Epidemiologically Important Resistant Gram-Positive Bacteria in Health Care
Cassandra D. Salgado
The incidence of clinically relevant antimicrobial resistance among gram-positive organisms has significantly increased. This has resulted in important changes in the way clinicians approach treatment of infections caused by these pathogens as well as fostered increased awareness for prevention and control, particularly in health care. This chapter focuses on three epidemiologically important gram-positive bacteria, Streptococcus pneumoniae, Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus with reduced susceptibility to vancomycin), and Enterococcus species. Common infections due to these organisms, common resistance mechanisms, treatment options, and prevention measures are discussed.
STREPTOCOCCUS PNEUMONIAE
S. pneumoniae replicates in chains when grown in liquid medium.
In the laboratory, pneumococci have been identified by (1) α-hemolysis when grown on blood agar media, (2) a negative catalase reaction, (3) susceptibility to optochin, and (4) solubility in bile salts.
In a susceptible host, several characteristics of S. pneumoniae likely contribute to infection; however, it is the outer polysaccharide capsule that is largely responsible for virulence of the organism.
The polysaccharide capsule protects the organism against phagocytosis from the cells it invades. The hosts’ specific immune response to capsular antigen (anticapsular antibodies) has served as the basis for serotype identification. There are currently more than 90 different serotypes, but serotypes 6, 14, 18, 19, and 23 are most prevalent and are responsible for the majority of disease.1
The cell wall, primarily composed of glycopeptides, covalently binds to the capsule. Antigens within the cell wall result in a profound inflammatory reaction, and most clinically relevant pneumococcal isolates produce an important virulence factor, pneumolysin, a cytotoxin, responsible for injuring neutrophils, endothelial cells, and alveolar epithelium.
S. pneumoniae colonizes the nasopharynx in 5% to 10% of adults and 20% to 40% of children.2 The rate of invasive disease has been reported as 15 per 100,000 persons per year worldwide. US data suggest that the incidence of pneumococcal disease has decreased, likely as a result of the administration of the protein-conjugate vaccine in children.3
S. pneumoniae is a common cause of pneumonia, sinusitis, and otitis media, likely resulting from direct spread and invasion. S. pneumoniae also causes meningitis, endocarditis, peritonitis, or bone and joint infections; however, these infections are more likely from hematogenous spread.
S. pneumoniae has developed resistance to many classes of antibiotics, including β-lactams, macrolides, tetracyclines, trimethoprim-sulfamethoxazole, and fluoroquinolones. Previous exposure to antibiotics, day care or preschool, nursing home, or other long-term care facility residence and a history of a recent respiratory infection (including viral infections) are risk factors for resistance. The most clinically relevant antibiotic resistance is that toward penicillin.
Penicillin inhibits S. pneumoniae by binding to penicillin binding proteins (PBPs); however, in resistant strains, the PBPs are altered and have much less affinity for penicillin (and often other β-lactams).
Resistance to penicillin is considered to be concentration dependent and the definition based upon achievable drug concentration in the cerebral spinal fluid (CSF); however, achievable drug concentration in CSF is often lower than what is achieved in plasma, inner ear fluid, or alveolar fluid.
In a nonmeningeal infection, S. pneumoniae is susceptible to penicillin when the minimum inhibitory concentration (MIC) is 2 µg/mL, intermediately resistant to penicillin when the MIC is 4 µg/mL, and resistant to penicillin when the MIC is ≥8 µg/mL. In meningeal infection, S. pneumoniae is considered susceptible to penicillin when the MIC 0.06 µg/mL and resistant when ≥ 0.12 µg/mL.4 Rates of penicillin resistance vary by geographic location and patient population. The clinician should be aware of the local and regional epidemiology corresponding to their patient cohort.
In the United States, use of the 7-valent protein conjugate pneumococcal vaccine has resulted in an 80% reduction in invasive disease and a >95% decrease in invasive S. pneumoniae isolates covered by the vaccine.3 However, there has been an increase among strains not included in the vaccine (type 6 (non-B), 19 (non-F), 35, 11, and 15), and many of these strains have demonstrated antimicrobial resistance.
Susceptibility to ceftriaxone, a common third-generation cephalosporin used for treatment of S. pneumoniae infections, is defined as susceptible if the MIC is <1.0 µg/mL, intermediately resistant if the MIC is = 2.0 µg/mL, and resistant if the MIC >4.0 µg/mL.
Up to one-third of S. pneumoniae isolates are resistant to macrolides, 20% to tetracyclines, 30% to trimethoprim-sulfamethoxazole, up to 10% resistant to clindamycin, and 5% to fluoroquinolones (higher among long-term care residents).5
Because of differing achievable drug concentrations, treatment decisions depend on the site of infection. First-line therapy for otitis media and sinusitis is high-dose amoxicillin (90 mg/kg/day divided into twice or three time daily doses). In the case of treatment failure or in the presence of a penicillin allergy, a macrolide may be used. If cross-resistance to penicillin as well as the macrolide class of antibiotics is common in the region, alternatives such as a third-generation cephalosporin should be considered.
