Chapter 129. Staphylococcal Infections (Part 12) doc

MRSA isolates are also resistant to other antimicrobial families, including aminoglycosides, quinolones, and macrolides.. The VISA strains appear to evolve under vancomycin selective pre

Chapter 129 Staphylococcal Infections

(Part 12)

As a result of the widespread dissemination of plasmids containing the enzyme penicillinase, few strains of staphylococci (<5%) remain susceptible to penicillin However, against susceptible strains, penicillin remains the drug of choice Penicillin-resistant isolates are treated with semisynthetic penicillinase-resistant penicillins (SPRPs), such as oxacillin or nafcillin Methicillin, the first of the SPRPs, is now used infrequently Cephalosporins are alternative therapeutic agents for these infections Second- and third-generation cephalosporins do not have a therapeutic advantage over first-generation cephalosporins for the treatment

of staphylococcal infections The carbapenem imipenem has excellent activity

against methicillin-sensitive S aureus (MSSA) but not MRSA

The isolation of MRSA was reported within 1 year of the introduction of methicillin The prevalence of MRSA has since increased steadily In many

hospitals, 40–50% of S aureus isolates are now resistant to methicillin Resistance

to methicillin indicates resistance to all SPRPs as well as all cephalosporins Many

MRSA isolates are also resistant to other antimicrobial families, including aminoglycosides, quinolones, and macrolides

Production of a novel penicillin-binding protein (PBP 2a or 2') is

responsible for methicillin resistance This protein is synthesized by the mecA

gene, which (as stated above) is part of a large mobile genetic element—a

pathogenicity or genomic island—called SCCmec It is hypothesized that

acquisition of this genetic material resulted from horizontal transfer from a related

staphylococcal species, such as S sciuri Phenotypic expression of methicillin

resistance may be constitutive (i.e., expressed in all organisms in a population) or heterogeneous (i.e., displayed by only a proportion of the total organism population) Detection of methicillin resistance in the clinical microbiology laboratory can be difficult if the strain expresses heterogeneous resistance Therefore, susceptibility studies are routinely performed at reduced temperatures (≤35°C for 24 h), with increased concentrations of salt in the medium to enhance the expression of resistance In addition to PCR-based techniques, a number of rapid methods for the detection of methicillin resistance have been developed

Vancomycin remains the drug of choice for the treatment of MRSA infections Because it is less bactericidal than the β-lactams, it should be used only after careful consideration in patients with a history of β-lactam allergies In 1997,

an S aureus strain with reduced susceptibility to vancomycin (VISA) was reported

from Japan Subsequently, additional clinical isolates of VISA were reported from

geographically disparate locations These strains were all resistant to methicillin and many other antimicrobial agents The VISA strains appear to evolve (under vancomycin selective pressure) from strains that are susceptible to vancomycin but are heterogeneous, with a small proportion of the bacterial population expressing the resistance phenotype The mechanism of VISA resistance is due to an abnormal cell wall Vancomycin is trapped by the abnormal peptidoglycan cross-linking and is unable to gain access to its target site

In 2002, the first clinical isolate of fully vancomycin-resistant S aureus

was reported Resistance in this and three subsequently reported clinical isolates

was due to the presence of vanA, the gene responsible for expression of

vancomycin resistance in enterococci This observation suggested that resistance was acquired as a result of horizontal conjugal transfer from a

vancomycin-resistant strain of Enterococcus faecalis Several patients had both MRSA and

vancomycin-resistant enterococci cultured from infection sites The isolates remained susceptible to chloramphenicol, linezolid, minocycline, quinupristin/dalfopristin, and trimethoprim-sulfamethoxazole (TMP-SMX) The

vanA gene is responsible for the synthesis of the dipeptide D-Ala-D-Lac in place

of D-Ala-D-Ala Vancomycin cannot bind to the altered peptide

Alternatives to the β-lactams and vancomycin have less antistaphylococcal activity Although the quinolones have reasonable in vitro activity against staphylococci, the frequency of fluoroquinolone resistance has increased

progressively, especially among methicillin-resistant isolates MSSA strains have remained more susceptible to the fluoroquinolones than have methicillin-resistant strains Of particular concern in MRSA is the possible emergence of quinolone resistance during therapy Resistance to the quinolones is most commonly chromosomal and results from mutations of the topoisomerase IV or DNA gyrase genes, although multidrug efflux pumps may also contribute While the newer quinolones exhibit increased in vitro activity against staphylococci, it is uncertain whether this increase translates into enhanced in vivo activity Other antibiotics, such as minocycline and TMP-SMX, have been successfully used to treat MRSA infections in the face of vancomycin toxicity or intolerance

Among the newer antistaphylococcal agents, the parenteral streptogramin quinupristin/dalfopristin displays bactericidal activity against all staphylococci, including VISA strains This drug has been used successfully to treat serious MRSA infections In cases of erythromycin or clindamycin resistance, quinupristin/dalfopristin is bacteriostatic against staphylococci

Linezolid—the first member of a new drug family, the oxazolidinones—is bacteriostatic against staphylococci, has been well tolerated, and offers the advantage of comparable bioavailability after oral or parenteral administration Cross-resistance with other inhibitors of protein synthesis has not been reported Resistance to linezolid, although limited, has been reported The efficacy of linezolid in the treatment of deep-seated infections such as osteomyelitis has not

yet been established There are insufficient data on the efficacy of either quinupristin/dalfopristin or linezolid for the treatment of infective endocarditis Daptomycin, a new parenteral bactericidal agent with antistaphylococcal activity,

is approved for the treatment of bacteremias (including right-sided endocarditis) and complicated skin infections It is not effective in respiratory infections This drug has a novel mechanism of action: it disrupts the cytoplasmic membrane Staphylococcal resistance to daptomycin has been reported Tigecycline, a broad-spectrum minocycline analogue, has bacteriostatic activity against MRSA and is approved for use in skin and soft tissue infections as well as intraabdominal

infections caused by S aureus A number of additional antistaphylococcal agents

(e.g., dalbavancin, oritavancin, and ceftobiprole) are undergoing clinical trials

Combinations of antistaphylococcal agents are sometimes used to enhance bactericidal activity in the treatment of serious infections such as endocarditis or osteomyelitis In selected instances (e.g., right-sided endocarditis), drug combinations are also used to shorten the duration of therapy Among the antimicrobial agents used in combinations are rifampin, aminoglycosides (e.g., gentamicin), and fusidic acid (which is not readily available in the United States) While these agents are not effective singly because of the frequent emergence of resistance, they have proved useful in combination with other agents because of their bactericidal activity against staphylococci

In vitro studies have demonstrated synergy against staphylococci with the following combinations: (1) β-lactams and aminoglycosides; (2) vancomycin and gentamicin; (3) vancomycin, gentamicin, and rifampin (against CoNS); and (4) vancomycin and rifampin In several instances, these in vitro observations have been supported by studies in the experimental animal model of endocarditis There

is limited information on combinations including newer agents such as daptomycin and tigecycline