Severe Pneumonia in Intensive Care
Patients affected by severe pneumonia need to be treated urgently and appropriately, given the importance of rapid pathogens' clearance in reducing infection-driven systemic inflammatory activation and preventing multiorgan dysfunction. Current guidelines for the treatment of severe pneumonia in ICU may help physicians in daily clinical practice (Table 2). IDSA/ATS recommendations for the management of SCAP in ICU highlight the importance of a combination therapy including a β-lactam and either azithroomycin or a respiratory fluoroquinolone; however, in the case of suspicion of Psudomonas or MRSA involvement, the antibacterial scheme should cover also these pathogens. In addition to the activity against a typical pathogens, macrolides have been advocated by some authors as an adjunctive tool in severe pneumonia because of their presumed immunomodulatory properties. A recent multicenter prospective cohort study, conducted in 27 ICUs of 9countries, showed that patients with SCAP showed a lower ICU mortality rate when treated with macrolides compared to fluoroquinolones (hazard ratio 0.48; P = 0.03). The empirical antimicrobial regimen for HCAP, HAP and VAP proposed by current guidelines is a triple drug scheme including MRSA and nonfermentative Gram-negative rods coverage. In a recent study conducted in four academic ICUs, better compliance to international recommendations with regards to HCAP/HAP/VAP empirical treatment was associated with increased mortality. Nonadherence to guidelines mainly included nonuse of combination therapy for Gram-negative infections. However, the lack of randomization, the differences of baseline clinical conditions and the higher frequency of Pseudomonas pneumonia in the compliant group raise many concerns about the clinical reliability of these results. The optimal treatment of severe pneumonia in critically ill patients includes the evaluation of numerous variables that may influence final microbiological and clinical outcome. Antimicrobials with good pulmonary distribution (such as linezolid) should be preferred, or alternative additional administration strategies might be added (aerosolized antibiotics); isolated microorganisms' minimal inhibitory concentrations (MICs) have to be carefully considered and antibiotics' bactericidal properties may be optimized by applying their pharmacodynamic/pharmacokinetic properties (time-dependent/concentration-dependent molecules). In addition, pathophysiological changes occurring during severe infections (increased cardiac output; leaky capillaries/altered protein binding; end-organ dysfunctions) modify drug clearance (Cl) and volume of distribution (Vd) according to their hydrophilic or lipophilic nature. Given their low pulmonary penetration, high aminoglycoside doses (i.e. amikacin 25 mg/kg) are needed in order to reach effective peak concentrations in critically ill patients, especially those ones with severe pneumonia. A recent systematic review has confirmed the pharmacodynamic/pharmacokinetic advantages of prolonged/continuous infusion of β-lactams; however, antibiotics' therapuetical drug monitoring (TDM) still represents the best tool to ensure optimal drugs exposure in critically ill patients. Despite the optimal duration of severe pneumonia being unclear, surrogate biomarkers, like procalcitonin, may be useful to guide antibiotic therapy duration. Some preclinical and clinical studies suggest the use of steroids as an adjunctive tool in critically ill patients with pneumonia; however, evidence from current literature does not recommend their extensive use in severe pneumonia. Subgroups of patients (i.e. those with pulmonary immune reconstitution inflammatory syndrome and with severe pneumonia evolving into ALI/ARDS despite adequate treatment) may benefit from their anti-inflammatory properties. In light of its immunomodulatory properties, the use of drotrecogin alfa activated (DAA) inpatients with severe pneumonia developing septic shock has been proposed in the past. However, given the negative results of a multinational placebo-controlled trial of DAA in septic shock (PROWESS SHOCK), requested by the European Medicines Agency and not yet published, the molecule has been recently withdrawn from the market [http://www.emea.europa.eu]. Other adjunctive therapies are under investigation, but results are still unconvincing (prostaglandin inhibitors, anticoagulant agents, surfactant, immunoglobulin, statins, γ-interferon).
