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CHAPTER 68: Approach to Infection in Patients Receiving Cytotoxic Chemotherapy for Malignancy 623

empirical antibacterial regimen by the addition of intravenous vanco- unexplained fevers. It is possible that these unexplained fevers may be
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mycin to improve the outcome for the febrile neutropenic episode are due to increased absorption of pyrogenic endotoxins through cytotoxic
important points to remember. Bacterial infections among TMP/SMX therapy–induced damaged intestinal epithelium. This consideration
518
recipients have been due to coagulase-negative staphylococci, viridans suggests that some unexplained fevers do not require continued anti-
streptococci, and TMP/SMX-resistant aerobic gram-negative bacilli bacterial therapy.
such as P aeruginosa. 511
Eight systemic reviews encompassing 29 meta-analyses have been ■ ANTIFUNGAL PROPHYLAXIS
published examining the role of fluoroquinolone-based antibacterial The major goals of antifungal prophylaxis strategies are to reduce the
chemoprophylaxis in neutropenic cancer patients. Fluoroquinolone- morbidity and mortality due to superficial and invasive opportunistic
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based antibacterial prophylaxis strategies have emerged as the preferred fungal infections and to reduce the use of toxic expensive antifungal
strategy for the prevention of pyrogenic, predominantly gram-negative therapy. Prophylactic strategies should be applied with a clear under-
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bacterial infection among cancer patients with expected neutropenia standing of the pathogenesis of the microorganisms involved.
beyond 7 to 10 days. These systematic reviews were able to detect
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prophylactic treatment effects for the fluoroquinolones in a variety of Filamentous Fungi: Filamentous fungi such as Aspergillus species, the
outcomes including microbiologically documented infection overall, dematiaceous fungi, Fusarium spp, Zygomycetes, and Scedosporium spp
gram-negative infections overall, and gram-negative bacteremia regard- are acquired by inhalation of spores called conidia. The conidia germi-
less of whether the controls were placebo, no treatment, or TMP/SMX. nate on the respiratory epithelium to produce invasive hyphae. There
Fluoroquinolone-based prophylaxis has been demonstrated to have an are three possible ways to prevent this. First, patients may be managed
effect upon infection-related mortality and overall mortality. 433 in units outfitted with high-efficiency particulate air (HEPA) filtration
The combination of fluoroquinolones with agents having additional systems. Though effective for reducing the risk of filamentous fungal
gram-positive activity such as penicillin, macrolides, or rifampin effec- infection, 426,427,519 and possible all-cause pulmonary infiltrates, it is
433
tively prevents gram-positive bacteremias as well. A meta-analysis expensive and has no impact for patients exposed to high concentra-
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of 1202 randomized subjects in 9 trials comparing fluoroquinolones tions of airborne conidia outside the nursing unit or for those who are
plus augmented gram-positive coverage to fluoroquinolones alone already infected before entering the unit. Second, topical agents such
demonstrated a reduction in total bacteremic episodes, streptococcal as amphotericin B sprayed by aerosol into the nares theoretically might
infections, coagulase-negative staphylococcal infections, and incidence reduce the risk of conidial germination. One randomized study evalu-
520
of fever. The incidence of documented infections, unexplained fever, ated the use of intranasal amphotericin B (5 mg/mL in sterile water with
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and infection-related mortality were not affected. Gram-positive pro- a total daily dose of 10 mg in three divided doses) in 90 neutropenic
phylaxis, however, increased the incidence of prophylaxis-related drug episodes. There was no significant difference in the empirical use of
toxicities, particularly with the use of rifampin. 251 intravenous amphotericin B (35% vs 27%); however, only 1 of 46 recipi-
Accordingly, chemoprophylaxis using oral fluoroquinolones where ents of aerosolized amphotericin B developed suspected or proven
the prevalence of fluoroquinolone-related gram-negative bacillary- invasive aspergillosis compared with 7 of 44 controls. Though encour-
resistance is low (<3%-5%) can reliably reduce the risk for invasive aging, intranasal amphotericin cannot be accepted as a satisfactory
gram-negative bacillary infection, and, if supplemented by gram- positive alternative to air filtration until further studies are done. Inhalation
agents such as rifampin, penicillin, or macrolides, can reduce the risk for of aerosolized amphotericin B has been studied as a strategy to reduce
invasive infections due to gram-positive microorganisms including viri- invasive aspergillosis. The incidence of possible, probable, or proven
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dans streptococci and coagulase-negative staphylococci, although this invasive aspergillosis in the aerosolized amphotericin B recipients was
strategy is not recommended. 65 4% compared to 7% in untreated control subjects. Further, there were
Under the appropriate conditions, it is possible that fluoroquinolone- no differences in overall mortality or in infection-related mortality.
