Neutropenia is when a person has a low level of neutrophils. Neutrophils are a type of white blood cell. All white blood cells help the body fight infection. Neutrophils fight infection by destroying harmful bacteria and fungi yeast that invade the body. Neutrophils are made in the bone marrow.
Bone marrow is the spongy tissue found in larger bones such as the pelvis, vertebrae, and ribs. Half of people with cancer who are receiving chemotherapy have some level of neutropenia.
It is a common side effect in people with leukemia. People who have neutropenia have a higher risk of getting serious infections. This is because they do not have enough neutrophils to kill organisms that cause infection. People with severe or long-lasting neutropenia are most likely to develop an infection. Treatment of Patients at High-Risk: The standard care of febrile neutropenia at high-risk of complications includes in-patient management with intravenous broad-spectrum antibiotics.
Based on these considerations, it is recommended to use a strategy that differentiates between first-line therapy based on molecules such as cefepime or piperacillin-tazobactam, and second-line therapy constituted of the carbapenems. This allows keeping a valuable alternative in case of emergence of resistance. However, such a strategy can be implemented only if the baseline incidence of ESBL-producing Gram-negative bacilli is low.
In fact, carbapenems are the most active drugs against these bacteria, and reduced the mortality in ESBL-producingK. These include a better activity against streptococci and methicillin-susceptibleS. Furthermore, less induction and decreased emergence of ESBLs, are reported with cefepime and piperacillin-tazobactam. No significant differences in response rates or mortality were observed in these individual trials. But, the continuously changing microbial distribution and the emergence of new mechanisms of resistance that occurred after the completion of many of these studies, contribute to obscure the interpretation of results and their relevance to the actual epidemiology.
Nevertheless, a recent meta-analysis focusing on response rate in the different comparative trials of empiric therapy of febrile neutropenia, showed superiority of the carbapenems and piperacillin-tazobactam over ceftazidime. In some situations, specific anti-anaerobic coverage is indicated. Piperacillin-tazobactam and carbapenems cover the majority of anaerobes, otherwise, for cephalosporins or aztreonam, metronidazole should be added. Although this is not a current first choice, in case of penicillin-allergy mediated by IgE where the risk of anaphylaxis is important, aztreonam combined with a glycopeptide is an acceptable alternative.
This question has been addressed in two recent meta-analyses which reviewed the studies that compared monotherapy with combination therapy. The conclusion was that of no advantage of the combination with an excess of toxicity. If any benefit is to be expected from combination therapy, it is within this subgroup that would occur.
But, no single study targeted specifically such patients. Another important question has been the addition of a glycopeptide to the initial regimen. In fact, among the Gram-positive pathogens that cause infection or bacteremia during neutropenia, very few cause a fulminant infection course with significant morbidity and mortality. These include viridans streptococci, S. Again, the local epidemiology and the penicillin or methicillin-resistance of these organisms, which is highly variable between institutions, plays an important role.
A recent Cochrane review of 13 randomized trials comparing the addition of an anti-Gram-positive antibiotic to the initial empiric regimen, did not show any benefit in reducing treatment failure, all cause mortality or Gram-positive superinfections. However, there are circumstances in which a glycopeptide or another antibiotic active against resistant Gram-positive bacteria, should be added up-front.
These include patients who are already known to be colonized by MRSA, if MRSA is endemic in the institution and in several skin infections that could be caused by resistant staphylococci as folliculitis, furonculosis and periporth cellulitis and also if penicillin-resistant viridans streptococci are prevalent in the institution.
Few studies have specifically addressed this question. According to the study by Cometta et al 6 conducted by the anti-infection group of the EORTC, the mean time for defervesence on piperacillin-tazobactam monotherapy was 5 days. Therefore, for patients without hypotension or sepsis and in whom no resistant pathogen is isolated, it seems reasonable to wait until day 5 before modification. On the contrary, for those who develop signs of sepsis, hypotension or other early findings of deterioration, at any time, a shift to non-cross resistant antibiotic is recommended.
Simultaneously, a thorough investigation including chest and sinus CT scan, galactomannan test and other diagnostic tests for viral or parasitic infections, should be undertaken. Algorithms 1 , 2 , 3 and 4 provide general lines of management according to specific situations of febrile neutropenia.
