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Subsequently, this phenomenon has been described with the penicillins for other gram-positive organisms (42,В 108), includingВ Streptococcus pneumoniae В and Enterococcus В faecalis .

The length of the PAE can range from 0-6 hours (Table 4), depending upon the penicillin. As stated previously, the type of organism can affect the PAE. The penicillins do not exhibit an appreciable PAE against gram-negative organisms.

Also, combinations of antimicrobial agents can result in a synergistic PAE. Combinations of penicillins plus various aminoglycosides have resulted in synergistic or additive PAEs forВ Enterococcus faecalis В and Enterococcus faecium В (86,В 108), along withВ Staphylococcus aureus В (100). Bactericidal activity of penicillins and other beta-lactams appears to be related to the Time > MIC, i need a prescription for amoxicillin as demonstrated in severalВ in vitro models.

A number of studies of beta-lactam agents demonstrated that increased half-life and not peak concentration influenced bactericidal activity (97,В 125,В 254,В 272). This implies that increased duration of drug exposure above the MIC would be more predictive of positive outcome versus increased drug doses and subsequent increased peak concentrations. Data from animal models supports Time > MIC as the primary determinant of efficacy for beta-lactam agents (75,В 247).

In a neutropenic mouse model infected withВ Pseudomonas aeruginosa , the impact of different dosing intervals of ticarcillin was studied.

Equivalent daily doses were administered every hour or every 3 hours.

The mice that received drug every hour (a lower dose administered more frequently) had a greater antibacterial effect (88).

These findings were also supported by studies ofВ Klebsiella В pneumoniae В pneumonia in rats (197), inВ Klebsiella pneumoniae В lung and thigh infections in neutropenic mice (132), Pseudomonas aeruginosa В infection in neutropenic rats (159),В Staphylococcus aureus В in rats recovering from hemorrhagic shock (142), and in Enterococcal endocarditis (231).

Additional data (247) demonstrated that for gram-negative infections, a Time > MIC of 100% of the dosing interval was most closely associated with outcome, whereas for gram-positive organisms, a Time > MIC of approximately 50% was all that was needed to be effective.

For gram-negative infections, continuous infusion of the penicillin may be most appropriate to maintain serum concentrations above the MIC for the entire dosing interval. Clinical trials examining the impact of Time > MIC for beta-lactams in relation to outcome is limited.

One study examined combinations of carbenicillin plus continuous infusion cefamandole, carbenicillin plus intermittent cefamandole, and carbenicillin plus continuous infusion tobramycin in febrile, neutropenic cancer patients (32). The most effective regimen was the carbenicillin plus continuous infusion cefamandole. Despite the fact that actual Time > MICs were not calculated, the most effective regimen most likely had the greatest Time > MIC, as the carbenicillin was administered every four hours, effectively providing serum concentrations that would remain above the MIC throughout the dosing interval. A study of cefmenoxime in 14 critically ill patients examined bacterial

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The use of cefuroxime as a single drug in the setting ofВ in vitro В resistance was associated with an increase in mortality, but this was not seen with discordant therapy when penicillins, ceftriaxone, or cefotaxime were used.

This finding may have been attributed to the dosage of 750 mg three times daily which does not provide coverage of time > MIC > 50% of the time for organisms with MICs of 4В пЃ­g/mL (269) A higher dosage in the order of 1500 mg q8h may be more appropriate versus resistant pneumococci where

time

The study by Bodey et al appears to support such dosing, however some small studies did not demonstrate any differences in response rates (129,В 270).

(270) was not randomized and the study by Lagast et al.

(129) only included 45 patients, most likely lacking sufficient power to detect a statistical difference. The advantage of continuous infusion would be the potential maximization of efficacy and potentially decreased costs (270). Disadvantages, however, include patient inconvenience with a continually infusing solution, lack of knowledge about proper dosing, and compatibility issues with other necessary intravenous drugs (248). Many of these concerns may be addressed by educational efforts. Other concerns include adequate tissue penetration with continuous infusion.

Some studies have demonstrated good penetration of continuous infusion beta-lactams into extravascular space (181,В 244). Other data appear to support intermittent injections resulting in increased tissue penetration, as seen in models of rabbit fibrin clots (14,В 131), however the concentrations achieved with continuous infusion may be adequately above the organism MIC to treat the infection.

A limitation of this model, however, is that the clots are implanted in the rabbit’s back and may not be an appropriate representation of physiology. Continuous infusion may be most beneficial in patients with impaired host defenses or in life-threatening infections. In these cases, patient convenience is less of an issue and the potential benefit from maximizing efficacy is greatest. Dosing by continuous infusion can be accomplished by use of nomograms (246) or by monitoring a steady-state serum concentration (after 4-5 half-lives or approximately 4-5 hours into the infusion for most penicillins) and adjusting the dose in relation to the serum concentration and the organism MIC. Use of a bolus dose may be used so that the patient’s serum concentrations will reach a therapeutic level quickly. 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 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 in Table 5 (93, 117, 160, 168, 200, 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.