Many different regimens have been evaluated and found to be acceptable for empiric therapy in febrile patients with neutropenia. Current recommendations support single-drug therapy with an antipseudomonal β-lactam as initial empiric therapy in febrile neutropenic patients.22 Piperacillin-tazobactam,23 imipenem,24 meropenem,25 cefepime,26 and ceftazidime27 have each been studied as a single agent. These drugs are active against most of the virulent pathogens infecting neutropenic patients. Doripenem, another carbapenem with antipseudomonal activity has not been studied in a prospective randomized control trial in febrile neutropenia. Ertapenem, a carbapenem that is attractive for its daily dosing schedule, lacks activity against pseudomonas and should not be used as empiric therapy.28 Differences in institutional sensitivity patterns should guide initial antibiotic selection, which should subsequently be tailored to culture results.
Although Gram-negative coverage with a single agent is associated with improved outcomes,29 among patients who are unstable or in whom antibiotic resistance is suspected, it is reasonable to add a second antibiotic active against Gram-negative organisms. Aminoglycosides may provide synergy against Gram-negative bacilli and further broaden the spectrum of antimicrobial activity, but they increase the risk of nephrotoxicity. No good evidence supports the simultaneous use of two β-lactam drugs. Fluoroquinolones in conjunction with another antibiotic are effective in patients who have not received quinolone prophylaxis.30
Patients with catheters, patients presenting with sepsis, patients with evidence of skin or soft-tissue infection, and other high-risk patients should be treated empirically for Gram-positive infections with vancomycin. Among patients without these risk factors, Gram-positive coverage should be added if fever persists for more than 3 to 5 days after Gram-negative treatment is initiated.22
The emergence of multidrug-resistant organisms has influenced the approach to empiric therapy. Approximately 60 percent of the hospital-acquired strains of Staphylococcus aureus now are methicillin-resistant S. aureus (MRSA), as are a growing number of community-acquired strains.31 Vancomycin, quinupristin/dalfopristin,32 linezolid,33 daptomycin,34 ceftaroline,35 and tigecycline36 are active against MRSA. However, it should be noted that daptomycin should not be used in pneumonia because of inactivation by surfactant. Tigecycline should be avoided in bloodstream infections because of inadequate serum levels, and the drug now carries a black box warning because of increased mortality seen with this agent. Dalbavancin, a second-generation glycopeptide that can be administered once per week, has been approved for treatment of MRSA skin and soft-tissue infections.37 Ceftobiprole is a broad-spectrum cephalosporin that is also active against MRSA, but is not yet approved in the United States.38
The emergence of vancomycin-resistant S. aureus strains may limit the use of vancomycin in the treatment of S. aureus infections in the future, although, fortunately, these isolates are currently quite rare.39 Toxicities of anti-MRSA agents as well as a comprehensive list of antibiotics with activity against MRSA still in development are reviewed in Ref. 40. Linezolid is a commonly used alternative to vancomycin, but causes thrombocytopenia and therefore must be used with caution in patients who are receiving chemotherapy.41 Daptomycin is a good alternative to vancomycin for bloodstream infections.
