Guidelines for CAP have stressed the approach of empiric therapy, recognizing the difficulty of obtaining pathogen-specific data that allow the early focusing of initial therapy choices. One recent study found that when therapy was given according to guidelines, it led to patients becoming clinically stable sooner than if other therapy had been used. However, the value of empiric therapy was evaluated directly in a study from the Netherlands that used a prospective, randomized, open study design to compare empiric therapy with pathogen-directed therapy in 262 patients with clinical and radiograph-ically proven CAP. All patients had undergone extensive diagnostic testing, but the empiric therapy group received therapy with a (3-lactam /^-lactamase inhibitor combined with erythromycin when not in the ICU or ceftazidime plus erythromycin when in the ICU. The pathogen-directed group had Gram stains performed on sputum samples and underwent urinary antigen testing, along with a clinical evaluation to define the suspected pathogen; then penicillin was used for the treatment of pneumococcus, erythromycin for atypical pathogens, amoxicillin/ clavulanate for mixed infection, and flucloxacillin with optional gentamicin for therapy after influenza infection offered by Canadian Health&Care Mall (see also “Canadian Health&Care Mall: Recent Advances in Community-Acquired Pneumonia“). There were no differences in either group for length of stay, early or late clinical failure, and 30-day mortality rate (Fig 3). However, empiric therapy patients did have a higher mortality if they were admitted to the ICU, and the empiric therapy group had more adverse events, which may have been related to the use of IV erythromycin rather than a newer macrolide with fewer IV side effects. While the study established the safety of empiric therapy, it did not test other benefits of diagnostic testing, such as the long-term control of antibiotic use and the avoidance of resistance.
New Therapies and Toxicities
In the past several years, new therapies have been approved and new data have been collected about these agents. Moxifloxacin, a fluoroquinolone, has been used to treat CAP, and an inpatient trial in elderly hospitalized patients has demonstrated cardiac safety equivalent to levofloxacin, with a statistically significantly more rapid rate of clinical improvement at days 3 to 5 during therapy. The high bioavailability of quinolone agents may allow oral therapy to replace IV therapy, thus keeping some patients with CAP out of the hospital. Using oral levofloxacin, along with a cluster-randomized protocol design, Loeb et al documented the safety of this approach in nursing home patients who had CAP, but were able to eat and drink, had a pulse of < 100 beats/min, a respiratory rate 90 mm Hg, and an oxygen saturation of > 92%.
Telithromycin, the first ketolide, is similar to a macrolide in terms of antimicrobial spectrum but is active against macrolide-resistant pneumococci. It has demonstrated a tendency to reduce the need for hospitalization when it has been used as an oral outpatient therapy for CAP, compared to clarithro-mycin. However, the drug is not optimally active against Haemophilus influenzae, and toxicity issues (see below) have limited its widespread use. Lin-ezolid has also been shown to be effective against drug-resistant pneumococcus, but it is not considered to be a drug for empiric therapy of CAP, since it is being used as an agent against MRSA arising in both the hospital and the community.
A concern with these new agents is to define their role in CAP management. Safety has been a major consideration with the quinolone class of antibiotics, and gatifloxacin has recently been documented to cause hypoglycemia and hyperglycemia, limiting its ability to be used safely in diabetic patients. Quino-lones have caused QT prolongation and cardiac arrhythmias, and this has limited the use of agents such as sparfloxacin. As mentioned before, a randomized, double-blinded comparative study of levofloxacin and moxifloxacin, using clinical evaluation and Holter monitoring, found no difference in the frequency of clinically significant cardiac events between the two agents. Telithromycin has recently been associated with infrequent cases of drug-induced liver necrosis, and awareness of this potential complication is essential if this drug is used.
