Prophylaxis of Infection in Cancer Patients

Description of the Problem

Malignancies and their treatments can result in immune defects which predispose patients to infections.

Hematologic malignancies such as multiple myeloma and chronic lymphocytic leukemia can cause defects in humoral and cellular immunity,
Acute leukemia causes mostly neutropenia but also may cause lymphocyte defects.
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Solid tumors can infiltrate and replace the bone marrow causing neutropenia.
More often, though, the treatment of malignancy by steroids, monoclonal antibodies, conventional chemotherapy, radiation therapy, and surgery can predispose the patient to infection.

Prevention of infection in the setting of predisposing therapy has therefore become an important part of effective cancer treatment. Some controversy exists as to the benefits versus the risks of infection prophylaxis in certain situations, such as the neutropenic patient with leukemia. We will not address the specific issues of bone marrow/stem cell/cord blood transplantation in this article.

Susceptibility to Infection in Non-neutropenic Patients with Malignancies

The most common problem predisposing to infection in patients with cancer is neutropenia. However, susceptibility to infection and indications for prophylaxis exist in non-neutropenic settings as well:

multiple myeloma, chronic lymphocytic leukemia: encapsulated bacteria
acute lymphocytic leukemia with steroid-based chemotherapeutic regimens: Pneumocystis jirovecii
steroid therapy for three weeks or more at doses greater than or equal to 15 mg/day (prednisone equivalent): Pneumocystis jirovecii
monoclonal antibody therapy with bortezomib: herpesviruses
monoclonal antibody therapy with alemtuzumab: Pneumocystis jirovecii, herpesviruses, invasive fungal infection
purine analogue therapy: Pneumocystis jirovecii, herpesviruses
temozolamide therapy (e.g. in patients with glioblastoma multiforme): Pneumocystis jirovecii
splenectomy: encapsulated bacteria

Susceptibility to Infection in Cancer Patients with Neutropenia

Infections associated with neutropenia have traditionally been most commonly caused by enteric gram-negative bacilli.

Since antibiotic prophylaxis for these organisms has become more widely used, gram-positive enteric bacteria have assumed greater importance.
About 20% of patients with <500 neutrophils will develop bacteremia.
The mortality rate from infection in neutropenic patients is estimated between 5-10%, and deaths usually are a result of infection with enteric gram negative bacilli.
Attempts at prevention of infection in neutropenic cancer patients have included

selective gut decontamination

trimethoprim-sulfamethoxasole preventive therapy,

most recently fluoroquinolone preventive therapy.

Studies of fluoroquinolone prophylaxis in neutropenic cancer patients have compared the incidence of infectious complications such as fever, bacteremia, and mortality but it has been difficult to assess the role of prophylaxis in the development of infections by resistant bacteria.

Numerous small studies of fluoroquinolone prophylaxis in neutropenic patients were performed in the late 1980’s and 1990’s, and conflicting data was obtained.

These have been reexamined by metaanalyses, and in 2005 two prospective, blinded, randomized studies were performed in an effort to clarify the potential benefits of prophylaxis.

Metaanalyses of Studies Examining Fluoroquinolone Prophylaxis

Cruciani et al., 1996: 13 randomized controlled trials performed between 1984 and 1994 comprising 1155 patients comparing a fluoroquinolone (not levaquin) to placebo or other antibiotics in neutropenic patients with AML, CML in blast phase, lymphomas, and solid tumors.

This metaanalysis demonstrated that fluoroquinolone prophylaxis reduced the incidence of gram negative rod bacteremia but not gram positive bacteremia or infection-related mortality.
In the same publication, another metaanalysis of 6 randomized controlled trials with 957 patients demonstrated that fluoroquinolone prophylaxis (not levaquin) plus a gram positive-active agent reduced the incidence of gram positive bacteremia versus fluoroquinolone or a non-absorbable antibiotic alone.

