The treatment of choice for Staphylococcus aureus infection is penicillin; but in most countries, penicillin-resistance is extremely common and first-line therapy is most commonly a penicillinase-resistant penicillin (for example, oxacillin or flucloxacillin). Combination therapy with gentamicin may be used to treat serious infections like endocarditis, but its use is controversial because of the high risk of damage to the kidneys. The duration of treatment depends on the site of infection and on severity.
Antibiotic alvz resistance in ''S. aureus'' was almost unknown when penicillin was first introduced in 1943; indeed, the original petri dish on which Alexander Fleming of Imperial College London observed the antibacterial activity of the penicillium mould was growing a culture of ''S. aureus''. By 1950, 40% of hospital ''S. aureus'' isolates were penicillin resistant; and by 1960, this had risen to 80%.
Researchers from Italy have identified a bacteriophage active against Staphylococcus aureus, including methicillin-resistant strains, in mice and possibly humans.
Mechanisms of antibiotic resistance
Staphylococcal resistance to penicillin is mediated by penicillinase (a form of β-lactamase) production: an enzyme which breaks down the β-lactam ring of the penicillin molecule. Penicillinase-resistant penicillins such as methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin and flucloxacillin are able to resist degradation by staphylococcal penicillinase.
Resistance to methicillin is mediated via the ''mec'' operon, part of the staphylococcal cassette chromosome mec (SCC''mec''). Resistance is conferred by the ''mecA'' gene, which codes for an altered penicillin-binding protein (PBP2a or PBP2') that has a lower affinity for binding β-lactams (penicillins, cephalosporins and carbapenems). This allows for resistance to all β-lactam antibiotics and obviates their clinical use during MRSA infections. As such the glycopeptide, vancomycin, is often deployed against MRSA.
Aminoglycosides such as kanamycin, gentamicin, streptomycin, etc. were once effective against Staphylococcal infections until the organism evolved mechanisms to destroy the aminoglycosides action, which occurs via protonated amine and/or hydroxyl interactions with the ribosomal RNA of the bacterial 30S Ribosome There are three main mechanisms of aminoglycoside resistance mechanisms which are currently and widely accepted: Aminoglycoside modifying enzymes, Ribosomal mutations, and active efflux of the drug out of the bacteria.
Aminoglycoside modifying enzymes are enzymes that inactivate the aminoglycoside by covalently attaching either a phosphate, nucleotide, or acetyl moiety to either the amine and/or alcohol functionality of the antibiotic; thus rendering the antibiotic through sterics or lack of charge, ineffective in ribosomal binding affinity. In ''Staphylococcus Aureus'' the best characterized aminoglycoside modifying enzyme is ANT(4')IA ''Aminoglycoside adenylyltransferase 4' IA''. This enzyme has been solved by X-Ray Crystallography The enzyme is able to attach an adenyl moiety to the 4' hydroxyl group of many aminoglycosides including kamamycin and gentamicin.
Glycopeptide resistance is mediated by acquisition of the vanA gene. The vanA gene originates from the enterococci and codes for an enzyme that produces an alternative peptidoglycan to which vancomycin will not bind.
Today, ''S. aureus'' has become resistant to many commonly used antibiotics. In the UK, only 2% of all ''S. aureus'' isolates are sensitive to penicillin with a similar picture in the rest of the world, due to a penicillinase (a form of β-lactamase). The β-lactamase-resistant penicillins (methicillin, oxacillin, cloxacillin and flucloxacillin) were developed to treat penicillin-resistant ''S. aureus'' and are still used as first-line treatment. Methicillin was the first antibiotic in this class to be used (it was introduced in 1959), but only two years later, the first case of methicillin-resistant ''S. aureus'' (MRSA) was reported in England.
Despite this, MRSA generally remained an uncommon finding even in hospital settings until the 1990s when there was an explosion in MRSA prevalence in hospitals where it is now endemic.
MRSA infections in both the hospital and community setting are commonly treated with non-β-lactam antibiotics such as clindamycin (a lincosamine) and co-trimoxazole (also commonly known as trimethoprim/sulfamethoxazole). Resistance to these antibiotics has also led to the use of new, broad-spectrum anti-Gram positive antibiotics such as linezolid because of its availability as an oral drug. First-line treatment for serious invasive infections due to MRSA is currently glycopeptide antibiotics (vancomycin and teicoplanin). There are number of problems with these antibiotics, mainly centred around the need for intravenous administration (there is no oral preparation available), toxicity and the need to monitor drug levels regularly by means of blood tests. There are also concerns that glycopeptide antibiotics do not penetrate very well into infected tissues (this is a particular concern with infections of the brain and meninges and in endocarditis). Glycopeptides must not be used to treat methicillin-sensitive ''S. aureus'' (MSSA) as outcomes are inferior.
Because of the high level of resistance to penicillins, and because of the potential for MRSA to develop resistance to vancomycin, the Centers for Disease Control and Prevention have published guidelinesfor the appropriate use of vancomycin. In situations where the incidence of MRSA infections is known to be high, the attending physician may choose to use a glycopeptide antibiotic until the identity of the infecting organism is known. When the infection is confirmed to be due to a methicillin-susceptible strain of ''S. aureus'', then treatment can be changed to flucloxacillin or even penicillin as appropriate.
Further Reading
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