Vancomycin-resistant Enterococcus (VRE) is being isolated with increasing frequency and presents a major challenge, particularly among neutropenic patients.42,43 Cefepime and ceftazidime lack activity against enterococcus. Linezolid,44 daptomycin,45 and quinupristin/dalfopristin,32 are the best agents currently available for treatment of serious VRE infections. Tigecycline also has activity against VRE,36 but should not be used in bloodstream infections because of inadequate serum levels. Quinupristin/dalfopristin is not active against Enterococcus faecalis. The minimum inhibitory concentration of the organism should be checked before initiating daptomycin because VRE isolates can have daptomycin resistance, even in the absence of prior daptomycin usage.46
Drug resistance among Gram-negative pathogens is also of great clinical concern in neutropenic patients. As a result of the rising prevalence of multidrug resistant Gram-negative organisms, older drugs, such as colistin, have been reintroduced into practice.47 Enteric pathogens, particularly Klebsiella and E. coli which produce extended-spectrum β-lactamases are a large and growing clinical problem. In up to 25 percent of cases of Gram-negative rod bacteremia in neutropenic patients, cultures ultimately grow extended-spectrum β-lactamase (ESBL)-producing pathogens.48 These organisms are resistant to all cephalosporins and exhibit varying and unpredictable degrees of sensitivity to aminoglycosides and quinolones. The carbapenems (imipenem, meropenem, doripenem, ertapenem) are active against these pathogens. Carbapenemase-producing organisms, currently relatively rare, may become an important clinical problem in the future. Data regarding treatment of infections caused by carbapenemase-producing organisms are limited to retrospective and noncontrolled, nonrandomized prospective studies but suggest that combination therapy with a carbapenem plus colistin, aminoglycoside, or tigecycline may be more effective than monotherapy.49,50
Systemic fungal infections are relatively common in neutropenic patients, and empiric antifungal therapy should be considered in febrile patients if empiric antibiotic therapy is not effective within 5 to 7 days.51 Historically, amphotericin B deoxycholate had been the drug of choice for the majority of fungal infections that develop in neutropenic hosts, although its position has been largely supplanted by the introduction of liposomal formulations of amphotericin in most centers, newer azole drugs, and echinocandins.52,53
There are three lipid-associated formulations of amphotericin currently available in the United States. AmBisome (liposomal amphotericin B); Abelcet (amphotericin B lipid complex); and Amphotec/Amphocil (amphotericin B colloidal dispersion). These three agents are not interchangeable. These formulations, particularly AmBisome, are less nephrotoxic, and appear to be at least as efficacious as nonlipid formulations. Infusion-related symptoms are not consistently less common with these preparations, but are generally manageable.54 Serum creatinine, potassium, and magnesium levels should be monitored closely while giving these medications. Amphotericin products remain the first-line agent in treatment of mucormycosis, although they are frequently used in combination with echinocandins.55
Although there are limited data to support its efficacy, it is common practice to give intravenous fluids prior to and sometimes after amphotericin infusion to mitigate nephrotoxicity.56 Fever and chills associated with administration of amphotericin may be treated or prevented with diphenhydramine hydrochloride, acetaminophen, or hydrocortisone.57
Fluconazole, an azole drug that can be administered orally or intravenously, is approved for treatment of C. albicans, Cryptococcus neoformans, and Coccidioides immitis. It is less active against non-albicans Candida species and is completely inactive against Candida krusei. It also lacks activity against Aspergillus.58
In contrast to fluconazole, itraconazole has modest activity against Aspergillus. It is less active than voriconazole but may have a role in milder infections or when voriconazole is not tolerated.59
Voriconazole is another azole drug, which is also available in intravenous and oral formulations. A large study concluded that voriconazole is as effective as liposomal amphotericin B as empiric therapy for neutropenic patients who are febrile, but these results are controversial.52,60 Oral voriconazole may be a good alternative to the intravenous formulation in neutropenic patients with uncomplicated persistent fever.61 It is the first-line therapy against Aspergillus.62 Side effects of voriconazole, which may limit its use in some patients, include visual abnormalities, hallucinations, and liver function test (LFT) abnormalities. Recent data suggest that voriconazole use in transplant recipients is associated with an increased rate of nonmelanoma skin cancers. The mechanism by which this occurs is currently unknown.63 Neurologic side effects may be related to blood levels of the drug, which vary widely depending upon a large number of factors including CYP2C19 genotype. There is mounting evidence that therapeutic drug monitoring improves safety and efficacy of voriconazole in the treatment of invasive fungal infections.64,65
Posaconazole is the newest approved azole. It is now available in intravenous and oral formulations. Its primary use has been prophylactic; however, it has shown promise as salvage therapy for invasive aspergillosis.66 Unlike the older triazoles, posaconazole is active against many species that cause mucormycosis, and it has been used successfully when other therapy has failed; however, there is no clinical trial data available at this time.67
Isavuconazole is an investigational broad-spectrum azole available in oral and intravenous formulations. It is currently in phase III trials comparing it to voriconazole for treatment of Aspergillus. It also has some activity against species that cause mucormycosis.68
