G. Douglas Campbell

Drug-Resistant Streptococcus pneumoniae

Streptococcus pneumoniae remains a major cause of infection in both children and adults, annually resulting in significant morbidity and mortality. The past two decades have seen an alarming worldwide increase in the incidence of drug-resistant S. pneumoniae (DRSP). DRSP is now common throughout the United States, and physicians are questioning how best to approach this epidemic. With the introduction of a number of newer antimicrobial agents, the potential for improved preventive measures, and a better understanding of DRSP, the approach to the management of DRSP infections may change greatly in the next few years. In this article we will review the development of DRSP, identify populations at increased risk of exposure to DRSP, address what approaches might be used to limit its spread, and suggest initial empirical therapy when treating patients with pneumonia due to DRSP.

Practice Guidelines for the Management of Patients with Blastomycosis

Guidelines for the treatment of blastomycosis are presented; these guidelines are the consensus opinion of an expert panel representing the National Institute of Allergy and Infectious Diseases Mycoses Study Group and the Infectious Diseases Society of America. The clinical spectrum of blastomycosis is varied, including asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease. Most patients with blastomycosis will require therapy. Spontaneous cures may occur in some immunocompetent individuals with acute pulmonary blastomycosis. Thus, in a case of disease limited to the lungs, cure may have occurred before the diagnosis is made and without treatment; such a patient should be followed up closely for evidence of disease progression or dissemination. In contrast, all patients who are immunocompromised, have progressive pulmonary disease, or have extrapulmonary disease must be treated. Treatment options include amphotericin B, ketoconazole, itraconazole, and fluconazole. Amphotericin B is the treatment of choice for patients who are immunocompromised, have life-threatening or central nervous system (CNS) disease, or for whom azole treatment has failed. In addition, amphotericin B is the only drug approved for treating blastomycosis in pregnant women. The azoles are an equally effective and less toxic alternative to amphotericin B for treating immunocompetent patients with mild to moderate pulmonary or extrapulmonary disease, excluding CNS disease. Although there are no comparative trials, itraconazole appears more efficacious than either ketoconazole or fluconazole. Thus, itraconazole is the initial treatment of choice for nonlife-threatening non-CNS blastomycosis.

Treatment of Blastomycosis with Higher Doses of Fluconazole

Recent clinical data suggest that fluconazole at daily doses of 200 to 400 mg for at least 6 months is moderately effective therapy for non-life-threatening blastomycosis. To examine the usefulness of higher doses of fluconazole therapy for this disorder, we conducted a multicenter, randomized, open-label study to determine the efficacy and safety of two different daily doses of fluconazole (400 and 800 mg) in the treatment of non-life-threatening blastomycosis. Of 39 patients evaluable for efficacy analysis, 34 (87%) were successfully treated, including 89% and 85% of patients who received 400 and 800 mg, respectively. Five (83%) of six patients for whom prior antifungal therapy had failed were successfully treated. The mean duration of therapy was 8.9 months for successfully treated patients. Nineteen patients (48%) reported adverse events, although most were minor. We conclude that fluconazole at daily doses of 400 to 800 mg for at least 6 months is effective therapy for non-life-threatening blastomycosis.

Overview of communityacquired pneumonia: Prognosis and Clinical Features

Despite the introduction of newer antibiotics, vaccinations, and better supportive care, CAP remains a common, frequently fatal disease. Age and coexisting illness influence which infectious agents are most likely to cause infection. Severity of illness and clinical features are influenced by various host factors and by the virulence of the infectious agent. Mortality and morbidity are reduced by the rapid institution of appropriate antimicrobial therapy. Because of the limitations of presently available diagnostic tests, many patients are begun on empiric regimens, and in up to half of these individuals, a cause is not identified. Although there are a number of potential pathogens, it is possible to identify likely pathogens based on easily identifiable clinical factors (age, presence of coexisting disease, severity of illness at presentation, and the need for hospitalization). Using this approach, CAP in immunocompetent adults may be divided into four categories. Once empiric therapy has been initiated, therapy should be continued for at least 72 hours unless clinical deterioration is noted. Within 4 days, fever and leukocytosis should return to baseline, but abnormal physical findings (i.e., crackles) require longer to resolve, especially with coexisting illness, and chest radiographic findings are the last to return to baseline and are especially delayed if the patient is bacteremic or has structural lung disease. Not all patients respond to initial empiric therapy. Reasons for this include antimicrobial resistance, the presence of nonbacterial pathogens (respiratory viruses), unusual bacterial pathogens, noninfectious causes that may mimic CAP, infectious complications (i.e., empyema), and pneumonia occurring in patients with unrecognized severe immunosuppression. Failure to improve after 72 hours and development of deterioration are indications for repeat diagnostic workup and consideration of alternative diagnoses. More invasive diagnostic tests are appropriate in severely ill patients and in those whose condition is deteriorating rapidly.

