Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients



Fever occurring in a neutropenic patient remains a common life‐threatening complication of cancer chemotherapy. The common practice is to admit the patient to hospital and treat him or her empirically with intravenous broad‐spectrum antibiotics. Oral therapy could be an alternative approach for selected patients.


To compare the efficacy of oral antibiotics versus intravenous (IV) antibiotic therapy in febrile neutropenic cancer patients.

Search methods

The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1) in The Cochrane Library, MEDLINE (1966 to January week 4, 2013), EMBASE (1980 to 2013 week 4) and LILACS (1982 to 2007). We searched several databases for ongoing trials. We checked the conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) (1995 to 2007), and all references of included studies and major reviews were scanned.

Selection criteria

Randomised controlled trials (RCTs) comparing oral antibiotic(s) to intravenous antibiotic(s) for the treatment of neutropenic cancer patients with fever. The comparison between the two could be started initially (initial oral) or following an initial course of intravenous antibiotic treatment (sequential).

Data collection and analysis

Two review authors independently assessed trial eligibility and methodological quality and extracted data. Data concerning mortality, treatment failures and adverse events were extracted from the included studies assuming an 'intention‐to‐treat' basis for the outcome measures whenever possible. Risk ratios (RR) with 95% confidence intervals (CI) were estimated for dichotomous data. Risk of bias assessment was also made in line with methodology of The Cochrane Collaboration.

Main results

Twenty‐two trials (3142 episodes in 2372 patients) were included in the analyses. The mortality rate was similar when comparing oral to intravenous antibiotic treatment (RR 0.95, 95% CI 0.54 to 1.68, 9 trials, 1392 patients, median mortality 0, range 0% to 8.8%). Treatment failure rates were also similar (RR 0.96, 95% CI 0.86 to 1.06, all trials). No significant heterogeneity was shown for all comparisons but adverse events. The effect was stable in a wide range of patients. Quinolones alone or combined with another antibiotic were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics.

Authors' conclusions

Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, and do not have pneumonia, infection of a central line or a severe soft‐tissue infection. The wide CI for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.


Liat Vidal, Itsik Ben dor, Mical Paul, Noa Eliakim‐Raz, Ellisheva Pokroy, Karla Soares‐Weiser, Leonard Leibovici


Plain language summary

Oral antibiotics for treating febrile neutropenia in cancer patients at low risk for complications

Neutropenia (low white blood cell count) is a complication of cancer chemotherapy that exposes patients to life‐threatening infections. Current practice for neutropenic patients with fever is hospital admission and treatment with intravenous antibiotics. Febrile neutropenia encompasses a spectrum of disease severity and low risk patients may be treated less aggressively. This review of randomised controlled trials showed comparable death and failure rates for oral and intravenous antibiotics for low risk patients, those with solid tumours or chronic leukaemia or lymphoma, and independent of age, source of infection and severity of the neutropenia.


Liat Vidal, Itsik Ben dor, Mical Paul, Noa Eliakim‐Raz, Ellisheva Pokroy, Karla Soares‐Weiser, Leonard Leibovici

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Oral antibiotic therapy can be safely offered to febrile children and adults with neutropenia who are haemodynamically stable, have no organ failure, can take oral medications, do not have pneumonia, infection of a central line or a severe soft‐tissue infection, and do not suffer from acute leukaemia. These criteria stand in close proximity to those of the IDSA guidelines for the treatment of neutropenic patients (Hughes 2002). Selection of candidates for oral therapy can also be based on the MASCC scoring system (Klastersky 2000).

The analysis offered no data in support of a specific oral regimen, but in light of the preponderance of Gram‐positive infections (EORTC 1990; Hughes 2002; Kamana 2005) the combination of a quinolone and a second drug active against Gram‐positive bacteria (for example ampicilin‐clavulanate) seems prudent.

This review did not refer to the issue of home therapy. It could be assumed that home therapy can be offered to a similar population as that approved for oral treatment. In some of the included studies oral therapy was given on an ambulatory basis. The view is that patients can be treated in hospital or under close supervision on an ambulatory basis.

Implications for research 

A future trial of oral versus intravenous antibiotic treatment should include febrile neutropenic patients with mild and stable sepsis, regardless of their underlying disorder, source of infection or neutrophil count. Its sample size should be based on considerations of equivalence (Jones 1996). The definitions of response and failure and the reported outcomes should be based on the guidelines on methodology for clinical trials involving patients with fever and neutropenia (Feld 1998; Feld 2000; Feld 2002).

For low risk patients (as defined by MASCC or the above criteria) different oral regimens should be compared. Using mortality as the primary outcome in such a trial might translate into a prohibitive sample size. However, the sample size of a trial needed to further reduce the CI shown in the present analysis might be smaller and manageable.

In addition, a randomised controlled trial comparing different oral antibiotic regimens in low risk patients with fever and neutropenia, and in particular fourth generation quinolones with activity against Gram‐positive bacteria and anaerobes versus a previous generation quinolone plus ampicilin‐clavulanate, is warranted.

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