The echinocandins, which include caspofungin, micafungin, and anidulafungin, are a class of intravenous drugs that has activity against a wide variety of Candida species as well as Aspergillus. They are generally well tolerated, and may become especially important as the prevalence of non-albicans Candida infections rises.69 Currently, only caspofungin is approved for first-line empirical use in febrile neutropenia.70 Caspofungin is also the only echinocandin approved as salvage therapy for aspergillosis; however, mounting evidences suggests that micafungin is also effective in the treatment of invasive Aspergillus infections.71 The echinocandins may have synergy with other antifungal agents against Aspergillus species and in treating mucormycosis.55,72 A randomized controlled trial evaluating echinocandins as part of combination therapy in Aspergillus treatment has been performed and results are expected soon. Anidulafungin, the newest approved echinocandin, has shown excellent efficacy in the treatment of candidiasis.73
P. jiroveci pneumonia may be treated with trimethoprim-sulfamethoxazole. Pentamidine or primaquine-clindamycin should be used for moderate to severe infections in patients who are allergic to or otherwise intolerant of trimethoprim-sulfamethoxazole, although data for alternative regimens is much more robust in the HIV-positive patient population.74 Other alternative regimens include dapsone-trimethoprim and atovaquone, although these are best used for mild PCP. Glucocorticoids are commonly given as adjunctive treatment in severe PCP, though the data for this among non–HIV-infected patients are conflicting.75
Empiric therapy with antifungal agents is currently the standard of care in high-risk neutropenic patients with persistent fever. However, preemptive antifungal treatment is being evaluated as a possible alternative to empiric therapy in select patients. With preemptive strategies, microbiologic, molecular, and radiologic monitoring is used to detect early evidence of invasive fungal infections and prompt initiation of therapy.76 Data from studies comparing empiric therapy with preemptive strategies are mixed.77,78,79 Surveillance with fungal cell wall components 1,3-β-D-glucan80 and galactomannan81 in the blood plays a role in preemptive therapy. Real-time polymerase chain reaction of fungal gene products is another technique that appears to have high sensitivity and specificity for detecting candidemia, although it will require standardization before widespread use is possible.82
Although currently not as large a problem as drug-resistant bacteria, the development of drug-resistant fungal organisms is a potential clinical threat. Prophylactic use of antifungals likely contributes to breakthrough infection with innately resistant species.83 Cross-resistance within and between classes of antifungals is another potentially important problem, which is deserving of clinical study.84
A limited number of options are available for treatment of viral infections. Acyclovir is active against herpes simplex and, at higher doses, against varicella zoster. Other agents, such as famciclovir and valacyclovir, are as effective in treating herpes simplex and zoster infections, and may be administered less frequently, but are not available for intravenous administration.85
Ganciclovir, valganciclovir, and foscarnet have efficacy in treatment of CMV disease and are also active against herpes simplex.86 They are most effective when they are used early in the course of the infection. Hence, frequent screening for CMV and early preemptive treatment in high-risk patients, such as transplant recipients, may allow for improved outcomes.87 Ganciclovir or valganciclovir is usually the first-line therapy against CMV, but results in marrow suppression in a significant percentage of patients who receive them. Foscarnet, a second-line agent, may be complicated by azotemia and electrolyte abnormalities.
Ribavirin plus an adjunctive immunomodulator such as RSV immunoglobulin (Ig) or intravenous immunoglobulin (IVIG) are used to treat RSV pneumonia in immunocompromised patients. Ribavirin can also be used to treat RSV upper respiratory tract infections, and may prevent spread to the lower respiratory tract as well as decrease mortality; however, prospective studies are needed.88 The optimal route of ribavirin administration (oral versus inhaled) is not yet known. Oseltamivir or zanamivir should be used if influenza A is suspected.89
Rates of Mycobacterium tuberculosis infection are high among patients with hematologic malignancy worldwide, and tuberculosis should be ruled out in neutropenic patients with lung infiltrates who have tuberculosis risk factors. First-line therapy for tuberculosis includes rifampin, isoniazid, pyrazinamide, and ethambutol.90
Infections with multidrug-resistant tuberculosis, defined as microbes resistant to rifampin and isoniazid, are difficult to treat and are associated with poor prognoses. The prevalence of multidrug-resistant tuberculosis varies tremendously by country.91 Drugs used to treat multidrug-resistant tuberculosis include fluoroquinolones, amikacin, capreomycin, and kanamycin. Extensively drug-resistant M. tuberculosis, which is defined as being resistant to rifampin, isoniazid, fluoroquinolones, and at least one injectable second-line agent, is a potentially a huge clinical problem.92
Although relatively uncommon, nontuberculous mycobacterial infections also occur in patients with hematologic malignancy. Mycobacterium avium-intracellulare complex is treated with clarithromycin, rifabutin, and ethambutol. Treatment of infections with rapidly growing mycobacteria is complicated and should be guided by an infectious disease specialist.13
Table 24–1 lists the drugs used as empiric therapy in neutropenic patients.