The rationale for empiric antifungal therapy in persistently febrile neutropenic patients, is based on the fact that early diagnosis of invasive fungal infections is difficult to establish and the mortality is increased by delay in adequate therapy. The concept of empiric antifungal therapy in neutropenic patients with persistent fever despite broad-spectrum antibiotics, has been introduced following two studies with a limited number of patients, comparing amphotericin B with placebo and showing a decrease in fungal infection-related mortality in patients receiving amphotericin-B deoxycholate.
Is this concept still true today? With this in mind, we see in the latest trials that the true rate of failure of empiric antifungal therapy which is the development of a breakthrough fungal infection and the absence of cure of base line fungal infection is 6. The need for empirical antifungal therapy during neutropenia has decreased secondarily to the implementation of more effective antifungal prophylaxis.
The next question is whether our new imaging techniques and new laboratory methods are able to detect invasive fungal infections early enough and whether they can serve to build-up a pre-emptive or a diagnostic-driven strategy in order to save unnecessary costs and drug exposure, without increase in mortality.
Thus, the pre-emptive or diagnostic-driven strategy is able to reduce the rate of antifungal overtreatment but the safety and cost effectiveness should be confirmed by large comparative prospective trials. Th e recovery of neutrophils in patients with severe infection and hematological malignancy plays a major role in resolution and survival. In order to palliate a temporary deficit in neutrophils, a logical approach was the development of transfusion of donor neutrophils as adjunctive therapy to antibiotics and antifungals, in neutropenic patients with refractory infections.
Although initial clinical successes were reported between s and beginning s, ganulocyte transfusion adjunctive therapy declined progressively due to several reasons. Besides, the availability of more advanced antimicrobials, the time and cost consuming procedure and a marginal effect demonstrated in randomized trials, all together contributed to this decline.
Higher yields and improved phagocytosis and killing of neutrophils with prolonged intravascular survival are obtained after stimulation. However, the clinical efficacy of this new generation of granulocyte transfusion is still limited to case reports and small non randomized series. A recent meta-analysis of 8 randomized controlled trials involving granulocyte transfusions, given therapeutically to neutropenic patients showed inconclusive evidence to support or refute the generalized use granulocyte transfusion therapy.
Thus, in the absence of definitive data, it is reasonable to provide granulocyte transfusions for neutropenic patients with hematological malignancy and documented bacterial or invasive fungal infection, not controlled by adequate antimicrobial therapy.
Individual small studies have generated conflicting results. A recent meta-analysis on 13 controlled trials comparing CSFs plus antibiotics versus antibiotics alone for the treatment of established febrile neutropenia, showed a benefit in terms of length of hospitalization and time to neutrophil recovery, in favor of CSFs, but no advantage on overall mortality and a trend toward a decrease in infection-related mortality.
This latter effect needs further investigation. Basic hygiene measures are reinforced in patients receiving chemotherapy. The prevention of oral mucositis is essential requiring standard dental care, gentle tooth brushing and chlorexidine mouth rinses.
Is neutropenic diet prohibiting uncooked meat, raw eggs, fresh vegetables, fruits and juices, necessary and effective in preventing infections? There are no evidence-based studies that addressed this issue and the existing ones are of small sample-size and biased by concomitant antibacterial and antifungal prophylaxis. A recent review on this controversial issue failed to show clear evidence from the literature Until we have more definitive data, it seems prudent to maintain the use of basic principles, prohibiting uncooked meats, raw eggs, seafood, fresh vegetables, fruits except oranges and bananas and aged cheese.
Palifermin, a recombinant human keratinocyte growth factor is able to protect several types of epithelial tissues exposed to radiotherapy or chemotherapy. It enhances cell proliferation and increases thickness of the epithelium of the gastro-intestinal tract. Skin rash and disconfort due to mucosal hypertrophy of tongue and gingiva are the main adverse events whereas high cost and risk of growth enhancement in tumors expressing keratinocyte growth factor receptor are additional drawbacks.