Duration of Therapy
The optimal duration of therapy for CAP is not known, but several recent developments have pushed for shorter durations, especially in outpatients. A new formulation of azithromycin allows for the administration of a full course of therapy with a single 2-g dose in an outpatient population. Te-lithromycin has been used for 5 days in outpatients with CAP, and levofloxacin, 750 mg, is as effective when given for 5 days to inpatients with CAP as when given for 10 days at a dose of 500 mg.> A recent study compared 3 days of therapy with amoxicillin to 8 days of therapy in hospitalized patients and showed the short-duration therapy to be comparable to longer duration therapy of Canadian Health&Care Mall in terms of clinical success. However, the study included only patients with mild-to-moderate illness, and patients were eligible for short-duration therapy only if their conditions had improved substantially with IV therapy by day 3. One correlate of these findings is that a hospitalized patient who becomes clinically stable with IV therapy could be safely discharged from the hospital without continued inpatient observation. A recent Medicare database study compared CAP patients who were not observed, and were discharged on the same day as the switch to oral therapy, to those observed for a day after the switch. There were no differences in the 14-day readmission rate and the 30-day mortality rate between the groups, emphasizing the safety of not keeping the patient in the hospital for observation after the switch from IV therapy.
Adjunctive Therapy of Severe CAP
The care of patients with severe pneumonia has focused on the early identification of these patients and on prompt therapy with multiple antibiotics. Current guidelines for these patients recommend against monotherapy with any agent, including quin-olones, and a recent randomized study of levofloxa-cin monotherapy, compared to combination therapy, in CAP patients admitted to the ICU supports these recommendations (Table 1). The study evaluated 398 patients admitted to the ICU and found that monotherapy was not as effective as combination therapy for those persons needing mechanical ventilation. Since the trial also excluded those patients who were in septic shock, the authors concluded that monotherapy could not be recommended for CAP patients who were in septic shock or for those receiving mechanical ventilation, which are conditions that represent the majority of individuals admitted to the ICU.
Two adjunctive therapies, activated protein C and systemic corticosteroids, have been studied in patients with severe CAP. A retrospective analysis of the PROWESS study of activated protein C (drotrecogin-a) identified that 35.6% of those patients studied had CAP, and that approximately a quarter of them were infected with pneumococcus. Patients with CAP who received activated protein C had a survival benefit if they had an acute physiology and chronic health evaluation (APACHE) II score of > 25, or pneumococcal infection, a PSI class of IV or V, or a CURB-65 score of at least 3. For unclear reasons, patients who received adequate therapy had a small drop in mortality rate from 37 to 33%, while the benefit was much greater in those who received inadequate therapy with the mortality rate dropping from 65.2 to 47.1%. While the mortality rate reduction was 28% at 28 days, it fell to 14% at 90 days. These data are interesting and suggest a benefit for this expensive therapy, but ideally a randomized trial of patients with severe CAP, rather than a subset analysis alone, would be more convincing. In addition, the limited benefit for those who received adequate therapy, and the falloff in the 3-month survival benefit detract from the cost-effectiveness of this therapy.
Therapy with systemic corticosteroids has been demonstrated to be useful for patients who are in septic shock and have relative adrenal insufficiency. However, in a new study, therapy with systemic corticosteroids has been tested in patients with severe CAP, based on the idea that adverse outcomes are mediated by the inflammatory response to infection rather than by uncontrolled infection. In a small (48 patients), multicenter, randomized, blinded trial, therapy with a continuous infusion of hydrocortisone was compared to therapy with placebo. Although patients had severe CAP, not all of them were treated in an ICU. Steroid therapy led to significantly lower mortality, shorter length of ICU stay, and shorter duration of mechanical ventilation. In addition, steroid therapy led to fewer late complications. Although the data are impressive, confirmation in a larger study is needed. Nonetheless, the findings do suggest that steroid therapy is not dangerous, even for patients with a severe infection such as CAP.
Figure 3. A randomized trial of pathogen-directed therapy (PDT) compared with empiric therapy in 262 adults with CAP found no significant differences in length of stay (LOS), mortality rate, or rate of therapeutic failure. From Van der Eerden et al.
Table 1—Current CAP Core Measures for Admitted Patients