Considering the dismal prognosis of febrile neutropenic patients with LI not treated promptly with an appropriate antimicrobial regimen, it is recommended to start therapy preemptively on the basis of clinical, imaging, and/or laboratory findings indicative of a particular infection in patients at risk for, but without proof of, this infection (Table 10.2). The type of underlying malignancy or immunosuppression has an instrumental impact on the selection of antimicrobial agents suitable for preemptive therapy.

The interpretation of microbiological findings in neutropenic patients with LI is difficult. Isolates typically origin from blood cultures or BAL samples. They may represent nonpathogenic contaminants, colonizers, co-pathogens, or microorganisms causing a separate infection. If etiologically significant pathogens are detected, particularly multiresistant bacteria, immediate modification of antimicrobial treatment to avoid fatal outcome due to delayed effective therapy is recommended [75].

The following findings indicate pathogens causative for lung infiltrates:

The following findings do not represent pathogens causative for lung infiltrates:

Potentially relevant findings are common respiratory viruses; isolation of Staphylococcus aureus, Legionella spp., or atypical mycobacteria in respiratory secretions; and positive CMV- or Pneumocystis-PCR from BAL.

In patients with a documented P. aeruginosa pneumonia, the primary combination antibacterial therapy including an antipseudomonal beta-lactam plus preferably an aminoglycoside or (if an aminoglycoside is contraindicated) ciprofloxacin is recommended [54, 114]. Depending on their in vitro susceptibility pattern, multiresistant gram-negative aerobes such as extended-spectrum beta-lactamase (ESBL)-producing E. coli, Enterobacter spp. or Klebsiella spp., as well as Acinetobacter spp. or P. aeruginosa require antimicrobial treatment combinations selected appropriately according to this pattern. Pharmacokinetic aspects (penetration to lung tissue, possible inactivation by surfactant) must always be included in this selection. In individual patients with pneumonia caused by multiresistant gram-negative pathogens, aerosolized colistin has been successfully used as a part of the antimicrobial strategy [100]. Stenotrophomonas maltophilia rarely causes pneumonia, while it is more frequently isolated from respiratory secretions representing selection of opportunistic microorganisms under broad-spectrum antibacterial treatment. In patients with suspected or documented S. maltophilia pneumonia, early antimicrobial intervention with high-dose trimethoprim-sulfamethoxazole (15–20 mg/kg/day of trimethoprim) is mandatory [2, 145]. It should be kept in mind that in vitro susceptibility may not predict clinical efficacy of antimicrobial agents in S. maltophilia infections [30].

Pneumonias caused by methicillin-resistant Staphylococcus aureus (MRSA) should preferably be treated with vancomycin, if no serious renal insufficiency is present. Linezolid is a valid alternative for first-line treatment [158]; however, the risk of severe thrombocytopenia or even pancytopenia associated with linezolid must be taken into consideration [51]. Daptomycin should not be used for treatment of pneumonia, because it is inactivated by surfactant [134].

CMV pneumonia typically affects patients who have undergone allogeneic stem cell transplantation. First-choice antiviral treatment options are foscarnet and ganciclovir. Foscarnet may be preferred because of its lack of myelosuppression, the latter being a serious adverse effect of ganciclovir [102]. On the other hand, reversible nephrotoxicity is one of the typical side effects of foscarnet [152].

Detailed recommendations for treatment of documented fungal pneumonia are provided in evidence-based guidelines [18, 83, 153]. Intravenous voriconazole and liposomal amphotericin B are recommended first-line choices for treatment of IPA. For zygomycosis (mucormycosis), liposomal amphotericin B is preferred. In patients with worsening LI and gas exchange within the first week of treatment, failure of antifungal therapy should only be considered if new LI emerge on control CT scans. At the same time, other causes such as a second infection, immune reconstitution syndrome, infiltrates caused by the underlying malignancy, toxicity from cancer treatment, and yet insufficient duration of antifungal treatment should be ruled out [97]. Combination antifungal first-line treatment in patients with invasive mold infections is controversial. A prospective clinical study comparing voriconazole alone with the combination of voriconazole with anidulafungin has not convincingly shown benefit from the combination in patients with proven and probable aspergillosis [93]. For treatment of zygomycosis (mucormycosis), a combination of liposomal amphotericin B and an echinocandin may be promising [139]; however, randomized studies on this subject have not been conducted. A combination of liposomal amphotericin B and the iron chelator deferasirox for the treatment of mucormycoses has shown inferior clinical results for the combination as compared to the antifungal agent alone [140].

Patients with proven PcP should be treated with trimethoprim-sulfamethoxazole (TMP/SMX; co-trimoxazole) at a dosage of TMP 15–20 mg/kg plus SMX 75–100 mg/kg daily, divided into three to four doses and continued for 2–3 weeks. Nonresponders after 14 days of treatment should be evaluated for a secondary infection by repeated bronchoscopy. In individual patients with persistent PcP, dihydropteroate synthase gene mutation may be taken into consideration [105]. In case of confirmed sulfa resistance or TMP/SMX intolerance, atovaquone oral suspension (750 mg three times daily), pentamidine inhalation (600 mg daily), intravenous pentamidine (4 mg/kg daily), and clindamycin (600 mg three times daily) plus primaquine (30 mg daily) may represent treatment alternatives [146], with clindamycin + primaquine presumably being the most effective option [137]. Subsequently, patients should be given secondary prophylaxis using oral TMP/SMX at a daily dosage of 160/800 mg given on 2–3 days per week or with monthly pentamidine inhalation at a dose of 300 mg. In patients with respiratory failure due to PcP, systemic corticosteroids may be beneficial, but clinical data from this setting are rare [43, 113].

Analysis of European data on the outcome of cancer patients requiring intensive care has shown an overall mortality rate of 27 %, which is not significantly different from non-cancer patients treated in the intensive care unit [144]. Neutropenic patients with respiratory failure due to LI may have a favorable outcome under appropriate intensive care including mechanical ventilation [35, 96, 110]. Even if respiratory failure is due to invasive pulmonary aspergillosis, survival can be achieved in 33 % of patients [22]. It is therefore not justified to reject cancer patients from intensive care because of their underlying malignancy [131].