Penicillinases inhibitors

It is clinically important to understand the nature of the mechanism of resistance to an antibiotic drug. For example, the -lactam resistance of Streptococcus pneumoniae is due to the appearance of altered penicillinbinding proteins. Thus, the use of a combination of a 3-lactam and a penicillinase inhibitor, such as clavulanate, wUl not overcome streptococcal -lactam resistance, because the mechanism of resistance is not due to the production of a penicillinase. 

Staphylococcus aureus Abscesses bacteremia cellulitis endocarditis osteomyelitis pneumonia others If methicillin-sensitive nafcillin or oxacillin If methicillin-resistant vancomycin gentamicin or rifampin 1 st-generation cephalosporin clindamycin erythromycin trimethoprim-sulfamethoxazole a penicillin + a penicillinase inhibitor... 

The natural penicillins, primarily G and V, have a relatively narrow spectrum. They act mostly on gram-positive organisms. The fact that proper selection of precursors could lead to new variations in the penicillin side chain offered the first source of synthetic penicillins. Penicillin V, derived from a phenoxy-acetic acid precursor, attracted clinical use because of its greater acid tolerance, which made it more useful in oral administration. Also, the widespread use of penicillin eventually led to a clinical problem of penicillin-resistant staphylococci and streptococci. Resistance for the most part involved the penicillin-destroying enzyme, penicillinase, which attacked the beta-lactam structure of the 6-aminopenicillanic acid nucleus (6-APA). Semisynthetic penicillins such as ampicillin and carbenicillin have a broader spectrum. Some, such as methicillin, orafi-cillin, and oxacillin, are resistant to penicillinase. In 1984, Beecham introduced Augmentin, which was the first combination formulation of a penicillin (amoxicillin) and a penicillinase inhibitor (clavulanic acid). Worldwide production of semisynthetic penicillins is currently around 10,000 tons/year, the major producers are Smith Kline Beecham, DSM, Pfizer, and Toyo Jozo. 

Ticarcillin, piperacillin, azlocillin—- T activity versus gram-negative rods, including Pseudomonas aeruginosa activity enhanced in combination with penicillinase inhibitors. 

Penicillinase inhibitors, such as davulanic acid and sulbactam, are suidde inhibitors. 

Metabolism of a substrate by an enzyme to form a compound that irreversibly inhibits that enzyme. Penicillinase inhibitors, such as clavulanlc acid and 5ul-bactam, are suicide inhibitors. 

One penicillinase inhibitor is a sulfone, which is easily prepared from penicillin by oxidizing the sulfur atom with a peroxyacid (Section 20.4). 

Ampicillin disturbs normal microflora and may cause yeast infections and also colitis due to staphylococcal or clostridial species. Maculopapular rashes occur quite frequently during use of ampicillin, especially if the drug is administered to patients with viral infections. Sulbactam (a penicillinase inhibitor) enhances activity, but no penicillin has activity against MRSA strains. The answer is (D). 

Semisynthetic penicillins such as ampicillin, carbenicillin have a broader spectrum. Some, such as methicillin, oraficillin, and oxacillin, are resistant to penicillinase. In 1984, Beechem introduced Augmentin, which was the first combination formulation of a penicillin (amoxillin) and a penicillinase inhibitor (clavulanic acid). In 1985, Beechem introduced Timentin, a ticarcillin/clavulanic acid combination, and Pfizer in 1987 introduced Unasyn, an ampicillin/sulbactam sodium combination. 

BLIC, /5-lactamase inhibitor combination BL/BLI, jS-lactamase/jS-lactamase inhibitor FGC, first-generation cephalosporin MIC, minimal inhibitory concentration PRP, penicillinase-resistant penicillin SGC, second-generation cephalosporin TGC, third-generation cephalosporin. Penicillinase-resistant penicillin nafcillin or oxacillin. 

Although some European countries still accept the results of the four plate test as confirming the presence of antibiotic residues in samples ( ), other work indicates that FPT test is not necessarily reliable. The occurrence of natural microbial inhibitors in tissues has frequently been noted (4,9,49,82), It has also been frequently observed that the results obtained by microbial and physicochemical procedures sometimes differ considerably (9,10,45,82,86), Results obtained in our laboratory suggest that even inactivation by penicillinase may not be totally specific for B-lactam antibiotics (W), The specificity of immunoassay procedures depends on the specificity of the antibody used in the test (95), Specific antisera are not widely available at present. Physicochemical procedures are therefore essential for identification and confirmation of suspect residues detected by microbiological tests. 

