Staphylococcus aureus drug resistance

The phenomenon of bacterial resistance to antibiotics was already known by the pioneers of the era of antibiotics, like Paul Ehrlich, who coined the term selective toxicity as the basic principle of antimicrobial therapeutics, as well as Gerhard Domagk, the inventor of the sulfonamide drugs, and Sir Alexander Fleming, the discoverer of the penicillins. When penicillin G was introduced into clinical practice in 1944, as many as 5% of the isolates of Staphylococcus aureus were resistant to penicillin, while 5 years later the percentage was 50%. 

Let us work out an example (Example 8.2). In a drug stability evaluation, an antimicrobial product was held at ambient temperature ( 68°F) for 12 months. The potency (%) through HPLC was measured, 10 colony-forming units (CPU) of Staphylococcus aureus (methicillin-resistant) were exposed to the product for 2 min, and the microbial reductions (logio scale) were measured. Table 8.2 provides the data. 

In this way Staphylococcus aureus becomes resistant to penicillin in the clinic. Penicillin-resistant strains isolated from patients secrete the enzyme p-lactamase ( penicillinase ). This enzyme hydrolyses the drug to penicil-loic acid, which is biologically inert (see Section 12.i). Penicillinase-producing staphylococci are inherently quite sensitive to penicillin. Hence small inocula can be inhibited by low concentrations of the antibiotic. It is, in effect, a race between the speed with which penicillin can kill the bacteria and the speed with which they can produce enough of the enzyme to destroy the penicillin (Knox, 1962). Actually penicillin can be made to induce some strains of Staph, aureus to produce penicillinase. No permanently resistant population of this bacterium has arisen in this way, and the organisms return fairly rapidly to the uninduced susceptible state when the penicillin is withdrawn. Much of the detail of penicillinase-induction was first worked out in Bacillus cereus (Pollock and Ferret, 1951). 

In recent years multi-drug resistance has increased among certain pathogens. These include aureus, enterococci andM. tuberculosis. Staphylococcus aureus... 

Bacterial resistance to antibiotics has been recognized since the first drugs were introduced for clinical use. The sulphonamides were introduced in 1935 and approximately 10 years later 20% of clinical isolates of Neisseria gonorrhoeae had become resistant. Similar increases in sulphonamide resistance were found in streptococci, coliforms and other bacteria. Penicillin was first used in 1941, when less than 1 % of Staphylococcus aureus strains were resistant to its action. By 1947,3 8% of hospital strains had acquired resistance and currently over 90% of Staph, aureus isolates are resistant to penicillin. Increasing resistance to antibiotics is a consequence of selective pressure, but the actual incidence of resistance varies between different bacterial species. For example, ampicillin resistance inEscherichia coli, presumably under similar selective pressure as Staph, aureus with penicillin, has remained at a level of 30-40% for mai years with a slow rate of increase. Streptococcus pyogenes, another major pathogen, has remained susceptible to penicillin since its introduction, with no reports of resistance in the scientific literature. Equally, it is well recognized that certain bacteria are unaffected by specific antibiotics. In other words, these bacteria have always been antibiotic-resistant. 

Gilbart J., Perry CR. Slocombe B. (1993) High-level mupirocin resistance in Staphylococcus aureus evidence for two distinct isoleucyl-tRNA synthetases. Antimicrob Agents Chemother, 31, 32-38. Godfrey A.J. Bryan L.E. (1984) Intrinsic resistance and whole cell factors contributing to antibiotic resistance, hv. Antimicrobial Drug Resistance (ed. L.E. Bryan), pp. 113-145. New York Academic Press. 

Scheinfeld N. (2007) A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus Aureus and enterococcus. J Drugs Dermatol 6 97-103. 

An additional disadvantage with many penicillin and cephalosporin antibiotics is that bacteria have developed resistance to the drugs by producing enzymes capable of hydrolysing the P-lactam ring these enzymes are called P-lactamases. This type of resistance still poses serious problems. Indeed, methicillin is no longer used, and antibiotic-resistant strains of the most common infective bacterium Staphylococcus aureus are commonly referred to as MRSA (methicillin-resistant Staphylococcus aureus). The action of P-lactamase enzymes resembles simple base hydrolysis of an amide. 

Among the many other non-oxicam-type substances discovered are a sultam pro-drug for potential P3-lactam thrombin inhibitors <1998BML3683>. Furthermore, an anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) pharmacophore based on the 1,2-thiazine structure has also been recently disclosed <1999BML673>. Workers at Bristol-Meyers Squibb have synthesized and evaluated sultam hydroxamates as MMP-2 inhibitors <2004JME2981>. Hydroxamate 38 displayed the best selectivity for MMP-2 over the other proteins in this superfamily of peptidases (Figure 27). As noted in Section 8.07.3.1, an X-ray crystal structure of 38 bound to the protein MMP-13 protein has been solved. 

Tikofsky, L.L., Barlow, J.W., Santisteban, C. and Schukken, Y.H. 2003. A comparison of antimicrobial susceptibility patterns for Staphylococcus aureus in organic and conventional dairy herds. Microbial Drug Resistance-Mechanisms Epidemiology and Disease 9 S39-S45. 

Mupirocin (Bactroban) inhibits a specific enzyme responsible for tRNA synthesis in susceptible bacteria. This drug is used topically to treat skin infections caused by Staphylococcus aureus or Streptococcus pyogenes. Likewise, mupirocin can be administered by nasal spray to treat local colonization of S. aureus in the nasal mucosa. This idea may be especially helpful in preventing systemic infection in individuals such as health care workers who are exposed to an outbreak of resistant strains of S. aureus. Local/topical administration of this drug is well tolerated, although some irritation of the skin may occur during topical use, and cough and respiratory irritation can occur when mupirocin is administered by nasal spray. 

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