Expired amoxicillin capsules

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, as demonstrated in

severalВ

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

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

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

Despite the fact that actual Time > MICs were not

calculated

A relationship between increased Time > MIC and increased eradication rates of gram-negative pathogens was found. Some recent clinical data has supported time > MIC as an important predictor of outcome. Some data suggests that a time > MIC of > 50% of the dosage interval is most appropriate for cephalosporins (53). The use of cefuroxime as a single drug in the setting ofВ in vitro В resistance was associated

with

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 > MIC is > 50%.

In vitro В data support more frequent administration of piperacillin in suppression of microbial growth (170).

As previously stated, data in humans comparing continuous infusion with intermittent dosing is limited. 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

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.