The postantibiotic effect (PAE) is defined as the time during which bacterial growth is inhibited after antibiotic concentrations have fallen below the MIC (1). Exposures of staphylococci, streptococci, and enterococci to different beta-lactams are consistently followed by PAEs of several hours in duration (2). This persistent suppression of gram-positive cocci growth supported the development of the intermittent dosing regimens for beta-lactam antibiotics. Traditionally, beta-lactams have been parenterally administered by intermittent intravenous infusion or intramuscular injection. These have been considered to be the optimal dosing regimens, are currently used, and seem to work reasonably well in clinical practice. However, due to the increasing number of immunocompromised patients, the rising incidence of gram-negative bacillary infections, and the availability of improved intravenous drug delivery systems, a practical challenge is the development of a more effective means of utilizing available antibiotics. New strategies for improving antimicrobial therapy have two primary objectives: improve patient outcome and decrease health care costs. In this sense, continuous infusion of beta-lactam antibiotics has been investigated and proposed as a new dosage regimen to achieve the most benefit with the least amount of drug (3).

Continuous infusion of beta-lactam antibiotics may provide the best overall clinical efficacy for treatment of infections with these antibiotics for a variety of reasons (2-8):

1. Most beta-lactam antibiotics do not demonstrate concentration-dependent killing. Three different patterns of bactericidal activity for beta-lactam antibiotics have been proposed. In general, beta-lactam antibiotics within the range of concentrations commonly achieved, demonstrate increased bacterial killing only until a finite point is reached; the optimal bactericidal action reportedly occurs at approximately a threshold value of four to five times the minimal inhibitory concentration (MIC) for the infecting organism. After that, further increasing the concentration of a beta-lactam antibiotics has a minimal effect. It appears that the bacterial kill is enhanced not by increasing beta-lactam concentrations per se, but by increasing the time that the antibiotic concentration is above the MIC. Finally, even a paradoxical pattern ("the Eagle effect") of bactericidal activity, which is characterized by a decreasing rate of killing at higher concentrations, has been reported. Consequently there is no advantage to achieving high antibiotic concentrations.
   
2. In contrast to the pattern with gram-positive cocci, no persistent in vitro growth suppression or very short PAEs are observed for beta-lactam antibiotics with gram-negative pathogens. The only exceptions among the beta-lactam class are the carbapenems, which possesses a PAE against a variety of gram-negative bacilli (8).
   
3. The duration of time that beta-lactam antibiotic levels in serum and tissue exceed the MIC has been shown to be the major pharmacokinetic parameter correlating with the efficacy of these drugs in animal models.
   
4. As soon as beta-lactam antibiotic levels fall below the MIC, most pathogens rapidly recover and start to grow again. Therefore, the goal of a dosage regimen for each individual beta-lactam should be to prevent the drug-free interval between doses from being long enough for the bacterial pathogen to resume growth.
   
5. Beta-lactam antibiotics exhibit short half-life values, which demand frequent drug administration. The greatest potential benefit of continuous infusion will be realized with the majority of beta-lactam antibiotics whose short half-life necessitates their repeated administration at 4-8 hour intervals. On the contrary, intermittent administration of beta-lactams with long half-lives would be preferred, and continuous infusion would then be a less attractive option.
   
6. Different studies have shown that continuous infusion of beta-lactam antibiotics may allow a smaller total daily dose of drug than intermittent infusion to achieve the same pharmacodynamic endpoint. Roosendaal et al. (9) demonstrated that 70 times less ceftazidime was needed to produce equivalent survival rates in neutropenic rats subjected to experimental pneumonia, when the drug was given by continuous infusion rather than by intermittent administration. Similarly, lower total doses have been reported in patients receiving continuous infusion of beta-lactam antibiotics (10).
   
7. Adverse drug reactions caused by beta-lactam antibiotics are not specifically related to constant serum or tissue concentrations. Furthermore, continuous intravenous infusion may result in lower toxicity than the administration of large and potentially toxic bolus doses.
   
8. Continuous intravenous infusion of beta-lactams could have a substantial impact on health-care costs. Potential savings could be achieved from reduced antibiotic doses, decreased pharmacy time (compounding), and decreased nursing time (administration), as well as the number of administration sets, intravenous bags, and other supplies used. Although drug cost should be a minor factor in clinical decision making. if the other parameteres discussed were proven to be comparable, even a conservative extension of this savings in antibiotic use extended to all patients receiving beta-lactam antibiotics would represent a significant cost savings.

Consequently, the extent of beta-lactam bactericidal activity in various tissues appears to depend more on the duration of exposure to drug levels above the MIC than on the magnitude of antibiotic concentrations (11). Craig and Ebert (3) stated that the goal of dosing regimens for beta-lactam antibiotics should be to maximize the time of exposure to active drug levels exceeding the MIC. This can be adequately and best attained delivering these antibiotics by continuous intravenous infusion.

