Chapter 24: Treatment of Infections in the Immunocompromised Host

Lisa Beutler; Jennifer Babik

INTRODUCTION

SUMMARY

Infection is a major cause of morbidity and mortality in patients with severe inherited or acquired neutropenia or aplastic anemia, qualitative disorders of neutrophils, and, notably, those persons receiving chemotherapy for treatment of hematologic neoplasms. Severe neutropenia and monocytopenia often result from the combined effects of replacement of marrow with malignant cells and superimposed intense chemotherapy. The severity and duration of the neutropenia determine the risk of infection. Bacterial infections may result in rapid clinical deterioration and even death. Fungal, viral, and parasitic infections also may result in potentially lethal complications during or after chemotherapy. This chapter considers methods of diagnosis of bacterial, fungal, viral, and protozoal infection and describes treatment regimens. Because prevention of infection during periods of neutropenia should reduce morbidity and improve outcome, attention is focused on prophylaxis against bacterial, parasitic, viral, and/or fungal infections.

RISK FACTORS AND INFECTING ORGANISMS

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SEVERITY OF NEUTROPENIA

Bacterial, fungal, viral, and parasitic organisms may cause infection in neutropenic patients.¹ Bacterial infections are the most frequent and usually the most serious. The risk for bacterial infection increases when the neutrophil count falls to less than 0.5 × 10⁹/L and becomes especially pronounced at neutrophil counts less than 0.1 × 10⁹/L.¹ The rate of decline and duration of neutropenia are important in determining the risk of bacterial infection. Disruption of mucosal barriers, especially in the oral cavity, esophagus, and bowel, further favors the development of infection by providing portals of entry.

Acronyms and Abbreviations:

CMV, cytomegalovirus; CT, computed tomography; ESBL, extended-spectrum β-lactamase; Ig, immunoglobulin; IVIG, intravenous immunoglobulin; LFT, liver function test; MRSA, methicillin-resistant Staphylococcus aureus; PCP, Pneumocystis jiroveci pneumonia; RSV, respiratory syncytial virus; VRE, vancomycin-resistant Enterococcus.

BACTERIAL PATHOGENS

Historically, Gram-negative bacilli have been the most commonly isolated pathogens. These organisms include Klebsiella, Escherichia coli, Pseudomonas, and Proteus. These bacteria are responsible for a variety of infections, including pneumonia, soft-tissue infections, perirectal infections, and bacteremia. Urinary tract infections are less frequent unless a urinary catheter is present or urinary tract obstruction has developed. Meningitis is uncommon.

At present, roughly half of all documented infections in neutropenic patients are caused by Gram-positive pathogens. This likely results from the popularity of semipermanent venous catheters and from the use of prophylactic regimens that are active against Gram-negative rods. Staphylococcal species and Enterococcus are now the pathogens most frequently isolated from neutropenic patients.² Several reports document the increasing frequency of viridans group streptococci as a major pathogen in neutropenic patients, especially in those receiving a hematopoietic stem cell transplant, perhaps because these patients have a higher incidence of mucositis.³ Among infections caused by both Gram-negative and Gram-positive organisms, antibiotic resistance is a growing problem and is discussed under “Bacterial Infections” below. Anaerobic infections are less common unless periodontal or gastrointestinal pathology coexists.

Patients with Hodgkin lymphoma, other lymphomas, or chronic lymphocytic leukemia primarily suffer from impaired cell-mediated immunity and diminished antibody production.⁴ Consequently, the spectrum of infections in these patients differs from that found in neutropenic patients. Bacterial infections, when they occur, tend to result from encapsulated organisms such as Pneumococcus or Haemophilus. Listeria and Nocardia infections also are seen more frequently in this group of patients.⁵

FUNGAL PATHOGENS

Fungal infections are common during periods of prolonged neutropenia and in patients with lymphomas or chronic lymphocytic leukemia who have impaired cell-mediated immunity. Candida species are most frequently isolated. Historically, Candida albicans had been the most common isolate; however, in recent years the number of non-albicans Candida infections has increased, partly as a consequence of widespread prophylaxis against C. albicans.⁶ The gastrointestinal tract serves as a reservoir for Candida, and erosive esophagitis may develop. Candida may also enter the bloodstream via indwelling catheters.

