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CHAPTER 68: Approach to Infection in Patients Receiving Cytotoxic Chemotherapy for Malignancy 613

Treatment failures were due to lack of prompt response and to persistent fever reduction was observed in one trial, and no analysis was pro-
fever very early after the initiation of the allocated regimen rather than vided in one other. The studies included in this analysis were flawed
objective indicators of failure (eg, persistence of resistant pathogens or by the failure to control for important variables including the dura-
progression at foci of infection). Patients receiving CA were more likely tion and intensity of neutropenia, type of cytotoxic therapy, and type
to receive vancomycin with persistence of fever at day +3 than recipi- of malignancy. On the basis of this review, Berghmans and colleagues
ents of the CAV regimen. Since the median time to defervescence could not recommend routine use of HGF in the treatment of febrile
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among high-risk febrile neutropenic patients is day 5 106,112,113,115,204 many neutropenic episodes. 254
were considered failures unnecessarily because of regimen modifica- American Society of Clinical Oncology guidelines do not recommend
tion before they would have had a chance to defervesce. Compulsion to HGF use as in neutropenic fever with suspected infection. 255,256 However,
modify the initial antibacterial regimen for persistent fever at day +3 is most do not follow these guidelines, as usage seems to be influenced
driven, in part, by previously published protocols reinforced by previ- more by reimbursement than evidence. 257-259,260
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ously published guidelines. 120,136 HGF have been evaluated in other nonneutropenic patient populations
Three other trials 244-246 examining the role of initial glycopeptide including community-acquired pneumonia, human immunodeficiency
therapy in febrile neutropenic cancer patients came to similar conclu- virus infection, neonatal sepsis, diabetic foot ulcer infections, acute
sions as the EORTC/NCIC trial ; that is, the inclusion of glycopeptides hepatic failure or cirrhosis, orthotopic liver transplantation, and critical
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as initial therapy results in modest improvements in response rates, care. While there appears to some promising results in some subgroups
particularly with gram-positive bacteremia, but has no impact on over- of patients, HGF have no proven benefit in nonneutropenic critically ill
all survival of the neutropenic episode. Second-line glycopeptide-based patients with regard to morbidity or mortality. 261
empirical antibacterial therapy for persistent fever has become quite
common. As noted above, almost half of cases enrolled in clinical tri- Considerations in the Assessment of Initial Empirical Antibacterial Therapy-
related Treatment Effects: Response to the initial empirical antibacterial
als have a glycopeptide administered for these reasons. 113,116,174-177,193-204 regimen has been defined by defervescence of neutropenic fever, and
The efficacy of empiric second-line glycopeptide therapy has been resolution of the associated signs and symptoms of infection. In unex-
studied in two randomized controlled trials. 178,247 Both studies failed to plained neutropenic fever, defervescence may be the only objective sign
demonstrate a significant treatment effect with regard to defervescence by which to gauge response. In clinical trials of empirical antibacterial
or overall mortality compared to placebo. Three systematic reviews therapy of high-risk febrile neutropenic patients, defervescence fol-
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with meta-analyses of this subject have concluded independently that lowed by the maintenance of an apyrexial state for 4 to 5 consecutive
glycopeptides should not be used routinely for the initial empirical days has been used as a common definition of response. Defervescence
regimen. 161,248,249 These observations have led to recommendations by plus resolution of baseline clinical foci of infection have been the major
the American, German, and Spanish guideline panels that glycopeptides criteria for response in clinically documented infections. Defervescence,
not be used as part of the initial empirical regimen for neutropenic fever resolution of the baseline signs and symptoms associated with the focus
unless there is evidence of gram-positive infection. 21,65,118,207,250 of infection, and eradication of the pathogen have been the criteria that
The use of glycopeptides as part of the initial first-line regimen define response for microbiologically documented infections.
