sociated with colonisation of either the lumen or outer surface of indwelling venous catheters result- ing in tissue invasion and infection. Yeast counts in the blood can be extremely high, reaching levels in excess of 1000 cfu/ml while the patient remains re- markably well. Cure is best achieved by removing the device in addition to a short course of therapy. Some candida species present problems as a result of their resistance to one or other of the available anti- fungal agents. Thus C. krusei and C. glabrata may colonize the gut following exposure to fluconazole and ketoconazole respectively, while C. lusitania is resistant to amphotericin B. C. tropicalis remains a problem since, although infection occurs, it is usu- ally recognized too late, the disease is usually well advanced, involving the major organs including the lung, and there is no really effective treatment.

Strategy for managing infection

Neutropenic patients managed without prophy- laxis of any sort are at higher risk of Gram-negative sepsis than those who receive either cotrimoxazole plus colistin or a fluoroquinolone. However, empiric therapy remains essentially the same for both groups, namely, prompt administration of broad- spectrum agents within a few hours of fever develop- ing. While there seems little significant difference in efficacy between monotherapy or treatment with an

T A B L E 2

R i s k f a c t o r s f o r i n f e c t i o n w i t h i n f r e q u e n t l y o c c u r r i n g o r g a n i s m s

I V G I O r a l U p p e r U r i - P r i o r

c a t h e - t r a c t c a v i t y a i r - n a r y a n t i -

t e r r e - w a y s t r a c t m i c r o -

l a t e d b i a l s

A chromobac ter +

Ci t robacter

En terobac ter +

)(an thomonas +

Bacil lus +

S t o m a t o c o c c u s +

v i r i d a n s s t r e p t o c o c c i -

c o a g - v e s t a p h y l o c o c c i +

Candida paraps i los is +

- 1 - . . . .

_ _ _ + +

+ + -- + +

- - + + - - +

- } - . . . .

- - + - - - - -I- + + -- _ +

+ -I- -- -- --

aminoglycoside-[3-1actam combination, the issue re- mains controversial and will not be rehearsed here. Suffice it to say that having explored monotherapy with ceftazidime over the last 10 years, our experi- ence has been very favourable having achieved an 90% success rate for Gram-negative bacteremia and a overall death-rate due to infection of around 8% of which only 1 in 4 occurred during the first 3 days of empiric therapy. Much more importantly, some modification is inevitable because either new infec- tion occurs or fungal infection develops irrespective of the initial regimen chosen. A strategy is therefore required for the whole period ofneutropenia to man- age infective complications that might occur. The most common approach is that of planned progres- sive therapy wherein adjustments are made every 2- 3 days until the patient becomes afebrile or all the potential causes of infection are covered by the best available agents. Using this strategy, around 10% of patients die as a result of infection while the number of patients receiving initial empiric therapy without any modification depends upon whether or not con- tinued fever for a specified time is used as an indica- tion for changing therapy. Our approach is to mod- ify therapy based on the clinical and microbiological findings and not just continued fever, with the result that around half the patients only receive initial monotherapy, whether or not they had bacteremia due to Gram-negatives even though amphotericin B is given after 5 days of persistent unexplained fever. The number of modifications might be reduced even further if diagnosis was more reliable. These results compare favourably with those achieved in other centers whether or not they, like us, use prophylaxis in many instances. In fact the key difference in re- sponse rates appears to depend upon how individual clinicians deal with persistent unexplained fever and how they interpret Gram-positive bacteremia rather than any real difference in the effectiveness of mod- ern empiric regimens.

Therefore it seems apposite to reconsider our whole approach to therapy, perhaps to begin antibi- otic treatment to pre-empt fulminant sepsis at the same time as chemotherapy or conditioning for transplantation. In effect, pre-emptive therapy would combine the function of both selective antimi- crobial prophylaxis and empiric therapy. Such a reg- imen would require an agent or agents that offers

250

reliable, bactericidal activity against the most likely pathogens by being given intravenously, and levels achieved in the mucosa should be sufficient to afford decontamination of the same potential pathogens preferably without disturbing the remaining com- mensal flora too seriously. Thereafter, treatment would only be changed if and when there is a clear clinical or microbiological indication to do so. Fluc- tuations in the temperature chart would not be an indication to change therapy since fever is not a relia- ble index of infection. Therapy would be continued until all signs and symptoms of infection are re- solved.

Risk groups would have to be better defined and identified. For instance, patients who are seroposi- tive for herpes simplex and in whom infection is likely to be reactivated would be most likely to bene- fit from acyclovir while those whose oral cavity and gut are colonized with certain Gram-negative rods or candida would be given supplementary local de- contamination with appropriate agents such as co- listin, and fluconazole respectively. Carriage of S. aureus would be an indication to administer mupir- icin if the pre-emptive therapy is likely to be inade- quate. Appropriate steps would have to be taken in order to minimize the risk of infection due to Asper- gillus which should include filtered air. Certain pa- tients at high risk might be given intravenous am- photericin B together with the same drug adminis- tered as an aerosol until such times as there is a safer and more effective alternative agent for prophylaxis. Clearly this approach to therapy would require close, daily review of each individual patient, the closest possible collaboration between clinicians and their nursing and laboratory colleagues, the opti- mum use of available diagnostic tests as well as the development of reliable tests for the detection of an- tigens and other microbial signatures. However, if pre-emptive therapy achieved equivalent results as current practices, the savings which might accrue from using fewer antibiotics could be diverted to in- vestment in improving diagnostics and employing sufficient staff that they could devote the requisite amount of time to each of their tasks without imped-

ing the opt imum functioning of the whole team. Pa- tients would also undoubtedly benefit since they would be less likely to receive an excess of antibiotics but would, instead, be assured both a greater conti- nuity and a better quality of clinical care.

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