Table 24–1.Coverage and Side Effects of Drugs Used as Empiric Therapy ||Download (.pdf) Table 24–1. Coverage and Side Effects of Drugs Used as Empiric Therapy
|Drug Category ||Drug ||Brand Name ||Activity ||Toxicity |
|Antipseudomonal penicillins ||Piperacillin-tazobactam ||Zosyn ||Methicillin-sensitive Staphylococcus, Streptococcus, Enterococcus faecalis, anaerobes, Pseudomonas aeruginosa, enteric Gram-negative rods ||Hypokalemia, antiplatelet effect |
|Antipseudomonal cephalosporins ||Ceftazidime ||Fortaz ||P. aeruginosa, enteric Gram-negative rods, methicillin-sensitive Staphylococcus* || |
| ||Cefepime ||Maxipime ||P. aeruginosa, enteric Gram-negative rods, methicillin-sensitive Staphylococcus ||Cefepime-induced neurotoxicity |
|Aminoglycosides ||Amikacin ||Amikin ||Enteric Gram-negative rods, P. aeruginosa ||Nephrotoxicity, ototoxicity |
|Tobramycin ||Nebcin |
|Gentamicin ||Garamycin |
|Glycopeptide ||Vancomycin ||Vancocin ||Staphylococcus (including MRSA), Streptococcus, E. faecalis, Corynebacterium ||Ototoxicity, red-man syndrome with rapid infusion |
|Carbapenem ||Imipenem ||Primaxin ||Gram-negative rods, Pseudomonas aeruginosa (except for ertapenem), methicillin-sensitive Staphylococcus, Streptococci, Enterococcus (imipenem), anaerobes ||Nausea, seizures (imipenem) |
|Meropenem ||Merrem |
|Ertapenem ||Invanz |
|Doripenem ||Doribax |
|Monobactam ||Aztreonam ||Azactam ||Gram-negative rods, P. aeruginosa || |
|Sulfonamides ||Trimethoprim-sulfamethoxazole ||Bactrim; Septra ||Pneumocystis jiroveci, some Gram-negative rods, Staphylococcus, Nocardia ||Sulfa allergy, increased creatinine, nausea, rash |
|Fluoroquinolones ||Ciprofloxacin ||Cipro ||Gram-negative rods, P. aeruginosa, viridans streptococci ||Nausea. Rare Achilles tendon rupture |
| ||Levofloxacin ||Levaquin ||Gram-negative rods, P. aeruginosa, viridans streptococci† || |
|Nucleosides ||Acyclovir ||Zovirax ||HSV, VZV ||Crystalluria |
| ||Valacyclovir ||Valtrex ||HSV, VZV || |
| ||Famciclovir ||Famvir ||HSV, VZV || |
| ||Ganciclovir ||Cytovene ||CMV ||Marrow suppression |
| ||Valganciclovir ||Valcyte ||CMV ||Marrow suppression |
|Phosphonoformate ||Foscarnet ||Foscavir ||CMV ||Renal failure, electrolyte abnormalities |
|Polyene antifungals ||Amphotericin B ||Fungizone ||Candida, Aspergillus, other fungi including mucormycosis ||Fever, chills, nausea, vomiting, renal failure hypokalemia, hypomagnesemia |
| ||Ampho-B lipid complex ||Abelcet ||Candida, Aspergillus, other fungi including mucormycosis ||Fever, chills, nausea, vomiting, increased creatinine |
| ||Ampho-B cholesteryl sulfate complex ||Amphotec ||Candida, Aspergillus, other fungi including mucormycosis ||Fever, chills, nausea, vomiting, increased creatinine |
| ||Liposomal ampho-B ||AmBisome ||Candida, Aspergillus, other fungi including mucormycosis ||Fever, chills, nausea, vomiting, increased creatinine |
|Azole ||Fluconazole ||Diflucan ||Candida, Cryptococcus, Coccidioides immitis ||LFT abnormality |
| ||Itraconazole ||Sporonox ||Candida, Aspergillus, Histoplasma ||CHF; drug–drug interactions |
|Voriconazole ||Vfend ||Aspergillus, Coccidioides, Histoplasma ||Loss of vision with intravenous prep |
| ||Posaconazole ||Noxafil ||Aspergillus, Coccidioides, Histoplasma, mucormycosis ||Nausea, diarrhea, LFT abnormality |
|Echinocandin ||Caspofungin ||Cancidas ||Aspergillus, Candida, mucormycosis‡ || |
| ||Micafungin ||Mycamine ||Aspergillus, Candida, mucormycosis‡ || |
| ||Anidulafungin ||Eraxis ||Aspergillus, Candida, mucormycosis‡ || |