should be reserved for patients at highest risk for serious gram-positive Treatment success, defined as above, and without modification of the
infection. 21,65,224 Such circumstances include clinical catheter-related infec- initial empirical antibacterial regimen, has been reported in systematic
tion, infection in patients receiving fluoroquinolone-based antibacterial reviews to be of the order of 60%. Another recent meta-analysis
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chemoprophylaxis associated with severe mucositis predisposing patients was able to demonstrate lower all-cause mortality rates among febrile
to viridans group Streptococcal bloodstream infections, 97,98,251 infection neutropenic patients receiving piperacillin/tazobactam as compared to
in the setting of colonization by methicillin-resistant Staphylococcus other agents. In that same review, carbapenems were associated with
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aureus (MRSA), bloodstream isolate characterized as gram-positive cocci similar all-cause mortality rates as other antibacterial regimens; lower
in groups and clusters (suggesting Staphylococcus spp and the likelihood failure rates and lower rates of antibacterial regimen modifications were
of a methicillin-resistant coagulase-negative Staphylococcus), and the set- observed for the carbapenems. Of note, carbapenems have been associ-
ting of septic shock without an identified pathogen. The caveat is that the ated with a higher risk for Clostridium difficile–associated diarrhea. 262
glycopeptide antibiotic should be discontinued in 2 to 3 days if a resistant The correctness of the initial empirical choice of antibacterial regimen
gram-positive infection has not been identified. has an important impact upon outcome in sepsis. Some environments
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The Role of Hematopoietic Growth Factors in the Management of Febrile with a high prevalence of multidrug-resistant (MDR) bacteria con-
Neutropenic Patients: The inclusion of hematopoietic growth fac- found the clinician’s initial empirical choice. In circumstances where
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tors (HGF), granulocyte (G-CSF), and granulocyte-macrophage the neutropenic fever is due to a bacterium resistant to the empirical
(GM-CSF) colony-stimulating factors in strategies for the prevention β-lactam, the rates of clinical success have been significantly lower, at
and management of febrile neutropenic patients remains unsettled. less than 10% and with higher all-cause mortality rates of approximately
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In an older retrospective study in which 30 unstable febrile neutrope- 25%. Carbapenems offer broad-spectrum activity against ESBL-
264
nic patients given HGF upon admission to the ICU were compared to producing gram-negative bacilli and may have an advantage where such
30 similar patients not given HGF, there were no detectable treatment organisms are prevalent. 265
effects upon the duration of neutropenia, the length of ICU stay, or There are several patterns by which failure of the initial empirical
overall survival. Berghmans and colleagues published a meta- antibacterial therapy to resolve the neutropenic fever is recognized. The
253
analysis to critically examine the evidence for use of these products International Antimicrobial Therapy Cooperative Group of the EORTC
in the treatment of febrile neutropenia. Eleven studies encompass- defines failure in several ways including death due to the primary
254
ing 1218 febrile neutropenic episodes published between 1990 and infection; persistence of bacteremia beyond the first 24 hours of therapy;
1998 were considered. Although six trials reported treatment effects breakthrough bacteremic infection while receiving the initial regimen;
for mortality, overall there was no effect on mortality. Further, there resistance to the initial β-lactam agent independent of the patient’s
were no differences when analysis was conducted by G-CSF ver- condition; failure to defervesce after the first 72 hours of initial therapy;
sus GM-CSF. The impact of HGF on length of hospitalization was modification of the initial empirical regimen within the first 72 hours
decreased in four trials, unaffected in four trials, and not reported in for reasons of shock, multiorgan damage, ARDS, or progression of the
three trials. Only three of six trials reporting on the impact of HGF primary infection. Based on these clinical trial-based definitions of
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on duration of antibacterial therapy demonstrated a reduction in this failure, a number of syndromes may be recognized.
outcome. In nine trials wherein the impact of HGF on the duration of First, patients may experience a persistence of the initial neutropenic
fever was reported, no treatment effects were observed in seven trials, fever (PNF). This occurs in 20% of cases.
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