Dr. Bharat Agarwal *
Department of Pediatrics.*
Important note
The above algorithm is based on a protocol agreed across all the London (UK) Pediatric Hematology centers. All large institutions should have a similar locally agreed protocol taking account of local patterns of infection and resistance. The above algorithm and notes are thus designed to show the principles of management of febrile neutropenia, rather than recommending specific antibiotics

  1. Febrile neutropenia is defined as: Neutropenia < x 10⁹/l or 1,000/ul) and fever > 38°C for more than 4 hr or on 2 occasions at least 4 hr apart or fever > 38.5°C on one occasion or clinical suspicion of sepsis in the absence of fever. Fever should be unrelated to the transfusion of blood products. Febrile neutropenia requires urgent investigation and empirical antibiotic therapy.

  2. A thorough examination for sites of sepsis including any central venous access devices. Blood cultures before the start of antibiotic therapy is imperative. Each lumen of a central line should be sampled and / or peripheral venous cultures taken. Urine should be sent for microscopy and culture and swabs taken from sites of overt infection. CXR done if clinically appropriate.

  3. Most institutions still recommend an anti-pseudomonal penicillin and aminoglycoside as first line therapy. The combination provides synergy against aerobic gram negative bacteria. Oto and nephrotoxicity are negative. Single drug therapy with an antipseudomonal penicillin or third generation cephalosporin is not as effective, whereas monotherapy with a carbapenem (imipenem, meropenem) may be as effective, but is usually reserved for second line or specific therapy. Viridans streptococci bacteremia in the neutropenic patient can lead to ARDS and there is evidence that outcome is improved by the addition of vancomycin at the outset. In other situations, no benefit has been demonstrated for the initial inclusion of vancomycin. Many centers are now substituting teicoplanin for vancomycin because of decreased nephrotoxicity.

  4. Positive isolates should be discussed with the microbiology department and therapy optimized while maintaining broad spectrum cover. High quality echocardiography should be arranged to look for signs of infective endocarditis, if Staphylococcus aureus is isolated and the length of therapy has been standard.

  5. Arrange CXR (for Aspergillus and interstitial pneumonitis) and consider echocardiography for vegetations, abdominal ultrasound for hepatosplenic candidiasis and high resolution chest CT (Aspergillus). Fungal infection is notoriously difficult to diagnose - it is thus now routine to initiate empirical amphotericin therapy at this stage.

  6. Although microbiologists recommend immediate line removal when S. aureus, Stenotrophomonas spp. or Pseudomonas spp. are isolated, this is not always clinically feasible and as long as the patient shows clinical recovery, many units will try to salvage the line. Clearly, persistently positive cultures in the face of appropriate antibiotic therapy necessitates line removal.

  7. Conventional amphotericin B is an effective but nephrotoxic anti-fungal agent, Liposomal preparations are now available and are as efficacious, less nephrotoxic, but much more expensive. Most units begin with conventional amphotericin B and progress to liposomal preparation when a predetermined rise in creatinine has occurred.

  8. Review antibiotics, consider second line therapy. Ultrasound/echocardiogram if not already done. Repeat CXR. Consider drug fever notoriously difficult to recognize. The addition of G-CSF may also be considered, but evidence to support its use in this situation is lacking. The evidence supporting the use of granulocyte transfusions is even less, although trials are now underway to try and identify particular situations where these may be of value.

  9. It is argued that antibiotics should be continued until neutropenia resolves, irrespective of the clinical condition of the patient or culture results. However, the algorithm above is suggested as a way of optimizing therapy whist minimizing toxicity, development of an antibiotic resistance and potential development of fungal infection.

  10. Pseudomonas app. and S. aureus need a minimum of 14 days therapy. A decision to stop antibiotics after a positive culture should be taken in conjunction with the microbiology department.

  11. Clearly, proven or suspicious fungal infections will require longer therapy and future prophylaxis. Oral itraconazole can be used for aspergillus infections and fluconazole for other fungal infections in the outpatient setting.
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