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CHAPTER 68: Approach to Infection in Patients Receiving Cytotoxic Chemotherapy for Malignancy 609

to gram-negative bacilli carrying extended-spectrum β-lactamases
(ESBL) as well as genes conferring coresistance to other antibacterial
classes such as the tetracyclines, fluoroquinolones, and aminoglycosides
has led to recommendations for carbapenems as initial treatments in
environments where ESBL-producing gram-negative bacteria are preva-
lent. In environments where carbapenemase-producing gram-negative
21
bacterial infections are prevalent, choices are restricted to tigecycline,
153
or colistimethate (polymyxin E) with poor outcomes in neutropenic
154
cancer patients. 155
The clinical assessment may identify features favoring infection by
gram-positive organisms, warranting additional agents in the initial
156
empirical antibacterial regimen. These predictors include infection sites
such as skin and soft tissue or central venous access devices associated
with S aureus and coagulase-negative staphylococci; colonization by
MDR bacteria that warrant consideration of glycopeptides (eg, vanco-
mycin) for MRSA, oxazolodinones (eg, linezolid), or lipopeptides (eg,
FIGURE 68-4. Palmar/plantar desquamation occurring on day 9 of treatment in a patient daptomycin) for VRE. 21,153 Community-acquired pneumonia in a region
receiving high-dose cytarabine. with high-level macrolide-resistant Streptococcus pneumoniae may also
require combination initial therapy. 157
Several guidelines panels recommend that febrile neutropenic cancer
52
for complications due to neutropenia, infection, underlying cancer, and patients at high risk for medical complications be hospitalized for
other comorbid conditions. Based on comorbidities and complications, intravenous empirical antibacterial therapy with a single antipseudo-
patients could be classified into three groups at high risk for complica- monal agent (monotherapy). 21,118,129,158,159 While there are circumstances
tions and one low-risk group. Group I (39% of the total) comprised where combination regimens may have an advantage (vide supra and
hospitalized patients usually with hematologic malignancies or hemato- Table 68-4), published evidence does not support routine use of com-
160
poietic stem cell transplant. Complication and morbidity rates were 34% bination regimens containing aminoglycosides or glycopeptides in
161
and 23%, respectively. Group II (8% of the total) comprised outpatients high-risk patients. In contrast, guidelines recommend consideration
with concurrent comorbidity and had complication and mortality rates of orally administered combination initial empirical antibacterial ther-
of 55% and 14%, respectively. Group III (10% of the total) comprised apy (eg, ciprofloxacin and amoxicillin/clavulanate) for low-risk febrile
21
outpatients with as yet uncontrolled or progressive cancer and had neutropenic patients being considered for outpatient management.
complication and mortality rates of 31% and 15%, respectively. Group Tables 68-3 and 68-4 list the commonly used agents and the circum-
IV (the low-risk group, 43% of the total) comprised outpatients with stances where they may be considered.
controlled or responding cancer and no comorbid processes. This group Combination regimens include two β-lactam agents 26,162,163 , combined with
had a complication rate of 2% and no deaths. These observations were aminoglycosides 107-109,111,112,114,115 or combined with fluoroquinolones. 106,164,165
prospectively validated in follow-up studies. 137,138 These results suggest Single-agent regimens consist of β-lactam agents 113-115,117,166-169 with or
that high-risk patients with characteristics corresponding to groups I to without β-lactamase inhibitors (tazobactam, clavulanic acid, or sulbac-
III should be admitted and managed as inpatients with careful monitor- tam) or fluoroquinolones. 170-172 Monotherapy with aminoglycosides is
ing for serious complications, whereas low-risk patients (group IV) can not recommended. 120
be managed on an outpatient basis. 138-146 β-lactam antibacterial agents may be categorized as extended-
The Multinational Association for the Supportive Care in Cancer spectrum antipseudomonal penicillins (eg, carbenicillin, ticarcillin with
developed and validated a scoring system to identify patients at low or without clavulanic acid, piperacillin with or without tazobactam,
risk for serious medical complications that would require admission to azlocillin, or mezlocillin), third- or fourth-generation antipseudomonal
hospital. 52,53,147 Identifying factors included absence of symptoms; hypo- cephalosporins (eg, moxalactam, ceftriaxone, ceftazidime, cefoperazone
tension; airflow obstruction; hematological malignancy; invasive fungal with or without sulbactam, cefpirome, or cefepime), or as carbapen-
infection; or dehydration. Further, status as an outpatient at the onset of ems (eg, imipenem/cilastatin, meropenem, or ertapenem). The addi-
the febrile neutropenic episode and age <60 years were also identify- tion of β-lactamase inhibitors enhances spectrum of activity against
ing factors. This system has been offered as a strategy for identifying β-lactamase-producing bacteria. 112,116,173-191
patients eligible for studies of more cost-effective, safe, outpatient-based In a review of prescribing behavior for 214 febrile neutropenic
management strategies. 148 patients in Canadian centers, single-agent initial empirical therapy was
■ EMPIRICAL ANTIMICROBIAL THERAPY carbapenem—2.3%, fluoroquinolone—0.9%). Combination therapy
administered in 42% of cases (third-generation cephalosporin—32%,
192
The empirical initial therapy for suspected infection in febrile neutrope- was administered in 58% of cases (antipseudomonal penicillin plus
aminoglycoside—29%, antipseudomonal cephalosporin plus aminogly-
nic patients is based on three assumptions. coside—15%, antipseudomonal β-lactam plus glycopeptide—11%).
192
1. The majority of infections are due to bacteria. 149 Vancomycin was part of the initial empirical antibacterial therapy in
2. The principal pathogens are aerobic gram-negative bacilli (E coli, 15% of cases. First modification with second-line therapy for persistent
K pneumoniae, and P aeruginosa) 107,149 , the predominance of gram- fever was administered in 87% of the cases after a median of 5 days.
Empiric amphotericin B was administered for persistent fever in 48%
positive organisms in blood cultures 102,106 notwithstanding. of cases after a median of 9 days. Previous studies have demonstrated
3. Inappropriate therapy for aerobic gram-negative bacteremia may be that glycopeptides are used as empirical second-line therapy in 40% to
associated with a high mortality and a median survival of less than 50% of cases after first-line empiric therapy with extended spectrum
150
72 hours. 151 cephalosporins. 113,116,174-177,193-204
Accordingly, empirical first-line therapy regimens are chosen for The Role of Aminoglycosides: Aminoglycosides have been part of the
their activity against these pathogens. The rising prevalence of multi- standard combination empirical antibacterial therapy for the manage-
drug resistant (MDR) bacteria has required a more critical approach ment of febrile neutropenic patients from the early 1970s to the 1990s.
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to the choice of initial empirical agents. The increase in infections due The combination of an aminoglycoside with an antipseudomonal

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