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384 Part V: Therapeutic Principles Chapter 24: Treatment of Infections in the Immunocompromised Host 385

mortality seen with this agent. Dalbavancin, a second-generation gly- preparations, but are generally manageable. Serum creatinine, potas-
54
copeptide that can be administered once per week, has been approved sium, and magnesium levels should be monitored closely while giving
37
for treatment of MRSA skin and soft-tissue infections. Ceftobiprole is these medications. Amphotericin products remain the first-line agent in
a broad-spectrum cephalosporin that is also active against MRSA, but is treatment of mucormycosis, although they are frequently used in com-
not yet approved in the United States. 38 bination with echinocandins. 55
The emergence of vancomycin-resistant S. aureus strains may limit Although there are limited data to support its efficacy, it is com-
the use of vancomycin in the treatment of S. aureus infections in the mon practice to give intravenous fluids prior to and sometimes after
39
future, although, fortunately, these isolates are currently quite rare. amphotericin infusion to mitigate nephrotoxicity. Fever and chills
56
Toxicities of anti-MRSA agents as well as a comprehensive list of anti- associated with administration of amphotericin may be treated or
biotics with activity against MRSA still in development are reviewed in prevented with diphenhydramine hydrochloride, acetaminophen, or
Ref. 40. Linezolid is a commonly used alternative to vancomycin, but hydrocortisone. 57
causes thrombocytopenia and therefore must be used with caution in Fluconazole, an azole drug that can be administered orally or
patients who are receiving chemotherapy. Daptomycin is a good alter- intravenously, is approved for treatment of C. albicans, Cryptococcus
41
native to vancomycin for bloodstream infections. neoformans, and Coccidioides immitis. It is less active against non-albi-
Vancomycin-resistant Enterococcus (VRE) is being isolated with cans Candida species and is completely inactive against Candida krusei.
increasing frequency and presents a major challenge, particularly It also lacks activity against Aspergillus. 58
among neutropenic patients. 42,43 Cefepime and ceftazidime lack activ- In contrast to fluconazole, itraconazole has modest activity against
45
44
ity against enterococcus. Linezolid, daptomycin, and quinupristin/ Aspergillus. It is less active than voriconazole but may have a role in
32
dalfopristin, are the best agents currently available for treatment of milder infections or when voriconazole is not tolerated. 59
serious VRE infections. Tigecycline also has activity against VRE, but Voriconazole is another azole drug, which is also available in
36
should not be used in bloodstream infections because of inadequate intravenous and oral formulations. A large study concluded that vori-
serum levels. Quinupristin/dalfopristin is not active against Enterococ- conazole is as effective as liposomal amphotericin B as empiric therapy
cus faecalis. The minimum inhibitory concentration of the organism for neutropenic patients who are febrile, but these results are controver-
should be checked before initiating daptomycin because VRE isolates sial. 52,60 Oral voriconazole may be a good alternative to the intravenous
can have daptomycin resistance, even in the absence of prior daptomy- formulation in neutropenic patients with uncomplicated persistent
61
cin usage. 46 fever. It is the first-line therapy against Aspergillus. Side effects of
62
Drug resistance among Gram-negative pathogens is also of great voriconazole, which may limit its use in some patients, include visual
clinical concern in neutropenic patients. As a result of the rising prev- abnormalities, hallucinations, and liver function test (LFT) abnormal-
alence of multidrug resistant Gram-negative organisms, older drugs, ities. Recent data suggest that voriconazole use in transplant recipients
47
such as colistin, have been reintroduced into practice. Enteric patho- is associated with an increased rate of nonmelanoma skin cancers. The
gens, particularly Klebsiella and E. coli which produce extended-spec- mechanism by which this occurs is currently unknown. Neurologic
63
trum β-lactamases are a large and growing clinical problem. In up to side effects may be related to blood levels of the drug, which vary widely
25 percent of cases of Gram-negative rod bacteremia in neutropenic depending upon a large number of factors including CYP2C19 geno-
patients, cultures ultimately grow extended-spectrum β-lactamase type. There is mounting evidence that therapeutic drug monitoring
(ESBL)-producing pathogens. These organisms are resistant to all improves safety and efficacy of voriconazole in the treatment of invasive
48
cephalosporins and exhibit varying and unpredictable degrees of sen- fungal infections. 64,65
sitivity to aminoglycosides and quinolones. The carbapenems (imi- Posaconazole is the newest approved azole. It is now available in
penem, meropenem, doripenem, ertapenem) are active against these intravenous and oral formulations. Its primary use has been prophy-
pathogens. Carbapenemase-producing organisms, currently relatively lactic; however, it has shown promise as salvage therapy for invasive
66
rare, may become an important clinical problem in the future. Data aspergillosis. Unlike the older triazoles, posaconazole is active against
regarding treatment of infections caused by carbapenemase-producing many species that cause mucormycosis, and it has been used success-
organisms are limited to retrospective and noncontrolled, nonrandom- fully when other therapy has failed; however, there is no clinical trial
ized prospective studies but suggest that combination therapy with a data available at this time. 67
carbapenem plus colistin, aminoglycoside, or tigecycline may be more Isavuconazole is an investigational broad-spectrum azole available
effective than monotherapy. 49,50 in oral and intravenous formulations. It is currently in phase III trials
comparing it to voriconazole for treatment of Aspergillus. It also has
Fungal Infections some activity against species that cause mucormycosis. 68
Systemic fungal infections are relatively common in neutropenic The echinocandins, which include caspofungin, micafungin, and
patients, and empiric antifungal therapy should be considered in febrile anidulafungin, are a class of intravenous drugs that has activity against
patients if empiric antibiotic therapy is not effective within 5 to 7 days. a wide variety of Candida species as well as Aspergillus. They are gen-
51
Historically, amphotericin B deoxycholate had been the drug of choice erally well tolerated, and may become especially important as the
69
for the majority of fungal infections that develop in neutropenic hosts, prevalence of non-albicans Candida infections rises. Currently, only
although its position has been largely supplanted by the introduction of caspofungin is approved for first-line empirical use in febrile neutro-
70
liposomal formulations of amphotericin in most centers, newer azole penia. Caspofungin is also the only echinocandin approved as salvage
drugs, and echinocandins. 52,53 therapy for aspergillosis; however, mounting evidences suggests that
There are three lipid-associated formulations of amphotericin cur- micafungin is also effective in the treatment of invasive Aspergillus
rently available in the United States. AmBisome (liposomal amphotericin infections. The echinocandins may have synergy with other antifungal
71
B); Abelcet (amphotericin B lipid complex); and Amphotec/Amphocil agents against Aspergillus species and in treating mucormycosis. 55,72 A
(amphotericin B colloidal dispersion). These three agents are not inter- randomized controlled trial evaluating echinocandins as part of combi-
changeable. These formulations, particularly AmBisome, are less neph- nation therapy in Aspergillus treatment has been performed and results
rotoxic, and appear to be at least as efficacious as nonlipid formulations. are expected soon. Anidulafungin, the newest approved echinocandin,
Infusion-related symptoms are not consistently less common with these has shown excellent efficacy in the treatment of candidiasis. 73

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