Amoxicillin and clavulanate potassium 875

In these cases, patient convenience is less of an issue and the clavulanate potassium amoxicillin potential benefit from maximizing efficacy is greatest.

Dosing by

continuous

Use of a bolus dose

may

Penicillins are bactericidal agents that exert their mechanism of action by inhibition of bacterial cell wall synthesis and by inducing a bacterial autolytic effect. Penicillins exert their bactericidal activity primarily by inhibiting bacterial cell wall amoxicillin for ear infection baby synthesis.

Though the exact mechanism of action is not fully elucidated, it appears that penicillins bind to penicillin-binding proteins (PBPs), which are enzymes (transpeptidases, carboxypeptidases, and endopeptidases) that play an important role in the formation and maintenance of the cell wall structure.

The cell wall is made up of peptidoglycan, or murein sacculus, which is a polymeric component consisting of long polysaccharide chains of N-acetylglucosamine and N-acetylmuramic acid cross-linked by shorter peptide chains. The formation of peptidoglycan can be divided into three stages, including precursor formation in the cytoplasm, linkage of precursor products into a long polymer, and finally cross-linking by transpeptidation.

It is the final transpeptidation process that is inhibited by penicillins by acting as a structural analog of acyl-D-alanyl-D-alanine (the substrate of the enzyme) and acylating the transpeptidase enzyme.

The peptidoglycan structure, and therefore the cell wall structure, is weakened, leading to cell death (234,В 236,В 266). Binding to PBPs 1A, 1B, 2, and 3 results in a bactericidal effect (219), however binding to PBPs 4, 5, and 6 is not lethal.

Also, there are differences in PBPs between gram-positive and gram-negative bacteria and there are differences in affinity between penicillin compounds to various PBPs.

There are several PBPs that the penicillins simultaneously inactivate. Inhibition of certain PBPs may be related to the activation of a bacterial autolytic process by inactivation of endogenous inhibitors of these autolysins or murein hydrolases (235).

These enzymes cleave parts of the cell wall to make room for peptidoglycan synthesis for cell wall expansion (109). With inhibition of cell wall synthesis, bacterial lysis can occur due to increased osmotic pressure.

This autolysis may be cell cycle dependent, that is, most likely to occur while the cell is dividing (147). Certain “tolerant” species of staphylococci and streptococci have been isolated which are autolysin-deficient. These organisms are inhibited, but not killed by penicillins (233). A limitation to the clinical use of penicillins is the emergence of resistant organisms.

Antimicrobial resistance can arise during therapy byВ selective pressureВ or can be present due to acquisition of a naturally resistant strain. A classic example of penicillin resistance is the case ofВ Staphylococcus aureus , which was susceptible to penicillin G when the compound was first discovered (around 1941).

Since that time, resistance occurs in >95% of strains, leading to the necessity of use of alternative compounds such as the antistaphylococcal penicillins or vancomycin. Resistance of other gram-positive and gram-negative organisms also occurs, which can lead to challenges in treatment of active infection. Resistance rates for different organisms vary according to geographic location and are summarized inВ Table 5В (93,В 117,В 160,В 168,В 200,В 206).

Of particular concern in the United States is the emergence of penicillin-resistant (and multi-drug resistant) pneumococci and methicillin-resistant staphylococci, as treatment options in these scenarios are limited (8, 237). There are three main mechanisms of resistance to penicillins, including: • enzymatic degradation of the penicillin, • inability of the penicillin to penetrate the cell membrane to reach its target site, • an alteration in the PBP target site. Inactivation by beta-lactamase enzymes is the most common mechanism of resistance to the beta-lactam agents.

The beta-lactamase reacts with the beta-lactam bond by hydrolysis forming acidic derivatives and subsequent loss of antibacterial activity.