based chemoprophylaxis can influence prescribing behavior for febrile Third, systemic antifungal therapy might prevent the progression of
neutropenic episodes. 512-514 A study from Duke University among hyphal growth once germination occurs. Systemic amphotericin B plus
autologous hematopoietic transplant recipients with ciprofloxacin pro- 5-FC has been used successfully to prevent reactivation of previously
phylaxis demonstrated that febrile neutropenic episodes could be safely documented invasive pulmonary aspergillosis among leukemia patients
treated with an empirical glycopeptide-based regimen. A study from undergoing further postremission cytotoxic therapy. Since this com-
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522
the University of Manitoba demonstrated that patients developing bination may be myelotoxic as well as nephrotoxic, it may be prudent
febrile neutropenic episodes while receiving ciprofloxacin prophylaxis to reserve this approach for those in whom opportunistic filamentous
during remission-induction therapy for AML could be treated safely and fungal infection has been proved by microbiologic or histopathologic
effectively with vancomycin plus ceftazidime-based strategy wherein the methods. The prophylactic role of newer approaches such as lipid for-
ceftazidime was discontinued before the patient defervesced provided mulations of amphotericin B, echinocandins, or the extended-spectrum
the serial rectal surveillance cultures and 24- to 36-hour blood cultures triazole antifungal agents is being studied.
revealed no evidence of aerobic gram-negative bacilli. In both these Itraconazole, a lipophilic extended-spectrum azole, has been exten-
514
studies, the oral ciprofloxacin prophylaxis regimen was continued sively evaluated for antifungal prophylaxis in a number of trials of very
throughout the treatment for the febrile neutropenic episode. Another heterogeneous patient populations. Two meta-analyses of these trials
study demonstrated that empirical systemic antibacterial therapy for failed to identify a prophylactic benefit of itraconazole, particularly when
febrile neutropenic episodes could be safely discontinued after 72 to administered as oral capsules, against mold disease due to Aspergillus
96 hours if the initial workup failed to provide evidence for clinically spp. 280,523 Studies performed in patients at higher risk for invasive asper-
or microbiologically documented infection and if prophylaxis was gillosis have been more positive, however. 524,525 Winston and colleagues
continued. These observations, while provocative, have not been fol- evaluated itraconazole in hematopoietic stem cell allograft recipients.
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524
lowed up in large randomized controlled studies. There was a significant reduction in the overall incidence of proven
Not all fevers in neutropenic patients represent infection; fever is invasive fungal infection but the protective effect upon mold infection
a poor outcome for trials of antibacterial prophylaxis in this patient was not statistically significant. A similar study from the Fred Hutchison
population. Better discriminators for infection are needed 515-517 to Cancer Center was able to demonstrate a significant reduction in the
guide empirical therapy. Although antibacterial prophylaxis studies overall incidence of invasive fungal infection and in invasive mold
have not yet had a major influence on use of empirical antibacterial infections. Despite this promising result, treatment-related adverse
525
therapies, there is optimism for the future. The prophylaxis-related events necessitating treatment withdrawal resulted in a higher overall
decrease in documented infections has been offset by an increase in mortality among itraconazole recipients. Study drug was discontinued

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