Neutropenic Fever – I Need The Vancz

Neutropenic fever, defined as a single temperature 38.3C (101F) OR 38.0C (100.4F) for one hour in patients whose granulocyte count are <500 cells OR <1000 cells with an expected decline to <500 over the next 48 hours. This is actually a fairly frequent occurrence in those who undergo intensive chemotherapy, especially in hematological malignancies, which tends to require inpatient admission in certain cases. Guidelines suggest the empiric use of an anti-pseudomonal antibiotics with certain risk factors leading to empiric use of anti-MRSA antibiotics. My experience has been that we never isolate an organism in these folks and this got me to think, are gram negatives really the cause of the majority of neutropenic fever? Makes sense, in my head, most neutropenic fevers come from gut translocation after the cytotoxic effects of chemo causes breakdown of mucosal surfaces.

The data seems to back this up. One cohort of 48 neutropenic patients recorded 111 infections, of which 40 had a documented bacteremia (2). Gram negatives tended to be the most commonly isolated organisms, with the top 30 organism being gram negatives:

Interestingly, most of the infections were derived from the patient’s own flora upon surveillance. Similarly, in a trial evaluating the combination of carbenicillin and gentamicin in a cohort of 48 patients found that 44% of these patients had a pseudomonas infection, with 85% of those infected having a gram negative infection (3). It seems the isolation of an organism is actually the exception rather than the rule. Indeed, in one randomized, double-blind, placebo-controlled trial patients were randomized to either amox-clav + cipro or IV ceftazidime in a 1:1 fashion  for low risk neutropenic fever (4). Infection was only documented in 32% of patients in the oral therapy group compared to 40% in the IV therapy group. Furthermore, there was no difference in outcomes between both groups:

In a small cohort of 94 episodes of neutropenic fever, only 29% had a documented infection, with 48% of cases being due to a gram negative organism (5). In a retrospective case-control study, most patients (66 out of 81) had a negative microbiological evaluation, while 13% of all isolates ended up being gram negative. Moreover, most (55%) had an undetermined source of infection (6). Notably, multivariate analysis found that pneumonia and enterocolitis had highest odds of serious complications:

A small study found that blood cultures identified bacteria in 36% of cases, with gram negatives making up the majority of them (7). In a cohort of 171 febrile neutropenia episodes, nearly 71% had no organism isolated. Importantly, only 2 out of 25 gram positive isolates were found to be due to MRSA (8). 

Recent data has corroborated these findings. In a prospective study (9) of 72 patients, 63% of patients had gram negative organisms isolated from blood cultures compared to gram positive (36.4%). Eight isolates of Staph aureus were isolated, of which only 3 were MRSA. Notably, while the vast majority of patients had a focus identified, the most common finding was a lack of infectious focus:

In another cohort of 105 patients, 80% of patients had a bacterial infection as the etiology of neutropenic fever, with gram negatives making up 50% of those compared to 29% of gram positives (10). Most infections involved the lower respiratory tract or the blood:

The largest retrospective cohort  compared 1139 bacterial strains isolated from 322 neutropenic patients and 749 non-neutropenic patients (11). In both cohorts, gram negatives tended to be isolated more often than gram positives, but to a greater degree in neutropenic patients (70.4% in neutropenic patients vs 55% in non-neutropenic patients). In terms of respiratory samples, pseudomonas and klebsiella were the more common isolates in neutropenic folks, compared to Staph aureus and E. faecalis in non-neutropenic patients:

This was a similar trend in bacteremia, though both groups had similar rates of gram positives (namely, CoNS):

The Question of Gram Positive Coverage

This is one of the lingering doubts when it comes to neutropenic fever. As seen above, the main culprit (in cases where an organism is isolated) tends to be gram negatives with a not insignificant portion being due to pseudomonas. Indeed, in some studies the presence of gram positives is associated with higher mortality. In a retrospective study evaluating the implementation of a neutropenic fever pathway, multivariate analysis found that growth of gram positive fungi was associated with higher mortality (12)

In cohort recruited over a 6-year period (13), 2340 clinically significant episodes of bacteremia in cancer patients were recorded, with most of the risk factors being the usual presence of a central line or ICU stay:

Over this period, there was an increase in gram positive isolates, with them making up around 61% of all isolates, with Staph aureus making up 12.3% here. In terms of mortality, methicillin resistant staph aureus was not associated with higher mortality (18% vs 23%):

So it stands to reason that, perhaps, perhaps in some scenarios, adding empiric vancomycin may help. This does not seem to pan out, unfortunately. A meta analysis of 14 randomized studies did not find a mortality benefit with the addition of glycopeptides (14) to neutropenic fever regimens (OR 0.67, 95% CI 0.42-1.05). However, treatment success was greater with the addition of a glycopeptide (OR 1.63, 95% CI 1.17-2.28). This only takes into account those who have bacteremia, as the removal of this cohort does not show any benefit in treatment success for glycopeptides (OR 1.12, 95% CI 0.92-1.36) i.e. adding vancomycin whenever there is no reason does not change outcomes. Similarly, a Cochrane review (15) of 8 RCTs that included 1242 patients did not find mortality benefit when adding gram positive coverage (RR 0.90, 95% CI 0.64 to 1.25), nor did it find that it was associated with higher overall failure (RR 1.0, 95% CI 0.79 to 1.27).  