On the other hand, several concerns and potential disadvantages have been identified (3, 8):

1. With continuous infusion, a delay in drug equilibration to tissues occurs because of the lag time for the concentrations in serum to reach steady state. However, the administration of a loading dose prior to continuous infusion would ensure the rapid onset of antibacterial activity.
   
2. Patient inconvenience due to decreased mobility (i.e., versus intramuscular injection or intravenous catheter with an heparin lock).
   
3. Continuous occupation of a lumen of intravenous access. This can be troublesome in situations that require multiple intravenous medications and/or fluids to be administered. Similarly, it may give rise to compatibility and stability concerns. This will require further consideration as studies are undertaken and policies are developed because some stability data suggest that the shelf life of some beta-lactam antibiotics may be less than 24 hours.
   
4. Continuous exposure to antimicrobial concentrations slightly in excess of the reported MIC could select subpopulations of resistant organisms that typically are not detected by MIC testing and usually are eliminated or inhibited by higher peak antimicrobial concentrations. Nevertheless, the development of resistance has not been reported in the clinical trials to date.

There are limited numbers of published studies which compared continuous infusion and intermittent injection of beta-lactams with regard to the rate or extent of tissue penetration; most of these studies have been performed in animal models and require extrapolation to humans. In general, the amount of drug delivered to the interstitial fluid, as measured by the area under the concentration-versus-time curve (AUC), was greater for intermittent injections or a single bolus injection than for constant infusion. However, much of the difference between regimens was reduced when animals were given an initial bolus dose prior to continuous infusion (3).

There are a number of studies in animal models comparing the efficacy of continuous infusion of beta-lactam antibiotics with that following intermittent injections (9, 12-17). In general, continuous infusion of penicillins and cephalosporins has been shown to be superior to intermittent doses in eradicating both gram-positive and gram-negative baterial infections, particularly after complement depletion and granulocytopenia. Nevertheless, studies of experimental infection caused by gram-positive cocci have produced conflicting results, with continuous infusion being more, equally or less effective than intermittent dosing regimens. In contrast, continuous infusion of beta-lactams has consistently exhibited greater potency than intermittent administration for members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Studies on the efficacies of beta-lactams used in combination with aminoglycosides have provided similar results.

Treatment with beta-lactam antibiotics by continuous infusions has resulted in good clinical efficay in a variety of patients, including those with neutropenia who failed therapy with intermittent dosing and those with cystic fibrosis infected with Pseudomonas aeruginosa (18, 19). Despite these successes, there are few randomized human clinical trials that have compared the efficacies of beta-lactams administered either by continuous infusion or by intermittent injection, which turned to be at least equally effective or with a slightly higher response rate for the constant-infusion regimen. Following a sequential clinical study protocol, Zeisler et al. (10) determined that a loading dose of cefuroxime followed by continuous intravenous infusion provided shorter length of treatment, lower total dose, shorter length of hospital stay, and cost savings when compared with intermittent intravenous piggy back infusion. They showed the use of continuous intravenous infusion cefuroxime in humans to be practical, useful, safe and cost-effective.

Neftel et al. (20) studied the effect of penicillin degradation during storage or prolonged infusions on the incidence of adverse reactions. They observed that the formation of antipenicillin antibodies and the sensitization of lymphocytes to penicillin in patients could be largely eliminated if doses were prepared just prior to administration. On the other hand, in none of the clinical studies which have simultaneously compared continuous infusion with intermittent injections of beta-lactams has any difference in the frequency of adverse reactions been reported.

Conclusions

1. Results of many in vitro and animal studies, and a few case series and clinical trials published to date suggest that continuous infusion may be the optimal method of beta-lactam administration. Further human trials are necessary to confirm existing data and support widespread administration of beta-lactams by continuous infusion.
   
2. There are potential microbiologic, clinical and economic advantages and not serious contraindications to the administration of beta-lactams by continuous infusion, especially for gram-negative bacillary infections. Such therapy might enhance the efficacy of these antibiotics against some organisms, while reducing treatment costs.
   
3. Comparative clinical trials should be encouraged to explore the impact of this method of administration on the incidence of adverse reactions, emergence of bacterial resistence, optimal continuous infusion dosing, and patient outcomes including morbidity, mortality, duration and cost of pharmacotherapy with beta-lactam antibiotics.
   
4. In clinical practice, continuous infusion of beta-lactam antibiotics may be attempted in individual patients with gram-negative bacilli infections that have failed to respond the standard intermittent infusion method. In this case, one standard dose of the antibiotic should be administered as a loading dose, and immediately followed by the usual total daily dose via continuous infusion.

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