Amoxicillin 500 clavulanic acid 125

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 more enzyme because it must be excreted into the extracellular space for the antibiotic to be inactivated, while the gram-negative bacteria’s enzymes are located in their periplasmic space.

Gram-positive bacteria that produce beta-lactamases (particularlyВ Staphylococcus ) can transfer resistance through plasmids or transposons. Plasmids are

extrachromosomal

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

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

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

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.

Omp F and Omp C are the two main porins, with Omp F being most permeable to beta-lactam agents.

Some mutants which lack Omp F porins can be resistant to beta-lactams due to decreased and slower penetration through the remaining porins (Omp C) and subsequent increased beta-lactamase degradation (66). Binding to the PBP is necessary for the penicillin to exert its antibacterial effect. There are natural differences in the affinity for penicillin to a PBP. For instance, the affinity of the Enterococcal PBP to the antistaphylococcal penicillins is very low versus a high affinity to penicillin G or ampicillin.

This accounts for the resistance seen in the case of oxacillin and Enterococcus. Mutations can occur which can result in changes in susceptibility of an organism, which is “normally” susceptible to a particular penicillin, usually by producing PBPs with a decreased affinity to the penicillin. An alteration in PBP2 byВ Staphylococcus В to PBP2a results in methicillin

resistance

WithВ Staphylococcus aureus В (241) this type of production of PBPs with decreased affinity for the penicillin is inducible by exposure to the agent, resulting in

decreased

penicillin

The genes that appear to be most affected are PBP 2b and 2x.

The current interpretive MIC breakpoints for penicillin as determined by the National Committee for Clinical Laboratory Standards (NCCLS) are 48 hours is an indication for repeat desensitization (210).

Cross-Reactivity with Other Beta-Lactams and Related Compounds. There is a concern over the potential for allergy to other beta-lactam compounds, such as cephalosporins, aztreonam, and the carbapenems, in patients allergic to penicillin.

Estimates of cross-reactivity with cephalosporins range from 2-10% (182,В 195), though there is data to suggest that the incidence is much lower (6). No major or minor determinants exist with cephalosporins, which could account for the low cross-reaction potential.

Cross reaction with the carbapenems may also occur, however the monobactams (aztreonam) appear the have a low propensity for eliciting an immune response and have not shown a cross-reaction with penicillin antibodies when testedВ in vitro В (1).

The bulky side chain, rather than the beta-lactam ring may be the site of immunologic reactivity. TheВ in vitro В studies (1,В 201) also demonstrated that cross-reaction between aztreonam and ceftazidime occurred, which is expected since the two compounds have identical side chains.

Though the risk of cross-reactivity appears to be low, in patients with a history of severe allergy it may be prudent to avoid the use of cephalosporins as good therapeutic alternatives are available.

The potential for a cross-reaction with penicillamine has also been explored, as penicillamine is a metabolite of penicillin degradation. A study examined 40 patients with a positive history of penicillin allergy. Sixteen patients skin tested positive for sensitivity to penicillin only and 1 patient had a positive penicillamine skin test (21). This data suggests that the incidence of cross-reaction is low, but that penicillamine should be administered with caution to these

patients

These adverse effects will be discussed according to body system affected. Perhaps the most common adverse reaction to orally administered penicillins is gastrointestinal effects. Diarrhea can occur in up to 20% and 5% of patients receiving oral ampicillin and amoxicillin, respectively. The incidence may be

increased

Other effects, such as nausea, vomiting, and epigastric distress may also occur. Diarrhea has also been reported in patients receiving intravenous penicillins (approximately 3%).

Antibiotic-associated pseudomembranous colitis caused byВ Clostridium difficile , may occur during or immediately after therapy with a penicillin due to changes in normal bowel flora from the broad spectrum coverage and overgrowth of this organism.

WhileВ Clostridium difficile В is “sensitive” to ampicillin and amoxicillin, it produces spore form, which survives.

In the scenario of diarrhea associated with presence ofВ Clostridium difficile В and depending upon the severity of illness, appropriate treatment with metronidazole or oral vancomycin should be considered.