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612 PART 5: Infectious Disorders

These investigators also observed a very high prevalence of FREC in superiority of imipenem/cilastatin over control arms largely based on
the stools of pigs and poultry and argued that the increased prevalence third-generation cephalosporins.
of human carriage of FREC may be linked to the high prevalence in Another meta-analysis comparing carbapenem monotherapy to
animal-based food products. The increased use of fluoroquinolones in β-lactam plus aminoglycoside combination therapy demonstrated fewer
animal feeds and in humans is believed to play a role in the selection treatment failures among with carbapenems in contrast to antipseudo-
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for FREC. In an environment with a high prevalence of gram-negative monal cephalosporin monotherapy. A similar analysis of the published
fluoroquinolone resistance, patients receiving ciprofloxacin chemo- clinical trials of meropenem monotherapy compared to ceftazidime-
prophylaxis while undergoing high-dose chemotherapy with stem cell based regimens with or without an aminoglycoside demonstrated greater
rescue became colonized with FREC in one-third of cases, increasing response rates among meropenem recipients. Such observations
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the likelihood of FREC bloodstream infections. 234 suggest the inferiority of third-generation cephalosporin monotherapy
Inappropriate use of fluoroquinolones is common. A case:control regimens compared to carbapenem monotherapy.
study of fluoroquinolone use in emergency departments demonstrated
inappropriate prescription of these agents in 81% of cases. Lastly, Piperacillin/Tazobactam for the Treatment of Febrile Neutropenic Patients:
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coresistance gram-negative bacilli to fluoroquinolones and other anti- Piperacillin/tazobactam plus amikacin therapy was successful in 61%
bacterials is being reported more frequently. 232,236 Inappropriate use of of febrile neutropenic patients studied by the European Organisation
fluoroquinolones in the community is strongly linked to resistance and for the Research and Treatment of Cancer compared to 54% of patients
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reduces the likelihood that this class of agents will be useful. 225,227 receiving ceftazidime plus amikacin (p = 0.05). Furthermore, the
time to defervescence was shorter among piperacillin/tazobactam
Double β-lactam Combinations: Regimens consisting of an antipseu- recipients (p = 0.01) and the frequency with which the initial regi-
domonal broad-spectrum β-lactam plus an extended spectrum third- men was modified by the addition of a glycopeptide was lower (24%
generation cephalosporin are safe and effective alternatives to β-lactam vs 35%; p = 0.002). Another large Italian trial examined the role of
plus aminoglycoside regimens 26,163,237 ; however, they are costly and do the aminoglycoside, amikacin, when combined with piperacillin/
not offer any advantages over broad-spectrum β-lactam/β-lactamase tazobactam. 116 The response rates overall between the two groups
inhibitor monotherapies. These regimens may have an occasional role were similar regardless of the classification of the febrile neutropenic
with preexisting renal insufficiency, where the patient is receiving con- episode as bacteremic, clinically documented, or unexplained fever.
comitant nephrotoxic agents (eg, cyclosporine or cis-platin) or where Clearly, aminoglycosides offered no advantage over piperacillin/
gram-positive organisms such as viridans streptococci are suspected. 26,93 tazobactam monotherapy. Piperacillin/tazobactam monotherapy has
The availability of effective β-lactam–fluoroquinolone or β-lactam been studied compared to extended spectrum cephalosporins with
monotherapy-based strategies has largely rendered double β-lactam or without aminoglycosides. 173-177 Overall unmodified success rates
regimens obsolete. 21 were significantly higher among piperacillin/tazobactam recipients.
