Resistance to penicillins

Gonorrhea. Gonorrhea, caused by Neisseriagonorrheae is the most commonly reported communicable disease in the United States. Approximately lO cases were reported to the Center for Disease Control (CDC) in 1979, but actual cases could be two to three times higher (99,100). In addition, an increasing number of strains are becoming resistant to penicillin, the antibiotic that is usually used to treat this disease. 

Acylation of 7-ACA with 2-thienylacetylchloride gives the amide cephalothin (43). Displacement of the allylic acetyl group by pyridine affords the corresponding pyridinium salt cephalori-dine (44). Both these compounds constitute useful injectable antibiotics with some activity against bacteria resistant to penicillin by reason of penicillinase production. 

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%. 

Additional culture and sensitivity tests may be performed during therapy because microorganisms causing the infection may become resistant to penicillin, or a superinfection may have occurred. A urinalysis, complete blood count, and renal and hepatic function tests also may be performed at intervals during therapy. 

The effectiveness of penicillin in the treatment of infections prompted research directed toward finding new antibiotics with a wider range of antibacterial activity. The cephalosporins are a valuable group of drugp that are effective in the treatment of almost all of the strains of bacteria affected by the penicillins, as well as some strains of bacteria that have become resistant to penicillin. The cephalosporins are structurally and chemically related to penicillin. 

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. 

Development of resistance to P -lactam antibiotics, including penicillins and cephalosporins, has significantly impacted the management of bacterial meningitis. Approximately 17% of United States pneumococcal CSF isolates are resistant to penicillin, and 3.5% of CSF isolates are resistant to cephalosporins.26 The Clinical and Laboratory Standards Institute (CLSI) has set a lower ceftriaxone susceptibility breakpoint for pneumococcal CSF isolates (1 mg/L) than for isolates from non-CNS sites (2 mg/L). Increasing pneumococcal resistance to penicillin G... 

Resistance to commonly prescribed antimicrobials such as the penicillins and macrolides/azalides increased dramatically in the late 1980s through the middle to late 1990s. Table 68-2 provides resistance information collected nationally from 1999 to 2004 using the Tracking Resistance in the US Today (TRUST) surveillance database.26 In 2004, the average national rate of resistance to penicillin and macrolides was approximately 18% and 25%, respectively. Susceptibility results alone do not account for clinical success or failures when treating pneumonia. 

Therefore, despite the 18% and 25% resistance to penicillin and macrolides, the clinical failure rate is less than this. Owing to the empirical treatment of CAP in the outpatient setting, establishing a meaningful clinical failure rate with any therapy is difficult to do. No studies have been performed that established a correlation between clinical failure rates with a particular antimicrobial agent and the percentage of resistant bacterial pathogens. 

Viridans streptococci than or equal to 30% Increasing resistance to penicillin ... 

The treatment of choice until susceptibility of the organism is known as the combination of vancomycin plus ceftriaxone. Penicillin may be used for drug-susceptible isolates with minimum inhibitory concentrations of 0.06 mcg/mL or less, but for intermediate isolates ceftriaxone is used, and for highly drug-resistant isolates a combination of ceftriaxone and vancomycin should be used. A high percent of S. pneumoniae is either intermediately or highly resistant to penicillin. 

Virtually all serotypes of S. pneumoniae exhibiting intermediate or complete resistance to penicillin are found in the current 23 serotype pneumococcal vaccine. A heptavalent conjugate vaccine is available for use in infants between 2 months and 9 years of age. Current recommendations are for all healthy infants younger than 2 years of age to be immunized with the heptavalent vaccine at 2, 4, 6, and 12 to 15 months. 

Therapy of Native Valve Endocarditis Caused by Strains of Viridans Group Streptococci and Streptococcus bovis Relatively Resistant to Penicillin... 

S. pneumoniae isolates are often intermediate resistant to penicillin (8% to 34%) and some are highly penicillin resistant (12% to 21%). Penicillin-resistant isolates are often resistant to multiple antibiotics. fl- Lactam resistance occurs in about 23% to 35% of H influenzae and in up to 100% of M. catarrhalis. 