DRUG-RESISTANT PATHOGENS IN COMMUNITY- AND HOSPITAL-ACQUIRED PNEUMONIA

Antimicrobial resistance has been a problem since the early days of the antibiotic era, but in recent years, this resistance has increased in the hospital and is being recognized more in the community setting. Respiratory pathogens such as S. pneumoniae and H. influenzae, for example, have developed resistance to traditional antimicrobial therapy, often over a very short period of time. This increase in resistance patterns requires physicians to closely monitor antimicrobial resistance in their community and to appreciate that some antimicrobial resistance mechanisms may result in resistance for a complete class of antibiotics or different classes of antibiotics with similar mechanisms of action.

THERAPY OF NOSOCOMIAL PNEUMONIA

HAP remains a major cause of morbidity and mortality among hospitalized patients. Although early appropriate therapy results in improved outcomes, the cause of HAP frequently is not known at the time antimicrobial therapy is initiated. Most cases of HAP result from microaspiration of oropharyngeal secretions previously colonized with pathogenic bacteria, and the spectrum of potential pathogens is broad. Taking several factors into account can narrow this spectrum, including severity of illness, length of stay before the onset of pneumonia, and presence of risk factors for specific pathogens. When therapy has been initiated, follow-up of microbial studies and careful monitoring of the patients course is important. The clinical improvement, even when therapy is appropriate, frequently takes days; therapy should not be changed for the first 2 to 3 days unless frank deterioration is noted. Patients who fail to respond or experience clinical deterioration should be re-examined carefully, and thought should be given to the possibility of other noninfectious processes.

The Role of Antimicrobial Therapy in Acute Exacerbations of Chronic Bronchitis

Acute exacerbations of chronic bronchitis (AECB) result in increased morbidity and mortality. The role of bacteria in AECB, the importance of antimicrobial therapy, and the choice of antimicrobial agents have been debated for decades. Fortunately, within the past few years, a number of studies and one consensus statement have been reported that have increased the understanding of the role of bacteria in AECB and suggest approaches in selecting antimicrobial therapy. This article will review these studies and present an empiric approach in treating AECB based upon the patients presenting findings, related risk factors, and potential antimicrobial resistance patterns that may be encountered.

Pleural effusion. What you can learn from the results of a 'tap'.

Pleural effusion may result from many disorders, some of them serious. Fortunately, this body fluid is easily accessible, and knowledge of its characteristics is an important tool in diagnosing the underlying disease. The authors describe radiographic and laboratory tests to use in determining the source of the problem.

E5 Monoclonal Immunoglobulin M Antibody for the Treatment of Gram-Negative Sepsis

Despite the advent of aminoglycoside and beta-lactam antibiotics and early antimicrobial intervention, overall morbidity and mortality associated with gram-negative sepsis and bacteremia remain high. Complications of sepsis have been related to the release of endotoxin from the cell walls of gram-negative bacilli. Although antibiotics can effectively kill gram-negative bacteria, they have no effect on lipopolysaccharide (LPS) and may, in fact, enhance its release when cell lysis occurs. Lipid A, the lipid portion of LPS, is composed of glucosamines, polar phosphate groups, and fatty acids. It represents the endotoxic component of gram-negative bacteria and is responsible for host responses to LPS, including fever, hypotension, and shock. E5 is a murine monoclonal immunoglobulin M antibody directed against the lipid A portion of the cell-wall endotoxin that is common to clinically important gram-negative bacilli. A clinical evaluation program of E5 included patients who were moderately to severely ill with clinical evidence of an infection usually caused by gram-negative bacteria. In pharmacokinetic and safety studies, laboratory tests revealed no evidence of antibody-mediated toxicity and serum antibody concentrations in the desired therapeutic range (>5 μg/mL) were found as late as 72 hours after initial infusion of E5. In a Phase II study, mortality rates at seven days in patients with documented gram-negative infection were 22 percent in the placebo group compared with 7 percent in the Estreated groups. In a large Phase III multicenter trial of patients who had not progressed to refractory shock, those treated with E5 were significantly more likely to survive; these patients also experienced significantly greater resolution of organ failures than those who were given placebo. E5 appears to be well tolerated; no antibody-mediated toxicity has been noted in any studies to date. Minor allergic reactions were the most common adverse effect observed in the 247 patients given at least part of one dose of E5 (less than two percent incidence). No drug interactions have been reported with E5. Overall, infusions of E5 administered in clinical trials as an adjunct to antibiotics and supportive therapy have enhanced resolution of organ failure associated with gram-negative sepsis and have reduced mortality in patients not in refractory shock.