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Extended-Spectrum Cephalosporins: The intrinsic activity of many Further, the frequency of second-line glycopeptide therapy was lower
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of the third- and fourth-generation cephalosporins against aero- with piperacillin/tazobactam. These observations demonstrate
bic gram-negative bacilli is high. These agents have been used the superiority of initial piperacillin/tazobactam monotherapy over
effectively as single agents for empirical treatment of suspected extended spectrum cephalosporins with or without aminoglycosides.
infection. 107-115,169,238 Empirical monotherapy has been shown to be Further, the need to modify the initial antibacterial regimen by the
effective in both low- and high-risk febrile neutropenic patient popu- addition of a glycopeptide (eg, vancomycin) for persistent fever is
lations and in those whose expected duration of severe neutropenia also significantly less than for the cephalosporin-based comparator
(ANC <0.5 × 10 /L) is either longer or shorter than 7 days. Experience groups. This has important implications with respect to cost, drug-
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suggests that single-agent empirical regimens require modification in related toxicities, and for selection of resistant microorganisms
one-third to one-half of patients with neutropenic periods in excess (eg, vancomycin-resistant Enterococcus).
of 1 week. 111,113-115 There is a lower likelihood that modifications will The Role of Glycopeptides in Febrile Neutropenic Patients: For more than
be necessary with short-term (<1 week) neutropenia. a decade, gram-positive bacteria have dominated as pathogens in
A meta-analysis examining the efficacy of ceftazidime monotherapy
compared to standard combination therapy for the empirical treat- microbiologically documented infections observed in neutropenic
patients. Two decades ago approximately 70% of bacteremic isolates
ment of febrile neutropenic patients failed to demonstrate a difference were gram-negative bacilli, whereas more recently approximately 60%
in the odds of overall treatment failure and failure in bloodstream to 70% are gram-positive cocci. 102,106,156 Almost 30 years ago, a ceftazi-
infections. Another meta-analysis compared the efficacy of cef- dime-based empirical trial observed more fatal gram-positive super-
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238
triaxone with (7 trials) or without (1 trial) an aminoglycoside and infections than expected. Subsequently, a small study demonstrated
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ceftazidime with (6 trials) or without (1 trial) an aminoglycoside or that the addition of vancomycin to ceftazidime therapy reduced the
azlocillin plus an aminoglycoside (1 trial). There were no differences in superinfection rate from 24% to zero, and the infection-related mor-
any outcomes, including mortality, noted in these comparative analy- tality rate by 91%. Such observations have led investigators to advo-
241
ses. These analyses demonstrate that empirical antibacterial therapy of cate the inclusion of glycopeptides as part of the first-line empirical
febrile neutropenic patients with once-daily ceftriaxone is as effective as antibacterial therapy in febrile neutropenic patients.
thrice daily ceftazidime. This has important implications for potential In contrast, two studies from the National Cancer Institute suggested
outpatient once-daily intravenous therapy.
that the vancomycin therapy may be safely delayed without increased
Carbapenems for Treatment of Febrile Neutropenic Patients: Both imipe- morbidity or mortality. 114,242 In order to examine this question further,
nem/cilastatin and meropenem have been studied widely as empirical the European Organization for Treatment and Research in Cancer
therapy in febrile neutropenic patients. A meta-analysis examined and the National Cancer Institute of Canada Clinical Trials Group
the efficacy of imipenem/cilastatin compared to a β-lactam plus ami- conducted a large randomized trial comparing empirical therapy with
noglycoside (11 trials) and to β-lactam monotherapy (ceftazidime, ceftazidime plus amikacin (CA) and ceftazidime plus amikacin plus
4 trials; cefoperazone/sulbactam, 1 trial) or β-lactam plus glycopep- vancomycin (CAV). The overall response rate was 76% among CAV
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tide (ceftazidime, 3 trials) or double-β-lactam therapy (cefoperazone/ recipients versus 63% among CA recipients (p < 0.001), the difference
mezlocillin, 1 trial; cefoperazone/piperacillin, 1 trial). There were largely due to differential response rates for gram-positive bloodstream
fewer treatment failures among imipenem/cilastatin recipients com- infections among CAV recipients. Despite the apparent superiority of
pared to β-lactam plus aminoglycoside combinations or to non- the CAV arm, persistently febrile CA patients at day +3 received van-
aminoglycoside-containing regimens. These analyses support the comycin resulting in no differences in overall success rates or mortality.
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