Dual beta-lactam therapy can be appropriate, however instances where this is the case are relatively few and occur fairly infrequently. In this article, an infectious diseases and antimicrobial stewardship pharmacist identifies several examples of when dual beta-lactam therapy can be appropriate.
Authored by: Timothy P. Gauthier, Pharm.D., BCPS-AQ ID
[Last updated: 17 April 2018]
One of the key roles antimicrobial stewardship programs play is to reduce antibiotic use that is not needed. In attempting to identify inappropriate antibiotic use, stewards may elect to target interventions based on factors such as duration of therapy, dosing strategy, route of administration, toxicity, or spectrum of activity.
When it comes to targeting inappropriate antibiotic use related to spectrum of activity, “unnecessary duplicate therapy” can be a topic of interest. This refers to when two antibiotics are covering the same organism, yet only one antibiotic is needed for the job. Exposing a patient to two medications instead of just one can be considered inappropriate, as it needlessly increases a person’s risk for adverse drug events and ecological consequences of antibiotic use (e.g., risk for Clostridium difficile infection).
As front-line antibiotic stewards review patient medication profiles for interventions to improve care, they seek out unnecessary duplicate therapy. Assessments of this nature typically include review of cases in which two beta-lactams are being employed at the same time.
Penicillins (e.g., penicillin, ampicillin, piperacillin-tazobactam), cephalosporins (e.g., cefazolin, ceftriaxone, cefepime), and carbapenems (e.g., meropenem, ertapenem) are all beta-lactam antibiotics. Use of any penicillin, cephalosporin, or carbapenem in combination with another represents dual beta-lactam therapy.
Dual beta-lactam therapy can be appropriate, however it frequently is not. In fact, dual beta-lactam therapy so frequently represents unintentional duplication of therapy that many infectious diseases specialists start by teaching their trainees about the few times when it is acceptable, rather than the long list of instances where it is not. This is the motivation of this article.
Here several examples of when dual beta-lactam therapy is appropriate are identified and discussed.
NOTE: This is not an exhaustive review of the literature and may not be a complete list of when dual beta-lactam therapy is appropriate.
Covering for Listeria monocytogenes by adding ampicillin to a cephalosporin
Ampicillin is generally regarded as the drug of choice for infections caused by Listeria monocytogenes. This organism exhibits intrinsic resistance to broad-spectrum cephalosporin antibiotics. In some clinical scenarios dual beta-lactam therapy with ampicillin + a cephalosporin is acceptable in order to provide Listeria monocytogenes coverage with ampicillin for a patient who requires a cephalosporin for other coverage.
One of the most well known examples for using this combination is for meningitis treatment. According to the 2004 IDSA meningitis guidelines (available here), patients with purulent meningitis aged less than 1 month or aged over 50 years should be covered for Listeria monocytogenes. Under these circumstances, it is appropriate to add ampicillin to cefotaxime for infants less than 1 month old and it is appropriate to add ampicillin to ceftraixone for adults over 50 years old.
Treatment of Enterococcal infective endocarditis
Ampicillin + ceftriaxone has emerged as a preferred treatment option for infective endocarditis caused by susceptible isolates of Enterococcus spp. One of the motivating factors for selecting this regimen as compared to ampicillin + gentamicin is that ampicillin + ceftriaxone spares the risk for gentamicin-associated nephrotoxicity.
While ampicillin + ceftriaxone is the more common combination used for this indication, there are also data on ampicillin + cefepime or ampicillin + ceftaroline.
The means by which these combinations work is thought to be a result of complimentary action versus penicillin binding proteins (PBPs). Ampicillin has at least some activity versus PBP 1, 4, and 5. Some cephalosporins can add substantially to this including activity versus PBP 2 and 3. The result of the greater overall PBP saturation is thought to produce more complete inhibition of cell wall synthesis and therefore enhanced bacterial killing.
Dual carbapenem therapy for bacteria producing Klebsiella pneumoniae carbapenemases
As bacteria exhibit increased resistance to available antibiotics clinicians are forced to get creative. Dual carbapenem therapy for Klebsiella pneumoniae carbapenemase (KPC) producing organisms is an example of this.
KPC enzymes hydrolyze carbapenems, thus rendering them inactive. KPC enzymes hydrolyze some carbapenems more readily than others and ertapenem is the most readily hydrolyzed carbapenem.
In using dual carbapenem therapy for KPC producing bacteria, the ertapenem acts as a suicide antibiotic that “distracts” the KPC enzymes while the second carbapenem goes to work treating the infection.
Data with dual carbapenem therapy for KPC producing bacteria remains somewhat limited, but it may be an option in some cases.
With unique patients and infections the potential clinical scenarios that can arise are vast. Drug resistance, antibiotic allergies, pharmacokinetic/ pharmacodynamic properties, and contraindications are just some of the factors that can impact which antibiotics can be options for a given patient case. When these factors start to add up, exceptional circumstances can arise.
It is impossible to list all exceptional circumstances, so here are two examples.
The first scenario is for a patient that requires salvage therapy for MRSA bloodstream infection with daptomycin + ceftaroline. At the same time if this person requires treatment for a Gram negative infection and a beta-lactam (e.g., meropenem) is the only viable option, then having dual beta-lactam therapy with ceftaroline + meropenem can be acceptable.
The second scenario is with treatment of drug-resistant Acinetobacter baumannii with meropenem (a carbapenem) + ampicillin-sulbactam (an aminopenicillin/ beta-lactamase inhibitor combination). There may be clinical cases where the practitioner wishes to treat Acinetobacter baumannii with meropenem + sulbactam. Unfortunately, in the United States sulbactam alone is not available. In turn, to achieve the desired drug combination the clinician is forced to use meropenem + ampicillin-sulbactam, because the only product available with sulbactam is ampicillin-sulbactam. Ampicillin + meropenem represents dual beta-lactam therapy, however under these exceptional circumstances this combination would be acceptable.
Dual beta-lactam therapy can be appropriate, however instances where this is the case are relatively few and occur fairly infrequently. As clinicians seek to be better stewards of antimicrobial drugs, they should beware potentially unnecessary coverage with multiple beta-lactams.
Recommended / Relevant Readings
- Peterson SC, et al. Combination of ceftriaxone and ampicillin for the treatment of Enterococcal endocarditis: a qualitative systematic review. Annals of Pharmacotherapy. 2017.
- Fernandez-Hidalgo N, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating Enterococcus faecalis infective endocarditis. Clinical Infectious Diseases. 2013.
- Werth BJ, et al. The combination of ampicillin plus ceftaroline is synergistic against Enterococcus faecalis. Journal of Antimicrobial Chemotherapy. 2015.
- Cprek J and Gallagher J. Ertapenem-containing double-carbapenem therapy for treatment of infectious caused by carbapenem-resistant Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy. 2015.
- Rhame C, et al. Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit? Diagnostic Microbiology and Infectious Diseases. 2014.
- De Pascale G, et al. Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched case–control study. Critical Care. 2017.
- Wong D, et al. Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges. Clinical Microbiology Reviews. 2017.
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