J. M. Ghuysen, Penicillin-Binding Proteins. Wall Peptidoglycan Assembly and Resistance to Penicillin Facts, Doubts and Hopes , bit. J. Antimicrob. Agents 1997, 8, 45-60. 

J. Coyette, M. Nguyrn-Disteche, J. Lamotte-Brasseur, B. Joris, E. Fonze, J. M. Frere, Molecular Adaptation in Resistance to Penicillins and Other /3-Lactam Antibiotics, Adv. Comp. Environ. Physiol. 1994, 20, 233-267. 

The bacterium Staphylococcus aureus, which is a major cause of infection in the developed countries, is now resistant to most antibiotics. It is usually present on the skin, where it causes no problems, but it can invade the body through cuts and wounds, including those caused by surgery. These bacteria are now prevalent in many hospitals, so that infection is a major problem for the medical staff in hospitals. The resistant bacterium is known as methicillin-resistant Staphylococcus aureus (MRSA). It is also known in the mass media as the super bug . Penicillin kiUs bacteria because the P-lactam group in the antibiotic inhibits a reaction that is essential for bacterial ceU wall production. Consequently, the bacteria cannot proliferate. Resistance to penicillin in many bacteria is due to production of an enzyme, p-lactamase, that degrades P-lactams. The antibiotic methicillin is one of a group of semisynthetic penicillins in which the P-lactam group is not... 

Streptococcal infections 1.2 MU IM. Many streptococcal strains are now resistant to penicillin. 

A senior British government veterinarian stated in 1962 (3)> When penicillin was first used in treating mastitis only 2% of the strains of staphylococci recovered from cases of mastitis were resistant to penicillin. Today the figure is over 70%. Between 1958 and 1961, resistance to penicillin (PEN) increased from 62.0% to 70.6%. Resistance to streptomycin (STR), tetracycline and chloramphenicol also increased (. Antibiotic resistance increased for isolates of both mastitis staphylococci and streptococci in Canada between I960 and 1967 (5). In Belgium (6), Staphylococcus aureus strains isolated from cases of bovine mastitis showed increase in PEN resistance from 38% in 1971 to 78% in 1974> but then no further increase to 1980. The resistance situation was reported to remain stable in the Federal Republic of Germany between 1962 and 1975 (7), as also in Australia between 1974 and 1979 (8 ) and Denmark, at a very low level, for the period 1963 to 1978 (9). 

Penicilhns that are resistant to penicilhnase are the drug of choice for infections resistant to penicillin G, Staph, aureus, or coagulase-negative staphylococci. They are also effective for infections caused by nonenterococcus types of streptococci, such as streptococci groups A, B, C, and G, as weh as pneumococci. 

Penicillinase-resistant penicillins The percentage of staphylococcal isolates resistant to penicillin G outside the hospital is increasing, approximating the high percentage found in the hospital. Therefore, use a penicillinase-resistant penicillin as initial therapy for any suspected staphylococcal infection until culture and sensitivity results are known. 

Some organisms, such as Staphylococcus aureus, Neisseria gonorrhoeae, and Haemophilus influenzae, may produce -lactamase and therefore be resistant to penicillin and its congeners. Testing for 3-lactamase production by isolates enables an early decision on the use of penicillin and congeners in treatment of the disease. 

Because of the ability of bacteria to develop resistance to penicillin, pharmaceutical companies must continually develop different penicillin compounds for continued use as an antibiotic. Different forms are also used depending on the type of infection, delivery method, and individual. The form discovered by Fleming and used by Florey was benzylpenicillin or Penicillin G. Today there are numerous compounds that are classified as penicillins that are marketed under various trade names. Early penicillins were biosynthetic compounds obtained from molds. Modern penicillins are semisynthetic in which penicillin obtained from natural sources is further synthesized to impart specific properties to the compound. 

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