Many bacteria produce a p-lactamase or penicillinase which opens the (3-lactam ring rendering some p-lactams ineffective. The problem of p-lactamase-producing bacteria can, in part, be overcome by the addition of a p-lactamase inhibitor such as clavulanic acid (as in co-amoxiclav). 

Inhibitor test with Direct assay S rein Jute (M. 16-18 h at 30 C None (visual check Penicillinase 41, ... 

In assays in which bromocresol purple indicator is incorporated into the medium (disc assay for penicillin, disc assay with indicator), a clear bluish zone around the disk appears if samples contain inhibitory substances. When addition of penicillinase to positive milk samples eliminates the zone, the inhibitors can be roughly identified as -lactams. Among these tests, the 3 h Bacillus stearothermophilus disc assay was selected in 1981 as the regulatory test for detecting antibiotic residues in milk. Although particularly sensitive to -lactams, this test is relatively insensitive to a number of commonly used antibiotics (20). 

The Sarcina lutea test is the official US Food and Drug Administration (FDA) test for detecting penicillin residues in milk and dairy products (41). In this test, milk samples are placed in stainless steel cylinders on an agar plate seeded with Sarcina lutea ATCC 9341. As milk diffuses into the agar, inhibitors prevent the growth of the organism, causing a zone the width of which is a measure of the antibiotic concentration. The test is sensitive to about 0.006 g/ ml penicillin G, and confirmation of positive results can be performed by the addition of penicillinase. 

The presence of -lactam antibiotics can be confirmed by digestion with Penase, a type I penicillinase, or with a -lactamase (109). In the seven-plate assay, Penase is incorporated in all but one plate to differentiate -lactam antibiotics from other types. However, -lactams such as cloxacillin and the cephalosporins are resistant to degradation by Penase (110-112). Thus, they may not be identified as -lactams by this procedure and are classified as unidentified microbial inhibitors. However, these Penase-resistant compounds can be degraded by other -lactamases. 

Correct answer a D. Amoxicillin plus clavulanic acid is an extended spectrum formulation that is penicillinase resistant because of the presence of a p-lactamase inhibitor, and is stable in acid. Methicillin, an antistaphylococcal penicillin, is penicillinase resistant but is not stable in acid. Carbeniciliin and piperacillin, antipseudomonai penicillins, are neither penicillinase resistant nor stable in acid. Penicillin V is a narrow spectrum antibiotic that is not penicillinase resistant but is stable in acid. 

Extended-activity spectrum The amino-penicillin amoxicillin is active against many Gram-negative organisms, e.g., colibacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of penicillinase (clavulanic acid, sulbactam, tazobactam). 

If the bacterium produces the enzyme -lactamase (penicillinase), the /8-lactam ring of the antibiotic will be enzymatically opened and rendered ineffective. Genes encoding these enzymes may be inherently present on the bacterial chromosome, or may be acquired via plasmid transfer (horizontal gene transfer) /3-lactamase gene expression may also be induced by exposure to /S-lactams. The production of a /3-lactamase by a bacterium does not necessarily rule out all treatment options with /3-lactam antibiotics. In some instances /3-lactam antibiotics may be co-administered with a /S-lactamase inhibitor. 

A disadvantage of ampicillin and amoxicillin is that they are inactivated by penicillinase, and more strains of H. influenzae are becoming resistant through penicillinase (p-lactamase) production. The addition of a p-lactamase inhibitor such as clavulanate (clavulanic acid) or sulbactam to a penicillin preparation can protect the penicillin component because these chemicals irreversibly inactivate bacterial P-lactamases. 

RECEPTOR ANTAGONIST reported to have little sedative action, tazifylline hydrochloride tazifyUine. tazobactam (inn] (tazobactam sodium [usan]) is an ENZYME INHIBITOR active against the P-lactamase ( penicillinase ) enzymes produced by Gram-positive and -negative bacteria. Clinically, it can be used co-administered with -lactamase susceptible penicillins and cephalosporins, enhancing their antibacterial actions, tazobactam sodium tazobactam. 

---