C
ASE STUDY 2 - Answer1. The organism infecting this patient was recovered from a culture of her blood. On Gram stain (Fig. 1), the organism is a gram-positive diplococcus. These diplococci are classically referred to as being "lancet shaped," although this may be difficult to appreciate on some Gram stains of the organism. When grown on 5% sheep blood agar, the organism is alpha-hemolytic. Organisms with these characteristics recovered form clinical specimens usually belong to the genus Streptococcus. The finding that this streptococcus is susceptible to the copper-containing compound optochin identifies this organism as Streptococcus pneumoniae ("pneumococcus"). Streptococci that are resistant to the activity of optochin belong to a group of organisms referred to as "green streptococci" or "viridans streptococci." S. pneumoniae is the most common cause of bacterial pneumonia, and with the widespread use of Haemophilus influenzae type b conjugate vaccine, it has emerged as the most common etiology of bacterial meningitis in the United States.
2. This patient has three risk factors for the development of pneumococcal pneumonia. This infection is more common in (i) the elderly, (ii) individuals with malignancy (in this case, multiple myeloma), and (iii) individuals receiving immunosuppressive agents (corticosteroids). Other individuals at risk are described in answer 6.
3. The organism in Fig. 2 is resistant to multiple antimicrobial agents including penicillin G (E-test MIC, > Fg/ml), erythromycin, and tremethoprim-sulfamethoxazole. It has reduced susceptibility to cefotaxime. The susceptibility of S. pneumoniae to beta-lactam antimicrobial agents can only be accurately ascertained by minimum inhibitory concentration (MIC) determinations. The recommended method for determining beta-lactam MICs is by microbroth dilution, a cumbersome technique which is not widely available for testing pneumococci. An alternative approach is the E-test method (shown in Fig. 2), which has been shown to correlate very well with the reference MIC method. In the E-test, a strip containing a gradient with increasing concentrations of an antimicrobial agent is placed on a plate freshly inoculated with an organism. After overnight incubation, a zone of inhibition shaped like an ellipse (thus the name "E"-test) is formed. Where the area of microbial growth intersects with the strip determines the MIC of the organism.
Pneumococcal resistance to penicillins and cephalosporins (beta-lactams) is due to resistant isolates possessing penicillin-binding proteins (PBPs) with reduced affinity for these drugs. PBPs are proteins involved in cell wall synthesis. Beta-lactam drugs act by binding to these proteins, thus inhibiting their activity. If the PBPs are modified and the beta-lactams have reduced affinity, the organism be comes resistant to the action of these agents. Many beta-lactam-resistant pneumococci are also resistant to classes of antimicrobial agents with other mechanism of action, such as erythromycin, which inhibits protein synthesis. The genomes of these multi-drug-resistant organisms possess a transposon which codes for several different types of resistance genes.
4. Multiply drug-resistant pneumococci are being encountered with increasing frequency throughout the world. In the United States, the organism is particularly problematic in children in group day care. Two factors contribute to this problem. First, respiratory infections are efficiently spread in a day care setting. Further, the infected children frequently receive antimicrobial agents. The combination of ease of transmission and antimicrobial pressure has resulted in the widespread dissemination fo drug-resistant organism. As many as 50% of children attending day care centers who harbor pneumococci have multi-drug-resistant isolates.
5. The polysaccharide capsule surrounding this organism is its major virulence factor. This capsule allows the pneumococcus to evade phagocytosis. The mechanism of this evasion is not completely understood. However, it has been long known that unencapsulated strains of pneumococci are avirulent, at least in experimental animals.
The pathologic event that occur in the lung in pneumococcal pneumonia have only recently begun to be understood. A second pneumococcal virulence factor, pneumolysin, has been recently recognized. This protein, a hemolysin, has cytotoxic activity and when injected into the lungs of experimental animals can cause pathological changes consistent the pneumonia. Understanding of the role of this virulence factor is limited, but it may explain some of the pathologic events seen in the lungs of people with pneumococcal pneumonia.
6. Many different patient populations are at increased risk for invasive pneumococcal disease. Individuals who are asplenic, or functionally splenic, including people with sickle cell disease; are over 65 years or under 2 years of age; have a malignancy, diabetes, or chronic heart, liver, or kidney disease; are chronically immunosuppressed because of connective tissue disease or organ transplantation; or are infected with HIV all are at increased risk for serious pneumococcal infection.
All at-risk individuals except those under 2 years old should receive pneumococcal vaccine. The current available vaccine contains capsular polysaccharide form 23 of the over 80 different pneumococcal serotypes. These 23 serotypes cause >90% of all serious pneumococcal infections. This vaccine is less than ideal. It is not protective in children less that 2 years old, the population in whom pneumococcal meningitis is most frequent. Even the most optimistic estimate would put the efficacy of this vaccine at no better than 75% in immunocompetent adults and lower in the immunosuppressed. (By comparison, many fo the childhood vaccines, i.e., measles, mumps, tetanus, etc., have efficacies of over 95%.)
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