Aspergillus and fungi that cause mucormycosis also may cause invasive disease. The use of mold-active prophylaxis may be associated with an increased incidence of mucormycosis.⁷ These organisms tend to colonize and infect the sinuses and bronchopulmonary tree.

Infections with Cryptococcus, Aspergillus, Coccidioides, Histoplasma, and Candida are more common in patients with leukemia or lymphoma who require chronic glucocorticoid treatment. Coccidioides and Histoplasma are endemic mycoses. Coccidioides is endemic in the southwestern United States, in particular in Arizona and the San Joaquin Valley in California. Histoplasma is endemic in the Ohio and Mississippi River Valleys. Emerging fungal infections with organisms such as Scedosporium have become more common with increased use of mold-active prophylaxis.⁸

Pneumocystis jiroveci is a ubiquitous, endogenous fungus that may cause pneumonia in neutropenic patients and in those with defective cell-mediated immunity.

VIRAL PATHOGENS

Viral infections are especially frequent in patients with impaired cell-mediated immunity. Among viruses that cause infections in immunocompromised hosts, herpes simplex, varicella zoster, cytomegalovirus (CMV), and adenoviruses are the most important. Cutaneous lesions and mucositis often are caused by herpes simplex. Herpes zoster infections may be especially severe and have a propensity for dissemination. Left untreated, primary varicella infections are associated with a high mortality rate. CMV may cause febrile illnesses associated with pneumonia, hepatitis, and/or gastrointestinal tract ulcerations. Respiratory syncytial virus (RSV) and influenza virus are important pathogens causing respiratory illness in stem cell transplant recipients in the winter months.⁹ Virus-associated hemorrhagic cystitis caused by BK virus and adenovirus is common among hematopoietic stem cell transplant recipients.¹⁰

MYCOBACTERIAL PATHOGENS

The association between lymphoid malignancies and tuberculosis, particularly among patients born outside the United States, has been recognized for more than a century. It threatens to become a more frequent, serious problem with the resurgence of tuberculosis and the increased prevalence of drug-resistant strains.^11,12 Nontuberculous mycobacterial infections are common in HIV-positive patients, but are less common in patients receiving chemotherapy.¹³

RECOGNITION AND DIAGNOSIS OF INFECTION

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The development of an infection in a neutropenic patient may be accompanied by dramatic clinical manifestations or by none at all. Any fever that develops is very suggestive of infection. However, hypothermia, declining mental status, myalgia, or lethargy also may indicate infection in these patients. The usual local signs of infection, such as pus formation, may be absent or delayed because they are mediated by neutrophils.¹⁴

A careful physical examination should be performed when such a change in condition is observed. Special attention should be paid to the mouth and teeth for evidence of thrush, ulcerations, or periodontal disease. The skin should be examined in detail. Innocuous-appearing skin lesions may be septic emboli or evidence of disseminated fungal infection. Ordinarily trivial injuries inflicted by venipuncture or intravenous catheters may become infected and result in sepsis. An increased incidence of perianal and perirectal infection is observed in neutropenic patients.¹⁵ Examination of the rectum and perineum may provide a clue to the source of fever in patients without other clinical findings. Although such examinations should not be performed unnecessarily on an immunocompromised patient, rectal or pelvic examination should not be deferred when searching for a cause of fever.

Chest radiographic films should be obtained initially and may need to be repeated, although this practice has been questioned in patients without respiratory complaints.¹⁶ Chest computed tomography (CT) may reveal lesions not detected on routine radiograms.¹⁷ Additional imaging should be guided by clinical presentation.