For treatment of bacteremia in a normal host, most experts would recommend cefuroxime, cefotaxime, or ceftriaxone at standard doses as achievable plasma levels typically exceed the desired MIC.
For meningitis suspected to be due to S. pneumoniae in a patient who has risk factors for resistance or in a geographic area where isolates exist with intermediate or high resistance to penicillin or ceftriaxone, higher doses of third-generation cephalosporins (cefotaxime 2 g IV every 4 hours or ceftriaxone 2 g IV every 12 hours) plus vancomycin should be utilized. Vancomycin does not readily penetrate the blood-brain barrier; thus, once susceptibilities return, if possible, treatment should be continued with a β-lactam.
STREPTOCOCCUS PNEUMONIAE PREVENTION
Limiting the use of unnecessary antibiotics in both the inpatient and outpatient setting, combined with continued vaccination of susceptible hosts are important measures to control the emergence of resistant S. pneumoniae.
The pneumococcal conjugate vaccine, PCV13, is routinely given to infants as a series of four doses (ages 2 months, 4 months, 6 months, and 12 through 15 months). The 23-valent pneumococcal polysaccharide vaccine, PPSV, is given for prevention of disease among older children and adults. These vaccines are currently recommended for use in all adults who are older than 65 years of age and for persons who are 2 years and older and at high risk for disease (e.g., sickle cell disease, asthma, smoking, HIV infection, or other immunocompromising condition.)
STAPHYLOCOCCUS AUREUS
S. aureus are named for their ability to grow in grape-like clusters in solid media. They are characterized by a positive catalase test and identified as S. aureus by a positive coagulase test.
Several virulence factors have been described including exotoxins (such as toxic shock syndrome toxin) and enterotoxins; leukocidin, which causes destruction of phagocytes; and catalases, coagulases, and hyaluronidases, which promote invasion and survival in tissue. Presence of the Panton Valentine leukocidin (PVL) gene encodes for release of a cytotoxin, which causes tissue necrosis and leukocyte destruction and has been associated with infections of greater severity.6
S. aureus colonizes the skin and mucosa, preferably the anterior nares. Ten percent to forty percent of the population are transiently colonized, and less commonly, some may become chronically colonized and as such may be at increased risk for clinical disease.
Synthetic penicillins (such as methicillin, oxacillin, and nafcillin) have been recommended as first-line therapy for S. aureus infections for decades; however, methicillin resistance among S. aureus has been a continuously emerging problem.
Methicillin resistance results when S. aureus acquires the staphylococcal cassette chromosome mec (SCCmec). Within this large mobile genetic element, the mecA gene mediates β-lactam resistance. Specifically, mecA encodes for an altered PBP, PBP2a, which has little affinity for β-lactam antibiotics conferring resistance to the entire class. Additionally, mecA is often flanked by IS431, an insertion sequence that acts as a “collector” for additional antibiotic-resistance genes for other classes of agents.
At least eight SCCmec cassettes have been described (types I through VIII) based largely on the mecA genes; however, types I through V have been the most studied. Types I, II, and III are large and are more likely to have multiple antibiotic-resistance encoding genes. Types IV and V are smaller, more mobile, and contain fewer antibiotic-resistance encoding genes.
MRSA is defined as having an MIC of >16 mg/L to methicillin or an MIC of >4 mg/L to oxacillin; however, rapid methods, which detect the presence of the mecA gene or its product, PBP2a, for identification of methicillin-resistance, are commonly utilized in health care.7
The epidemiology of MRSA continues to develop, but most continue to rely on whether or not the organism is considered health care associated or community associated, as the prevalence, resistance patterns, and clinical syndromes depend on this classification.
Health Care-Associated MRSA
Health care-associated MRSA (HA-MRSA) has traditionally been defined as being isolated from a patient 72 hours or more after admission to a health care facility. These strains often harbor the SCCmec types I, II, or III and may be multidrug resistant.
HA-MRSA infections include pneumonia, central line-associated bloodstream infections (CLABSI), and surgical site infections (SSI). In 2008, the National Healthcare Safety Network (NHSN) of the Centers for Disease Control (CDC) released a report of antimicrobial-resistant pathogens associated with hospital infections in the United States. The pooled mean proportion of all device-related infections due to MRSA was 8%; however, this varied by type of infection and by patient care area.8 In 2009, a report by the International Nosocomial Infection Control Consortium (INICC) described hospital infections in 173 ICUs from 25 countries in Latin America, Asia, Africa, and Europe.9 Rates of MRSA infections in these international ICUs were generally higher than rates reported from NHSN ICUs. For example, the proportion of S. aureus CLABSI resistant to methicillin among INICC ICUs was 84.1% versus 56.8% reported among NHSN ICUs.Related posts:
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