Amoxiclav 600

These organisms are not susceptible to this class of penicillins. Anaerobic activity ranges from minimal to none and gram-negative activity is virtually nonexistent.

Because of the need for improved coverage against gram-negative organisms, further manipulation of the side chain was conducted.

By adding an amino group to the basic penicillin compound, the aminopenicillins were developed. The spectrum of activity against gram-positive organisms is similar to that of the natural penicillins. These agents retain activity against streptococcal sp. and have slightly greater activity againstВ Enterococcus В (ampicillin) andВ Listeria monocytogenes В versus the natural penicillins. The added side chain does not, however, inhibit hydrolysis byВ Staphylococcal В penicillinases or gram-negative beta-lactamases. The enhanced spectrum of these drugs includes activity against gram-negative bacilli,

includingВ

coli ,В Proteus mirabilis ,В Salmonella В sp., andВ Shigella В sp. These drugs were developed in the 1960s and were, at that time, very effective against these organisms. Presently, however, many strains of these gram-negative organisms are resistant to ampicillin.

Combinations of an aminopenicillin plus a beta-lactamase inhibitor, such as clavulanic acid or sulbactam, are useful for treatment of infections caused by beta-lactamase producing organisms.

A carboxyl group substitution in place of the amino group yields penicillin compounds that

have

Pseudomonas

Their spectrum of activity includes that of ampicillin, while also encompassingВ Enterobacter ,В Providencia ,В Morganella , indole-positiveВ Proteus , andВ Pseudomonas aeruginosa , with ticarcillin having slightly greater activity againstВ Pseudomonas aeruginosa В

versus

Coverage againstВ Klebsiella В andВ Serratia В are

less

The activity against Streptococci is slightly less that of the natural penicillins and ampicillin. Of the drugs in this class, piperacillin has the most activity againstВ Pseudomonas aeruginosa В (52, 255). As with the carboxypenicillins, drugs in this class are susceptible to inactivation by bacterial beta-lactamase production, unless combined with a beta-lactamase inhibitor (e.g.

When choosing an antimicrobial agent and designing appropriate dosing regimens for the drug, it is important to consider spectrum of activity, but also incorporate known pharmacodynamic principles about the drug. In this manner, efficacy can potentially be maximized while toxicity can be minimized. Some excellent reviews on these concepts have been published (71,В 76).

Such pharmacodynamic variables that are important to consider for the penicillins includes concentration-independent bactericidal activity, the post-antibiotic effect (PAE), and the duration of the dosing interval the drug’s serum concentrations spend above the level of the organism’s MIC (Time > MIC).

All beta-lactam drugs (including the penicillins) exert relatively concentration-independent bactericidal activity, meaning that the concentration of drug does not appreciably affect its ability to exert an antibacterial effect (25,В 209).

This assumes, however, that a level that exceeds the organism’s MIC is attained.

Theoretically, the bactericidal rate at 2 times above the MIC or 4 times above the MIC would be the same.

However, once the

drug

This effect, however, does not appear to be clinically significant, as there is very limited data to support decreased bactericidal activityВ in vivo В due to high serum concentrations. Another factor that may influence bactericidal activity is bacterial inoculum size. Generally, the more dense the bacterial population (i.e.

the older the infection), it is more likely that there will be resistant variants of the organism present. This may be the case with nosocomial gram-negative pneumonias or other serious infections. Treatment with a penicillin as monotherapy may result in a relapse after completion of therapy when the resistant sub-variants are no longer suppressed and begin to regrow. This scenario is not unique to the penicillins, and in fact may occur with other antibiotics when used as monotherapy.

The bactericidal activity of the penicillins does not appear to be affected by changes in pH or oxygen tension.

The location of the organism is important, however, asВ in vitro efficacy may not correspond toВ in vivo В efficacy. Penicillins and other beta-lactams do not penetrate well into phagocytes (104), thus limiting

their

In addition, penicillins only exert their bactericidal effect on bacteria that are actively replicating. Combinations of a beta-lactam plus another agent, such as an aminoglycoside, kill some organisms most effectively.

Synergy is defined as an effect, such as bactericidal activity, that is significantly greater with the combination than the sum of the two agents when used alone.

The mechanism of this effect with penicillins and aminoglycosides may be due to cell wall disruption by the penicillin, facilitating increased entry of the aminoglycoside into the bacteria (158). Enterococcal endocarditis is such an example, as penicillin monotherapy results in bacteriostatic activity and very high relapse rates after treatment (149), while the combination of penicillin plus an aminoglycoside is bactericidal (157). Other organisms for which synergy seems to be important with regard to the penicillins includesВ Pseudomonas aeruginosa . Again, a combination of an antipseudomonal penicillin plus an aminoglycoside may result in increased bactericidal activity.

This has been demonstratedВ in vitro В and animal studies (5,В 77,В 118), but there is limited data in humans to support these findings.В In vitro В synergy between

the

spectrum

There is data to suggest that synergistic combination therapy results in increased survival versus non-synergistic combinations of drugs (124,В 130,В 204).

Antibacterial antagonism is defined as a resulting effect that is significantly less in combination than with either of the two drugs when used as monotherapy.

This effect has been demonstrated with the

penicillins

Combinations of penicillin plus chloramphenicol have demonstratedВ in vitro В antagonism against pneumococci (188), however, clinically this may be of little importance since the

combination

activity

Antagonism can also occur due to a physical incompatibility with inactivation between two drugs when infused together. This can occur with carbenicillin or ticarcillin with an aminoglycoside. These drugs should therefore not be mixed in the same infusion.

The PAE is defined as a persistent suppression of bacterial growth after effective exposure to an antimicrobial agent when serum concentrations of the drug have fallen to levels below the MIC. This effect differs between infecting organisms and between drugs.

The mechanism of the PAE is not entirely clear, but may be due to persistent binding of the penicillin to penicillin-binding proteins (PBPs) and the time that is necessary for the organism to resynthesize new PBPs (218). The PAE was first noted with penicillin G andВ Staphylococcus aureus В (179), when it was noted that there was a short

period