Another procedure that has demonstrated encouraging results in the prevention of oral mucositis with good tolerance is low level energy laser therapy. However, the two major strategies that have been developed to decrease complications during neutropenia are the administration of myeloid growth factors and antibiotic prophylaxis. On the other hand, the concept of antibiotic prophylaxis takes its origin from the decontamination of the gastro-intestinal tract developed in the s by non absorbable antimicrobials such as neomycin, colistin, polymyxin B or gentamicin, vancomycin and nystatin.
Study results with these drugs were discordant mainly because of the gastro-intestinal intolerance and bad tasting. In s, trimethoprim-sulfamethoxazole and nalidixic acid were used for prophylaxis showing also mixed results. Trimethoprim-sulfamethoxazole was associated with high incidence of cutaneous rashes, and increased colonization byP.
The fluoroquinolones, introduced in the mid s, had good bactericidal activity against enterobacteriacae and for ciprofloxacin, activity againstP. Fluoroquinolones are well tolerated, have little toxicity and preserve the anaerobic flora. Patients who are afebrile and develop signs and symptoms of infection should also be treated empirically with the same regimen as high-risk patients.
Initial treatment with vancomycin and other antibiotics effective against gram-positive cocci are not recommended as standard empirical antibiotic treatment for patients with FN.
However, these agents may be considered in modifications of initial treatment as additional therapy for patient-based needs, such as suspicion of catheter-related infection, skin or soft-tissue infection, pneumonia, hemostatic instability, or antibiotic resistance. The IDSA guidelines recommend therapy modifications for patients with a positive blood culture with a risk of infection with antibiotic-resistant organisms.
If methicillin-resistant Staphylococcus aureus is suspected, the initial antibiotic regimen can be modified to include vancomycin, daptomycin, or linezolid. Suspicion of vancomycin-resistant enterococcus calls for the addition of linezolid or daptomycin.
If extended-spectrum beta-lactamase—producing gram-negative bacteria is suspected, patients may benefit from the early use of carbapenem. The addition of polymyxin-colistin or tigecycline to the early treatment is appropriate if the presence of Klebsiella pneumoniae carbapenemase-producing bacteria is suspected. Patients allergic to penicillin may be given cephalosporin, but either ciprofloxacin and clindamycin or aztreonam and vancomycin are recommended in cases of immediate hypersensitivity.
Patients with FN at low risk of complications may be initially treated with empirical antibiotics administered orally or intravenously in the inpatient setting.
Patients meeting select criteria of clinical stability and adequate gastrointestinal absorption may be eligible for treatment switch from intravenous to oral administration of antibiotics. Recommended treatment for low-risk patients includes combination oral antibiotic therapy with ciprofloxacin and amoxicillin-clavulanate.
Other orally administered regimens commonly used in clinical practice are monotherapy with levofloxacin or ciprofloxacin and combination with ciprofloxacin and clindamycin. If a patient is being treated for FN with fluoroquinolone prophylaxis, a fluoroquinolone cannot be used as an initial empiric therapy.
Additionally, selected patients who are at low risk for complications and have family support and appropriate culture status may be eligible for transitioning treatment with intravenous or oral empiric therapy to the outpatient setting.
Patients who continue to present with fever and worsening signs and symptoms of infection are to remain in hospital rather than being discharged. Empiric antifungal therapy is not recommended for routine use in low-risk patients. Initiation of empiric antifungal therapy is recommended for patients who continue to have persistent fever of unidentified cause following 4 to 7 days of antibiotic treatment, and who present with neutropenia that is expected to last more than 7 days.
In patients with FN who are already receiving anti-mold prophylaxis, the switch to an agent in a different antifungal class should be considered. However, there are insufficient data to determine which antifungal agent is most appropriate. The assessment of response and duration of therapy outlined by clinical practice guidelines for the management of FN recommend daily patient reviews following administration of empiric therapy to determine needs for subsequent management.
Daily assessments include laboratory tests and cultures for infection, fever trends, and toxicity of treatment. Kenneth V. Disclosures CJ and JA declare that they have no competing interests. Differentials Drug fever Tumor fever Thromboembolism More differentials. NCCN clinical practice guidelines in oncology: hematopoietic growth factors external link opens in a new window Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression external link opens in a new window More guidelines.
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