There are several classification schemes for the numerous beta-lactamases, including those of Jack and Richmond (116), Richmond and Sykes (191), and Bush (44,В 45). The Bush scheme classifies according to substrate preference and susceptibility to clavulanate inhibition. A limitation of these schemes, however, is that they can be confusing due to numerous codes and abbreviations (140).

Both gram-positive and gram-negative organisms produce beta-lactamases, mediated either by plasmids or chromosomes.

An important difference is that gram-positive organisms generally produce amoxicillin trihydrate 500mg more enzyme because it must be excreted into the extracellular space for

the

Gram-positive bacteria that produce beta-lactamases (particularlyВ Staphylococcus ) can transfer resistance through plasmids or transposons. Plasmids are extrachromosomal genetic material that are autonomous, self-reproducing and can be conjugating.

By conjugation, the genetic information is transferred to otherВ Staphylococcus В species, includingВ aureus В and epidermidis .

Transposons are DNA elements that can move from one part of the bacterial chromosome to another. Genetic information can be transferred to other bacteria through movement of the transposon to a plasmid or from direct transfer to another bacteria’s chromosome, known as conjugative transposons (216).

Beta-lactamases ofВ Staphylococcus В can be inducible by use of beta-lactam antibiotics, meaning that after exposure to a beta-lactam agent, the organism can greatly increase beta-lactamase production. The inducible production generally ceases after the beta-lactam is removed (172). As stated previously, gram-negative bacteria secrete beta-lactamases into the periplasmic space and are effective in protecting the PBPs located on the bacterial inner membrane from the antibiotic. These enzymes can be either chromosomally-encoded or plasmid-encoded (227). They are produced either constitutively (production of a constant amount of beta-lactamase regardless of exposure to beta-lactam agents) or are inducible and can affect beta-lactam compounds in different ways. Some agents are quickly destroyed, while others are destroyed at a much slower rate and therefore have increased antibacterial activity.

Production of stably derepressed mutants is a concern during therapy with beta-lactam agents that are weak inducers of beta-lactamase production, such as extended-spectrum and third generation cephalosporins.

These mutants produce increased quantities of beta-lactamases (hyperproduction) despite removal of the inducible antibiotic. This is most likely to occur with the chromosomally- mediated Bush Group I enzymes for which the preferred substrate is cephalosporins.

Rapid emergence of resistance can occur in this circumstance, particularly in infections caused byВ Pseudomonas aeruginosa В orВ Enterobacter cloacae В (50,В 141), due to selection of the mutants after the more susceptible organisms are killed during treatment.

In this instance, the mutants can proliferate and can become the predominant infecting organism.

The only effective beta-lactam would be a carbapenem, as Class I beta-lactamases can hydrolyze all other types of beta-lactams agents. Extended-spectrum beta-lactamases (ESBLs) are plasmid mediated with a wide substrate profile. These enzymes are a relatively recent problem, affecting some strains ofВ Klebsiella sp. The emergence of ESBL-producing organisms has been linked with the widespread use of extended-spectrum cephalosporins (154,190).

A carbapenem is a drug of choice against these organisms, while beta-lactamase inhibitor combinations may also be effective (93).

It is easier for penicillins to acetylate the PBPs in gram-positive bacteria because these bacteria have only a thick cell wall layer protecting the PBPs on the inner membrane. Gram-negative bacteria, however, have an outer membrane composed of a lipopolysaccharide and phospholipid bilayer and between the layers is a periplasmic space.

Another space separates the inner membrane with the cytoplasmic membrane. PBPs are located in the cytoplasmic membrane and are protected by beta-lactamases. In the outer membrane there are proteins, known as porins, which act as channels for nutrients and waste products into and out of the bacteria.

Penicillins may enter the gram-negative bacteria by this route.

Porin permeability to penicillins depends upon size of the molecule, hydrophilicity, and electrical charge (267). Decreases in the number of porin channels have been reported to be a mechanism of resistance to beta-lactam agents (105). Most research has been conducted with the outer-membrane proteins (Omp) ofВ E.