Engels et al., 1998: 18 randomized controlled trials performed from 1966 to 1996 in 1408 neutropenic cancer patients comparing a quinolone (not levaquin) for prophylaxis to no antibiotic prophylaxis (9 trials) or trimethoprim-sulfamethoxasole prophylaxis (9 trials). Studies included patients with hematologic malignancies, bone marrow transplants, and solid tumors. This metaanalysis demonstrated

quinolone prophylaxis significantly reduced gram-negative rod bacteremia, microbiologically documented infection, total infection, and to a lesser extent, fever,
No effect on clinically documented infection, gram-positive bacteremia, or infection-related mortality.

Gafter-Gvili et al., 2005: patients with hematologic malignancies and solid tumors, some undergoing bone marrow transplant, from 95 randomized controlled studies performed between 1973 and 2004 comparing antibiotic prophylaxis (52 trials using a quinolone but not levaquin) to placebo, nothing, or another antibiotic. This metaanalysis concluded that

prophylaxis reduced the incidence of fever, infection-related mortality, and bacteremia.
the effects were larger in trials of poorer quality
the prophylaxis benefit was not as great in trials of higher quality.

Large Randomized, Placebo-Controlled, Double-Blind Trials of Levaquin for Prophylaxis of Bacterial Infection in Neutropenic Cancer Patients

Cullen et al. (2005) published a randomized, double-blind, placebo-controlled trial comparing levoquin to placebo in 1565 patients with solid tumors or lymphomas who have received chemotherapy. This outpatient trial did not include G-CSF support and included up to six cycles of chemotherapy. The patients received seven days of trial medication, beginning just before the development of neutropenia.

Significant reduction in incidence of fever, probable infections, and hospitalizations for infection occurred during the first cycle of chemotherapy for the levaquin-treated group compared to the placebo-treated group.
No differences in mortality or severe infections were seen, few deaths occurred during the study.
Emergence of resistant organisms was not assessed in this study.

Bucaneve et al. (2005) compared levaquin to placebo in a randomized, double-blind, placebo-controlled trial in 675 assessable patients with acute leukemia, solid tumor, or lymphoma (mostly auto-transplant patients in the latter two groups). The patients received trial medication throughout the period of neutrophils<1000 in patients who received chemotherapy and were expected to be neutropenic at least seven days.

The incidence of fever, gram-negative bacteremia, polymicrobial bacteremia, and microbiologically documented infection were significantly lower in the levaquin group,
In subgroup analysis remained lower whether the patients had leukemia or not.
No difference in overall mortality
No difference in infection-related mortality, between the levaquin and placebo groups.
41/47 single bacteria causing bacteremia in the levaquin-treated group were resistant to levaquin, compared to 32/68 in the placebo-treated group.

Is There a Greater Risk of Development of Resistant Infection in Patients Treated with Bacterial Prophylaxis?

Given the problem of bacteria resistant to commonly used antibiotics, and the ever-increasing problem of hospital-related infections with resistant bacteria, it is reasonable to be concerned that infections which do develop in neutropenic patients who receive antibiotic prophylaxis may well be resistant to our usual antibiotic armamentarium and therefore more difficult to treat. The recent appearance of multidrug resistant Enterobacteriaceae, including resistance to carbapenems, is especially frightening. Several studies have suggested an increase in levaquin-resistant bacteria when levaquin is used as prophylaxis, including MRSA, VRE, and MDR E. coli and P. aeruginosa. As MDR Enterobacteriaceae become more common, analyses of large numbers of patients for colonization with and infection by these resistant gram negative bacilli will need to be done.

Prophylaxis of Fungal and Viral Infections in Neutropenic Patients with Acute Leukemia

N/A

Recommendations for Prophylaxis

Non-neutropenic patients:

multiple myeloma, chronic lymphocytic leukemia: intravenous gamma globulin is commonly used but no formal recommendation
acute lymphocytic leukemia: P. jirovecii prohylaxis (trimethoprim-sulfamethoxasole, dapsone, or atovaquone) is recommended
steroid therapy for more than three weeks with daily doses at least 15 mg prednisone: P. jirovecii prohylaxis is recommended
monoclonal antibody therapy with bortezomib: acyclovir or equivalent prophylaxis is recommended
monoclonal antibody therapy with alemtuzumab: P. jirovecii prophylaxis, acyclovir or equivalent prophylaxis, and fluconazole prophylaxis is recommended
purine analogue therapy: P. jirovecii prohylaxis and acyclovir or equivalent prophuylaxis is recommended
temozolamide therapy: P. jirovecii prophylaxis is recommended
splenectomy: pre-splenectomy vaccination if possible against S. pneumoniae, H. influenzae type b, and N. meningitidis