|Oxazolidinone ||Linezolid ||Zyvox ||Staphylococci (including MRSA), Enterococcus (including VRE), streptococci ||Thrombocytopenia, anemia, small risk of serotonin syndrome with concomitant SSRIs, mitochondrial side effects with prolonged use |
|Lipopeptide ||Daptomycin ||Cubicin ||Staphylococci (including MRSA), Enterococcus (including VRE), streptococci ||Creatinine kinase elevation |
Adjustment or modification of the initial antimicrobial regimen may be necessary for several reasons. Results of cultures may suggest another regimen would be more active or less toxic. All cultures may remain negative while the patient fails to respond to the regimen. Fever may recur following an initial response to therapy, raising the possibility of a second infection.
Adjusting therapy based on a culture report usually is straightforward, but the other two situations may pose dilemmas. In these circumstances, resistant organisms or noninfectious causes of fever, such as drug fever or recurrence of malignancy, must be considered. Repeat cultures and careful clinical reappraisal may prove helpful.
Antibiotic therapy for a specific infection is commonly continued for a defined minimum period of time and until the granulocyte count reaches 0.5 × 109/L. Although this strategy reduces the number of relapsing infections, it may increase the risk of superinfection and antibiotic toxicity. In low-risk patients whose fever resolves without a documented source of infection, empiric intravenous therapy can usually be stopped and replaced by an oral regimen until counts recover. Alternatively, there is some evidence that returning to a prophylactic regimen in select patients before the absolute neutrophil count reaches 0.5 × 109/L is also a reasonable approach.93 If antibiotics are discontinued or deescalated, close observation is required, and therapy should be reinstituted at any suggestion of recurrent infection.
FEVER FOLLOWING RECOVERY FROM CHEMOTHERAPY
Fevers occasionally persist or even begin after the granulocyte count has returned to normal levels. Drug fever and engraftment syndrome are considerations in this setting, although a deep-seated infection must be excluded.94 Hepatosplenic candidiasis is one important consideration in these patients, although its incidence has likely decreased in the setting of widespread antifungal prophylaxis discussed under “Fungal Infections” below.95 Elevated serum alkaline phosphatase levels and the presence of multiple “punched-out” lesions in the liver on CT are common findings with hepatic involvement. Blood cultures are frequently negative so biopsy may be required to establish a microbiologic diagnosis.96 Hepatosplenic candidiasis requires prolonged therapy. Several regimens have been proposed, including fluconazole,97 caspofungin,98 and liposomal amphotericin B,99 but there are no randomized trial data. Persistent symptoms despite treatment may be a result of immune reconstitution inflammatory syndrome and may be relieved by adjuvant treatment with glucocorticoids.100 Cure is difficult to achieve regardless of the regimen used and mortality is high.101
Indwelling catheter infections are another important consideration in persistent fever after hematologic recovery. Diagnosing catheter infections remains a major challenge, and the use of catheter-sparing diagnostic techniques should be considered, as the need to remove catheters is patient and organism dependent. Coagulase-negative Staphylococcus spp. are most commonly isolated and are generally amenable to catheter-sparing treatment. If the catheter is to be retained, a 10- to 14-day course of antibiotics is recommended.102 If a tunnel infection is present, successful therapy is less likely without catheter removal.