So no to vancomycin? Perhaps not in all scenarios. I tend to agree with the guidelines here; if there is no reason for a gram positive infection i.e. cellulitis or central line, no reason to add it. What about things like the “Karius” test or broad-range PCR? The former may take a while to get to the frontline while the latter may be used in very niche scenarios (i.e. that mass in the lung no one has any idea what it is despite weeks of eval) . Regardless, as more data mounts up, empiric therapy may be cut short baring certain conditions being met (see 16). 

So to sum up: 

• Neutropenic fever is common
• Use anti-pseudomonal gram negative coverage upfront
• Vancomycin only if there are risk factors

References:

1. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. doi: 10.1093/cid/cir073. PMID: 21258094
2. Schimpff SC, Young VM, Greene WH, Vermeulen GD, Moody MR, Wiernik PH. Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med. 1972 Nov;77(5):707-14. doi: 10.7326/0003-4819-77-5-707. PMID: 4628214.
3. Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med. 1971 May 13;284(19):1061-5. doi: 10.1056/NEJM197105132841904. PMID: 4994878.
4. Freifeld A, Marchigiani D, Walsh T, Chanock S, Lewis L, Hiemenz J, Hiemenz S, Hicks JE, Gill V, Steinberg SM, Pizzo PA. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med. 1999 Jul 29;341(5):305-11. doi: 10.1056/NEJM199907293410501. PMID: 10423464.
5. Lynn JJ, Chen KF, Weng YM, Chiu TF. Risk factors associated with complications in patients with chemotherapy-induced febrile neutropenia in emergency department. Hematol Oncol. 2013 Dec;31(4):189-96. doi: 10.1002/hon.2040. Epub 2013 Jan 9. PMID: 23303687.
6. Jeddi R, Achour M, Amor RB, Aissaoui L, Bouterâa W, Kacem K, Lakhal RB, Abid HB, BelHadjAli Z, Turki A, Meddeb B. Factors associated with severe sepsis: prospective study of 94 neutropenic febrile episodes. Hematology. 2010 Feb;15(1):28-32. doi: 10.1179/102453310X12583347009577. PMID: 20132659
7. Bansal S, Advani SH. Pattern of bloodstream infections in patients with hematological malignancies in a tertiary care centre. Indian J Cancer. 2014 Oct-Dec;51(4):447-9. doi: 10.4103/0019-509X.175308. PMID: 26842155.
8. Courtney DM, Aldeen AZ, Gorman SM, Handler JA, Trifilio SM, Parada JP, Yarnold PR, Bennett CL. Cancer-associated neutropenic fever: clinical outcome and economic costs of emergency department care. Oncologist. 2007 Aug;12(8):1019-26. doi: 10.1634/theoncologist.12-8-1019. PMID: 17766662.
9. Özdemir SK, Iltar U, Salim O, Yücel OK, Erdem R, Turhan Ö, Undar L. Investigation of seasonal frequency and pathogens in febrile neutropenia. Memo. 2019;12(2):119-122. doi: 10.1007/s12254-018-0468-z. Epub 2019 Jan 15. PMID: 32218873; PMCID: PMC7091104.
10. Lakshmaiah KC, Malabagi AS, Govindbabu, Shetty R, Sinha M, Jayashree RS. Febrile Neutropenia in Hematological Malignancies: Clinical and Microbiological Profile and Outcome in High Risk Patients. J Lab Physicians. 2015 Jul-Dec;7(2):116-20. doi: 10.4103/0974-2727.163126. PMID: 26417163; PMCID: PMC4559624.
11. Zhu J, Zhou K, Jiang Y, Liu H, Bai H, Jiang J, Gao Y, Cai Q, Tong Y, Song X, Wang C, Wan L. Bacterial Pathogens Differed Between Neutropenic and Non-neutropenic Patients in the Same Hematological Ward: An 8-Year Survey. Clin Infect Dis. 2018 Nov 13;67(suppl_2):S174-S178. doi: 10.1093/cid/ciy643. PMID: 30423039.
12.  Zuckermann J, Moreira LB, Stoll P, Moreira LM, Kuchenbecker RS, Polanczyk CA. Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes. Ann Hematol. 2008 Feb;87(2):139-45. doi: 10.1007/s00277-007-0390-7. Epub 2007 Oct 16. PMID: 17938926.
13. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis. 2003 May 1;36(9):1103-10. doi: 10.1086/374339. Epub 2003 Apr 14. PMID: 12715303.
14. Vardakas KZ, Samonis G, Chrysanthopoulou SA, Bliziotis IA, Falagas ME. Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a meta-analysis of randomised controlled trials. Lancet Infect Dis. 2005 Jul;5(7):431-9. doi: 10.1016/S1473-3099(05)70164-X. PMID: 15978529.
15. Beyar-Katz O, Dickstein Y, Borok S, Vidal L, Leibovici L, Paul M. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2017 Jun 3;6(6):CD003914. doi: 10.1002/14651858.CD003914.pub4. PMID: 28577308; PMCID: PMC6481386.
16. la Martire G, Robin C, Oubaya N, Lepeule R, Beckerich F, Leclerc M, Barhoumi W, Toma A, Pautas C, Maury S, Akrout W, Cordonnier-Jourdin C, Fihman V, Venditti M, Cordonnier C. De-escalation and discontinuation strategies in high-risk neutropenic patients: an interrupted time series analyses of antimicrobial consumption and impact on outcome. Eur J Clin Microbiol Infect Dis. 2018 Oct;37(10):1931-1940. doi: 10.1007/s10096-018-3328-1. Epub 2018 Jul 26. PMID: 30051357.