P-lactamases resistant penicillins

As a general rule these agents are rather less active than benzylpenicillin against Gram-positive cocci, but more active than the P-lactamase-resistant penicillins (above). They have useful activity against Enterococcus faecalis and many strains of Haemophilus influenzae. Enterobacteriaceae are variably sensitive and laboratory testing for sensitivity is... 

The mechanisms of action of penicillins, the bacterial modes of resistance to penicillins, the penicillin subgroups, their biodisposition, and adverse affects are provided. The subgroups discussed are the penicillins that are p-lactamase susceptible with a narrow spectrum of activity, p-lactamase-resistant penicillins having a very narrow spectrum of activity, and J3-lactamase—susceptible penicillins with a i wider spectrum of activity. The common penicillins and their susceptible organisms are listed for each I subgroup. 

In complicated exacerbations with risk of Pseudomonas aeruginosa, recommended therapy includes a fluoroquinolone with enhanced pneumococcal and P. aeruginosa activity (levofloxacin). If IV therapy is required, a /f lactamase resistant penicillin with antipseudomonal activity or a third- or fourth-generation cephalosporin with antipseudomonal activity should be used. 

It is known that p-lactamase catalyzes the rapid hydrolysis of the p-lactam ring of penicillins and cepharosporines. The hydrolytic activity of these enzymes eliminates the bacteriocidal action of many p-lactam antibiotics and makes the organism resistant to these molecules. For this reason, the p-lactamase inhibitors have long been regarded as promising targets from a medicinal viewpoint. A comparison between the kinetic characteristics of p-lactamase and penicillin-sensitive enzymes (carboxy-peptidase and transpeptidase) is of interest in this respect. p-Lactamases very efficiently hydrolyze p-lactam in contrast to penicillin-sensitive enzymes [high /e4 in Eq. (9)]. 

Penicillin Source Acid Resistance Oral Absorption (%) Plasma Protein Binding (%) p-Lactamase Resistance (S. aureus) Spectrum of Activity ainical Use... 

Cephem antibiotics have been the world s most frequently used antibiotics in the treat ment of a variety of bacterial infections. They have a broader antimicrobial spectrum and are more resistant to p-lactamases than penicillin. In additiem, people with allergies to penicillin are usually not sensitive to cephem antibiotics (1>2). 

Combination treatments often involve the use of broad-spectrum penicillin and P-lactamase-stable penicillin. Clinically useful combinations include ampidox (ampi-dllin and doxadllin) and magnapen (ampidUin and fludoxadllin). These combinations are usually indicated for infections caused by susceptible organisms where a mixed infection is present and includes penidllin-resistant staphylococd. 

Bacteria produce chromosomady and R-plasmid (resistance factor) mediated P-lactamases. The plasmid-mediated enzymes can cross interspecific and intergeneric boundaries. This transfer of resistance via plasmid transfer between strains and even species has enhanced the problems of P-lactam antibiotic resistance. Many species previously controded by P-lactam antibiotics are now resistant. The chromosomal P-lactamases are species specific, but can be broadly classified by substrate profile, sensitivity to inhibitors, analytical isoelectric focusing, immunological studies, and molecular weight deterrnination. Individual enzymes may inactivate primarily penicillins, cephalosporins, or both, and the substrate specificity predeterrnines the antibiotic resistance of the producing strain. Some P-lactamases are produced only in the presence of the P-lactam antibiotic (inducible) and others are produced continuously (constitutive). 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important P-lactamases (10—14,57,58) including penases, and Richmond-Sykes types 11, 111, IV, V, VI ([Bacteroides). Type I Cephases are poorly inhibited. Clavulanic acid synergizes the activity of many penicillins and cephalosporins against resistant strains. The chemistry (59—63), microbiology (64,65), stmcture activity relationships (10,13,60—62,66), biosynthesis (67—69), and mechanism of action (6,26,27,67) have been reviewed. 

P-Lactamases are enzymes that hydrolyze the P-lactam ring of P-lactamantibiotics (penicillins, cephalosporins, monobactams and carbapenems). They are the most common cause of P-lactam resistance. Most enzymes use a serine residue in the active site that attacks the P-lactam-amid carbonyl group. The covalently formed acylester is then hydrolyzed to reactivate the P-lacta-mase and liberates the inactivated antibiotic. Metallo P-lactamases use Zn(II) bound water for hydrolysis of the P-lactam bond. P-Lactamases constitute a heterogeneous group of enzymes with differences in molecular structures, in substrate preferences and in the genetic localizations of the encoding gene (Table 1). 

Resistance to antibiotics is usnally due to the acquisition of genes that express enzymes that can inactivate the antibiotics (e.g. P-lactamase degrades the lactam ring in penicillin (see below) or that can modify the structure of proteins that are necessary for the antibiotic to enter the... 

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... 

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. 

Large substituents often prevent enzymatic attack on a drug, thereby prolonging its useful life. This technique was used to impart resistance to p-lactamase to the semisynthetic penicillins. The need for the proximity of the phenyl group to the lactam is quite interesting phenylbenzyl penicillin (8-26) is inactive as an enzyme inhibitor because the phenyl group no longer hinders access of the enzyme to the lactam bond. 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

It shares with penicillin extremely low toxicity but some danger of allergic reactions. Other semisynthetic penicillins are resistant to P-lactamases, enzymes produced by penicillin-resistant bacteria which cleave the four-membered (i-lactam ring of natural penicillins and inactivate them. 

P-Lactamases destroy antibiotic with the p-lactam nucleus. Neisseria qonorrhoeae is now largely resistant to penicillin because of penicillinase activity. 

The cephalosporins are p-lactam antibiotics that are closely related both structurally (Figure 30.7) and functionally to the penicillins. Most cephalosporins are produced semi-synthetically by the chemical attachment of side chains to 7-aminocephalosporanic add. Cephalosporins and cephamydns have the same mode of action as the penidllins and are affected by the same resistance mechanisms, but they tend to be more resistant than the penidllins to p-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. 

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