Gram-negative,103 S. aureus,104 and fungal105 infections of the catheter usually necessitate its removal. This may be followed, if necessary, by insertion of a new catheter at a different site once blood cultures have cleared. Antibiotic therapy for at least 14 days is recommended. Chlorhexidine and silver-impregnated central venous catheters may prevent bloodstream infections in neutropenic patients.106 Catheter infections and their management are reviewed in detail elsewhere.102
Twenty years ago, treatment of the febrile neutropenic patient outside of the hospital would have been unthinkable. Economic pressures, coupled with the widespread availability of home infusion services and more potent oral antibiotics, have made outpatient therapy an option for some of these patients.107
Outcomes among patients with neutropenic fever treated as outpatients seem to be comparable to those observed in hospitalized patients, provided the patients are selected properly and appropriate monitoring can be ensured. Suitable candidates for home therapy include patients who are expected to have a short duration of neutropenia and who have few comorbidities.108,109 Individuals who remain febrile, who require multiple antibiotics, or who are unreliable are not candidates for home therapy. Rigorous family education is crucial for a successful outcome.
In view of the high mortality rate associated with infections in neutropenic patients, preventive measures remain a priority. Careful attention to sterile technique and personal hygiene is of the utmost importance in the prevention of bacterial infection during neutropenia. Instrumentation should be avoided whenever possible. Intravenous access sites should be carefully maintained. In addition, systemic antibiotics are currently widely used as prophylaxis against Gram-negative infections in neutropenic patients.
The use of prophylactic antibiotics reduces the number of Gram-negative infections and all-cause mortality in high-risk patients who are expected to have prolonged, severe neutropenia and is recommended in these patients.110 By contrast, the use of antibiotic prophylaxis in lower-risk patients expected to have a shorter duration of neutropenia is of much less certain benefit, and is not recommended in most cases.111 Several studies show a reduction in mortality in high-risk patients given prophylactic antibiotics, but the contribution of this practice to the emergence of drug-resistant pathogens must be taken into account when deciding whether to employ it.112,113 Furthermore, although the agents used for this purpose are generally safe, the risk of drug toxicity must also be taken into consideration. Adverse events associated with antibiotic prophylaxis include drug fever, rash, and worsening of cytopenias. Infection with C. difficile is a potentially serious risk of prophylaxis.114 Incidence of C. difficile infection is high in stem cell transplant recipients, and patients who receive high-risk antibiotics including fluoroquinolones more frequently acquire infection with this organism.115 This potential complication deserves strong consideration, as drug-resistant, hypervirulent strains of this organism have become more prevalent over the last several years.116
The fluoroquinolones, particularly ciprofloxacin and levofloxacin, have received considerable attention for their ability to prevent Gram-negative infections in neutropenic patients.110 Ciprofloxacin has more activity against Pseudomonas, whereas levofloxacin is more active against Gram-positive organisms. Unfortunately, indiscriminate use of these agents in the community, as well as prophylactic use, has led to a greatly increased prevalence of quinolone-resistant Gram-negative organisms. Up to 85 percent of Gram-negative isolates from patients with febrile neutropenia are resistant to quinolones,117 and quinolone prophylaxis has resulted in an increased incidence of quinolone-resistant viridans streptococci.118 Prophylactic use also eliminates these agents from therapeutic use in the same patient.119 For these reasons, some centers abandoned the use of prophylactic quinolones in certain patients.120,121,122 These studies consistently showed a decrease in fluoroquinolone resistance in isolates from neutropenic patients. While some studies have failed to show an increase in the incidence of bacteremia with discontinuation of prophylaxis,120 in at least two cases, institutional cessation of quinolone prophylaxis resulted in an increased incidence of bacteremia caused by Gram-negative organisms, which was reversed by reinstitution of fluoroquinolone prophylaxis.121,122 In summary, there is, at present, a clear role for quinolone prophylaxis in some patients. However, because of increasing resistance to these drugs, it is important to continuously monitor their efficacy and discourage their unnecessary use.
