Amox tr

Again, a combination of an antipseudomonal penicillin plus an aminoglycoside may result in

increased

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 extended spectrum penicillins (azlocillin, mezlocillin) and ciprofloxacin has also been demonstrated (153,В 178,В 225).

Immunocompromised patients are a population who may benefit the most from antipseudomonal synergy.

There is data to suggest that synergistic combination therapy

results

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 of time where bacterial regrowth did not occur after exposure to the drug.

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

Bactericidal activity of penicillins and other beta-lactams appears to be related to the Time > MIC, 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

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 eradication rates as a function of Time > MIC (203).

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 an increase in mortality, but this was not seen with discordant therapy

when

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 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 amoxicillin antibacterial 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

In these cases, patient convenience is less of an issue and the potential benefit from maximizing

efficacy

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

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

that

The cell wall is made up of peptidoglycan, or murein

sacculus

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

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,В 237).

There are three main mechanisms of resistance to penicillins, including: • enzymatic degradation of the penicillin, • inability of the

penicillin

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 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 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 amoxicillin online without prescription 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.