Treatment
Patients affected by severe pneumonia need to be treated urgently and appropriately, given the importance of rapid pathogens' clearance in reducing infection-driven systemic inflammatory activation and preventing multiorgan dysfunction. Current guidelines for the treatment of severe pneumonia in ICU may help physicians in daily clinical practice (Table 2). IDSA/ATS recommendations for the management of SCAP in ICU highlight the importance of a combination therapy including a β-lactam and either azithroomycin or a respiratory fluoroquinolone; however, in the case of suspicion of Psudomonas or MRSA involvement, the antibacterial scheme should cover also these pathogens. In addition to the activity against a typical pathogens, macrolides have been advocated by some authors as an adjunctive tool in severe pneumonia because of their presumed immunomodulatory properties. A recent multicenter prospective cohort study, conducted in 27 ICUs of 9countries, showed that patients with SCAP showed a lower ICU mortality rate when treated with macrolides compared to fluoroquinolones (hazard ratio 0.48; P = 0.03). The empirical antimicrobial regimen for HCAP, HAP and VAP proposed by current guidelines is a triple drug scheme including MRSA and nonfermentative Gram-negative rods coverage. In a recent study conducted in four academic ICUs, better compliance to international recommendations with regards to HCAP/HAP/VAP empirical treatment was associated with increased mortality. Nonadherence to guidelines mainly included nonuse of combination therapy for Gram-negative infections. However, the lack of randomization, the differences of baseline clinical conditions and the higher frequency of Pseudomonas pneumonia in the compliant group raise many concerns about the clinical reliability of these results. The optimal treatment of severe pneumonia in critically ill patients includes the evaluation of numerous variables that may influence final microbiological and clinical outcome. Antimicrobials with good pulmonary distribution (such as linezolid) should be preferred, or alternative additional administration strategies might be added (aerosolized antibiotics); isolated microorganisms' minimal inhibitory concentrations (MICs) have to be carefully considered and antibiotics' bactericidal properties may be optimized by applying their pharmacodynamic/pharmacokinetic properties (time-dependent/concentration-dependent molecules). In addition, pathophysiological changes occurring during severe infections (increased cardiac output; leaky capillaries/altered protein binding; end-organ dysfunctions) modify drug clearance (Cl) and volume of distribution (Vd) according to their hydrophilic or lipophilic nature. Given their low pulmonary penetration, high aminoglycoside doses (i.e. amikacin 25 mg/kg) are needed in order to reach effective peak concentrations in critically ill patients, especially those ones with severe pneumonia. A recent systematic review has confirmed the pharmacodynamic/pharmacokinetic advantages of prolonged/continuous infusion of β-lactams; however, antibiotics' therapuetical drug monitoring (TDM) still represents the best tool to ensure optimal drugs exposure in critically ill patients. Despite the optimal duration of severe pneumonia being unclear, surrogate biomarkers, like procalcitonin, may be useful to guide antibiotic therapy duration. Some preclinical and clinical studies suggest the use of steroids as an adjunctive tool in critically ill patients with pneumonia; however, evidence from current literature does not recommend their extensive use in severe pneumonia. Subgroups of patients (i.e. those with pulmonary immune reconstitution inflammatory syndrome and with severe pneumonia evolving into ALI/ARDS despite adequate treatment) may benefit from their anti-inflammatory properties. In light of its immunomodulatory properties, the use of drotrecogin alfa activated (DAA) inpatients with severe pneumonia developing septic shock has been proposed in the past. However, given the negative results of a multinational placebo-controlled trial of DAA in septic shock (PROWESS SHOCK), requested by the European Medicines Agency and not yet published, the molecule has been recently withdrawn from the market [http://www.emea.europa.eu]. Other adjunctive therapies are under investigation, but results are still unconvincing (prostaglandin inhibitors, anticoagulant agents, surfactant, immunoglobulin, statins, γ-interferon).
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