The use of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor to raise the absolute neutrophil count has been shown to decrease the incidence of fever in patients on high risk chemotherapy regimens, elderly patients, and patients with certain comorbid conditions.123,124 However, there is no definitive evidence that prophylaxis with these agents reduces infection-related mortality or overall survival.125
Low-bacteria diets are often recommended to patients expected to experience neutropenia, but their effectiveness at preventing infection has not been shown.126 Similarly, the efficacy of reverse isolation, though often employed as a prophylactic measure, has not been demonstrated.127
Acyclovir and its prodrug valacyclovir are effective at preventing recurrent herpes simplex infections in patients receiving chemotherapy.128 Long-term treatment with acyclovir also prevents reactivation of varicella-zoster virus in hematopoietic stem cell transplant recipients,129 as well as in patients undergoing chemotherapy for multiple myeloma.130 Varicella-zoster immunoglobulin is recommended as postexposure prophylaxis for high-risk, nonimmune patients.131
Hematopoietic stem cell transplant recipients have a high risk of CMV infection. Patients at particular risk include those who are seropositive before transplantation, seronegative patients who receive transplants from seropositive donors, and those who receive highly immunosuppressive conditioning regimens prior to transplantation.132,133 The use of CMV seronegative blood components can markedly decrease the transmission of CMV to seronegative patients; leukocyte reduction similarly prevents transmission.134 Ganciclovir,135 oral valganciclovir,136 and CMV immune globulin infusions have been used to prevent CMV infection in transplant recipients. Ganciclovir and valganciclovir frequently cause myelosuppression, which may complicate the management of neutropenic patients on these medications.137 In addition, the emergence of CMV antiviral resistance has been reported in association with preventive treatment.138 CMV prophylaxis among patients receiving conventional chemotherapy has not been as widely studied, but currently there is no evidence supporting its use in this population.139 Many centers take a preemptive approach, screening patients regularly for CMV viremia and initiating therapy only when CMV is detected. Prophylactic immunotherapy may have benefit in patients unable to tolerate the potential myelotoxicity of antiviral therapy.140 Recent randomized controlled trials have suggested that novel anti-CMV agents letermovir and brincidofovir may be effective at preventing CMV replication in stem cell transplant recipients.141,142
Immunizations with killed vaccines such as influenza are recommended. Live-attenuated vaccines, such as measles and zoster, should be avoided during immunosuppression.143
The high mortality rate of invasive fungal infections in neutropenic patients makes their prevention extremely important. Antifungal prophylaxis in these patients has been studied for more than 2 decades, yet there is still a great deal of controversy surrounding its efficacy.144 Studies on prevention of fungal infections in neutropenic patients are difficult to evaluate. Results of the various studies have been conflicting, partly because different definitions and outcomes were applied, different doses of antifungal agents were administered, and the numbers of study patients have often been small.
As with antibacterial prophylaxis, the clearest benefit of antifungal prophylaxis is seen in patients expected to have severe, prolonged neutropenia, particularly allogeneic transplant recipients. Antifungal prophylaxis is not indicated in patients who are undergoing chemotherapy with low levels of myelotoxicity.22 When deciding whether to treat prophylactically, drug toxicity must be taken into account. In addition, prophylactic use of antifungal agents may select for more resistant strains of fungus and lead to breakthrough infection with organisms inherently resistant to the agent used for prophylaxis. For example, certain prophylactic regimens active against Candida may actually increase the incidence of Aspergillus infections.145 The ability of antifungal agents to prevent systemic infection in high-risk patients has been shown in several studies, but their ability to reduce all-cause mortality has not been definitively established.146
Several azole drugs have been studied as prophylactic agents. A number of studies document a statistically significant reduction in superficial and invasive fungal infections when fluconazole is used prophylactically.147 However, breakthrough infection with Aspergillus, Candida glabrata, and Candida krusei have occurred with fluconazole prophylaxis.83 Itraconazole and voriconazole148 have a broader spectrum of activity, are more effective at preventing Aspergillus infection, and are generally well tolerated.149 Prophylaxis with posaconazole is associated with a reduced risk of Aspergillus infection, and a trend toward lower mortality.150
Echinocandins have become popular antifungal prophylactic agents. Caspofungin has been shown to be as effective as itraconazole in preventing Aspergillus and Candida infections.151 Micafungin was shown to be superior to fluconazole at preventing systemic fungal infections in hematopoietic stem cell transplant recipients.152 Anidulafungin, the newest echinocandin, remains to be studied as a prophylactic agent.
P. jiroveci pneumonia can be prevented with trimethoprim-sulfamethoxazole.153 Dapsone and atovaquone have each been used as a second-line prophylactic agent in hematopoietic stem cell transplant recipients, and in some cases may be preferred based on the risk of marrow suppression from trimethoprim-sulfamethoxazole.154,155 Although P. jiroveci is a ubiquitous organism, institutional variability in the incidence of infection is observed; therefore, the need for prophylaxis varies.