Blood cultures should be collected prior to initiation of antibiotic therapy, and periodically thereafter if fever persists. If an indwelling venous catheter is present, a blood culture as well as cultures from each lumen of the catheter should be obtained for bacterial and fungal pathogens. Differential time to positivity of central and peripheral cultures may be helpful in diagnosing catheter-associated infections.¹⁸ Sending two or three cultures improves the likelihood of recovering fastidious organisms. If differential time to positivity cannot be performed, potentially infected intravenous lines should be cultured upon removal.

Other cultures should be obtained based on presenting symptoms and risk factors. Urine cultures should be sent in patients with an indwelling urinary catheter, those whose urinalysis is suspicious for infection, and those who have urinary symptoms. Sputum cultures may be helpful in patients with respiratory symptoms or findings on chest radiographs, but must be interpreted with caution, because the results may reflect the flora colonizing the oropharynx rather than the pathogens infecting the lung. Pulmonary fungal and viral infections, which may be difficult to document using conventional culture techniques, may be diagnosed by polymerase chain reaction and antigen detection sent from nasal washes or bronchoalveolar lavage samples.^19,20 Skin lesions of a suspicious nature should be biopsied and cultured. Stool should be cultured as well as examined for ova and parasites, and Clostridium difficile in patients with diarrhea. In some patients, testing for rotavirus, norovirus, and adenovirus also may be appropriate.

Patients with findings on chest CT that are consistent with pneumonia who do not respond to initial therapy and in whom initial microbiologic testing is negative may benefit from transbronchial biopsy or CT-guided biopsy of affected tissue.²¹

TREATMENT AND PREVENTION

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INITIAL TREATMENT

Bacterial Infections

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

Fungal Infections

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

Viral Infections

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

Mycobacterial Infections

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

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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

Cytovene

Marrow suppression

Valcyte

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

Ampho-B, amphotericin B; CHF, congestive heart failure; CMV, cytomegalovirus; HSV, herpes simplex virus; LFT, liver function test; SSRI, selective serotonin reuptake inhibitor; VRE, vancomycin-resistant Enterococcus; VZV, varicella-zoster virus.

*Ceftazidime has less activity than cefepime against methicillin-sensitive Staphylococcus aureus and viridans streptococci.

^†Levofloxacin has more reliable activity against viridans streptococci than ciprofloxacin.

^‡Echinocandins are commonly used in combination with amphotericin in the treatment of mucormycosis, but are not used as monotherapy.

ADJUSTING THERAPY

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.

DURATION OF THERAPY

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

OUTPATIENT THERAPY

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.

PREVENTION OF INFECTIONS

Bacterial Infections

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

Viral Infections

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

Fungal Infections

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.

INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION RECIPIENTS

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Patients receiving hematopoietic stem cell transplants are at risk for the same infections occurring in patients rendered neutropenic by chemotherapy. Graft-versus-host disease and the immunosuppressive agents used to treat it result in a particularly high incidence of infection in this group of patients. CMV and varicella zoster virus, are especially troublesome. Infection in stem cell transplant patients has been reviewed¹⁵⁶ and is discussed in Chap. 23.

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Chapter 24: Treatment of Infections in the Immunocompromised Host

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INTRODUCTION

RISK FACTORS AND INFECTING ORGANISMS

SEVERITY OF NEUTROPENIA

BACTERIAL PATHOGENS

FUNGAL PATHOGENS

VIRAL PATHOGENS

MYCOBACTERIAL PATHOGENS

RECOGNITION AND DIAGNOSIS OF INFECTION

TREATMENT AND PREVENTION

INITIAL TREATMENT

Bacterial Infections

Fungal Infections

Viral Infections

Mycobacterial Infections

ADJUSTING THERAPY

DURATION OF THERAPY

FEVER FOLLOWING RECOVERY FROM CHEMOTHERAPY

OUTPATIENT THERAPY

PREVENTION OF INFECTIONS

Bacterial Infections

Viral Infections

Fungal Infections

INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION RECIPIENTS

REFERENCES

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