Neutropenic patients with lymphomas or solid tumors, typically outpatients:

levaquin 500 mg orally each day during the period of chemotherapy-induced neutropenia (relatively short, as G-CSF is used in most of these patients)
reasonable to use for all cycles of chemotherapy-induced neutropenia, but especially the first cycle

Neutropenic patients with acute leukemia, inpatient setting after induction or re-induction chemotherapy:

our practice is not to use antibacterial prophylaxis given the lack of improvement in mortality in all studies and the theoretical risk of increasing the incidence of antibiotic-resistant, hospital-acquired infection in the inpatient setting
some centers use levaquin 500 mg orally each day during the period of neutropenia
posaconazole antifungal prophylaxis 200 mg po tid
acyclovir (or equivalent) antiviral prophylaxis in patients with a prior history of herpes simplex or herpes zoster clinical infection

Neutropenic patients with acute leukemia, outpatient setting after consolidation chemotherapy or persistently neutropenic:

there is no specific evidence to support a specific practice in this group
our practice is to use levaquin 500 mg orally each day during the period of neutropenia, in the hope of preventing hospitalizations, with less (but not none) concern about drug-resistant infections in the outpatient setting
in persistently neutropenic patients, diflucan antifungal prophylaxis 400 mg orally each day
in persistently neutropenic patients acyclovir (or equivalent) antiviral prophylaxis

What's the Evidence?

Bucaneve, G, Micozzi, A, Menichetti, F. “Levofloxacin to prevent bacterial Infection in patients with cancer and neutropenia”. N Engl J Med. vol. 353. 2005. pp. 977(randomized, double-blind, placebo-controlled trial of levofloxacin vs.placebo in patients with acute leukemia, solid tumor, or lymphoma showing fewer bacterial infections in the levofloxacin group but no difference in mortality)

Cornely, OA, Maertens, J, Winston, DJ. “Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia”. N Engl J Med. vol. 356. 2007. pp. 348(randomized controlled trial showing the efficacy of posaconazole in patients at high risk for invasive fungal infections)

Cruciani, M, Rampazzo, R, Malena, M. “Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: ameta-Analysis”. Clin Infec Dis. vol. 23. 1996. pp. 795(Older metaanalysis of studies from 1984-1994 showing that fluoroquinolone prophylaxis reduced the incidence of gram negative rod bacteremia but not gram positive bacteremia or infection-related mortality).

Cullen, M, Steven, N, Billingham, L. “Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas”. N Engl J Med. vol. 353. 2005. pp. 988(randomized, double-blind, placebo-controlled trial comparing levoquin to placebo in 1565 patients with solid tumors or lymphomas showing a decrease in fever and probable bacterial infections but no difference in mortality between the two groups).

Engels, EA, Lau, J, Barza, M. “Efficacy of Quinolone Prophylais in Neutropenic Cancer Patients: A Meta-Analysis”. J Clin Oncol. vol. 16. 1998. pp. 1179(Another older metaanalysis of prophylaxis studies before 1996 showing quinolone prophylaxis significantly reduced gram-negative rod bacteremia and microbiologically documented infection, but had no effect on clinically documented infection, gram-positive bacteremia, or infection-related mortality).

Freifeld, AG, Bow, EJ, Sepkowitz, KA. “Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America”. Clin Infec Dis. vol. 52. 2011. pp. e56(most recent guidelines from the IDSA regarding management of neutropenic patients)

Gafter-Gvili, A, Fraser, A, Paul, M, Leibovici, L. “Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients”. Ann Intern Med. vol. 142. 2005. pp. 979(reviewed 95 randomized controlled studies from 1973-2004 showing that prophylaxis reduced the incidence of fever, infection-related mortality, and bacteremia, but also that many trials were not of high quality)

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