Continuous infusion of beta-lactam
a potential strategy to improve parenteral antimicrobial
A Consensus Document by the PharmPK List
Please, send your comments and ammendments to the co-ordinator:
Crisanto.Ronchera@uv.es, Valencia, Spain.
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):
- 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
- 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).
- 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.
- 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.
- 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.
- 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).
- 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.
- 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
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):
- 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.
- Patient inconvenience due to decreased mobility (i.e., versus
intramuscular injection or intravenous catheter with an heparin
- 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
- 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
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.
- 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.
- 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.
- 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
- 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
- Rotschafer JC, Zabinski RA, Walker KJ. Pharmacodynamic factors
of antibiotic efficacy. Pharmacotherapy 1992; 12 (Suppl.):
- Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro:
a review. Scandinavian Journal of lnfectious Diseases 1991; 74
- Craig WA, Ebert SC. Continuous infusion of beta-lactam
antibiotics. Antimicrobial Agents and Chemotherapy 1992; 36:
- Bundtzen RW, Gerber AU, Cohn DL, Craig WA. Postantibiotic
suppression of bacterial growth. Reviews on Infectious Diseases
1981; 3: 28-37.
- Gudmundsson S, Vogelman B, Craig WA. The in-vivo
postantibiotic effect of imipenem and other new antimicrobials.
Journal of Antimicrobial Chemotherapy 1986; 18 (Suppl.E): 67-73.
- Leggett JE, Ebert S, Fantin B, Craig WA. Comparative
dose-effect relations at several dosing intervals for beta-lactam,
aminoglycoside and quinolone antibiotics against gram-negative
bacilli in murine thigh-infection and pneumonitis models.
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- Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S,
Craig WA. Correlation of antimicrobial pharmacokinetic parameters
with therapeutic efficacy in an animal model. Journal of
Infectious Diseases 1988; 158: 831-847.
- Vondracek TG. Beta-lactam antibiotics: is continuous infusion
the preferred method of administration?. The Annals of
Pharmacotherapy 1995; 29: 415-424.
- Roosendaal R, Bakker-Woundenberg IAJM, van der Berg JC, Michel
MF. Therapeutic efficacy of continuous versus intermittent
administration of ceftazidime in an expenmental Klebsiella
pneumoniae pneumonia in rats. The Journal of Infectious Diseases
1985; 152: 373-378.
- Zeisler JA, McCarthy JD, Richelieu WA, Nichol MB. Cefuroxime
by continuous infusion: a new standard of care?. Infections in
Medicine 1992; 9: 54-60.
- Gerber AU, Feller C, Brugger HP. Time course of the
pharmacological response to beta-lactam antibiotic in vitro and in
vivo. European Journal of Clinical Microbiology 1984; 3: 592-597.
- Bakker-Woudenberg IAJM, van der Berg JC, Fontijne P, Michel
MF. Efficacy of continuous versus intermittent administration of
penicillin G in Streptococcus pneumoniae pneumonia in normal and
immunodeficient rats. European Journal of Clinical Microbiology
1984; 3: 131-135.
- Bergeron MG, Simard P. Influence of three modes of
administration on the penetration of latamoxef into intersticial
fluid and fibrin clots and its in-vivo activity against
Haemophilus influenzae. Journal of Antimicrobial Chemotherapy
1986; 17: 775-784.
- Gengo FM, Mannion TW, Nightingale CH, Schentag JJ. Integration
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- Lavoie GY, Bergeron MG. Influence of four modes of
administration on penetration of aztreonam, cefuroxime, and
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- Livingston DH, Wang MT. Continuous infusion of cefazolin is
superior to intermittent dosing in decreasing infection after
hemorrhagic shock. The American Journal of Surgery 1993; 165:
- Thauvin C, Eliopoulos GM, Willey S, Wennersten C, Moellering
RC. Continuous-infusion ampicillin therapy of enterococcal
endocarditis in rats. Antimicrobial Agents and Chemotherapy 1987;
- Daenen S, de Vries-Hospers H. Cure of Pseudomonas aeruginosa
infection in neutropenic patients by continuous infusion of
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- David TJ, Devlin J. Continuous infusion of ceftazidime in
cystic fibrosis. Lancet 1989; i: 1454.
- Neftel KA. Effect of storage of penicillin-G solutions on
sensitization to penicillin-G after intravenous administration.
Lancet 1982; i: 986-988.
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