Infectious Diseases II
ix.
Sulbactam/durlobactam
| (a) | Only agent developed for the treatment of carbapenem-resistant Acinetobacter baumanii |
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(CRAB)
| (b) | Sulbactam has intrinsic activity to Acinetobacter spp., whereas durlobactam had broad- |
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spectrum activity to class A, C, and D Ξ²-lactamases.
| (1) | Antimicrobial activity of sulbactam is because of its ability to inactivate penicillin- |
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binding protein.
| (2) | Durlobactam is a nonβΞ²-lactam/Ξ²-lactamase inhibitor with expanded coverage of |
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class D Ξ²-lactamases.
| (c) | FDA approved in 2023 for the treatment of hospital-acquired and ventilator-associated |
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bacterial pneumonia
| (d) | A randomized multicenter trial showed sulbactam/durlobactam administered in |
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combination with imipenem-cilastatin was noninferior to colistin for the primary efficacy
end point of 28-day all-cause mortality for the treatment of CRAB.
Combination therapy
| (a) | Several retrospective studies suggested that the use of combination therapy is warranted |
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for the treatment of CRE, particularly a regimen involving colistin, tigecycline, and a
carbapenem. Interpreting these studies is difficult. Many were noninterventional, hence
leading to the evaluation of many treatment regimens. The increased ratio of the number
of treatment regimens to the number of patients substantially increases the risk of spurious
findings. If no optimal therapy exists for a patient, combination therapy may be considered.
These therapies include scenarios in which the carbapenem MIC may be slightly elevated
or in which therapies with suboptimal PK/PD (i.e., colistin and tigecycline) are used.
| (b) | A recent retrospective study that evaluated the role of combination therapy for |
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carbapenem-resistant gram-negative pathogens showed that combination therapy with
several agents, all of which had in vitro sensitivity, led to improvements in outcomes. In
contrast, combination therapy with several agents, not all of which had in vitro sensitivity,
did not lead to improvements.
| (c) | Several case reports recommend considering combining ertapenem with another |
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carbapenem for the treatment of carbapenem-resistant pathogens. This approach takes
advantage of the increased affinity for ertapenem seen in vitro with carbapenemases.
Hence, administering ertapenem as a sacrificial carbapenem may allow a different
carbapenem to exert its effects. Recent systematic review identified 171 patients who were
treated with this combination carbapenem strategy, and found clinical and microbiological
success reported in 70% of patients. However, this practice requires further testing; hence,
it cannot currently be recommended.
| (d) | If using polymyxin, combination therapy with another agent that has a susceptible MIC |
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is recommended.
Multidrug-resistant Pseudomonas
Resistance mechanisms seen with Pseudomonas aeruginosa are unpredictable. The presence of
several mechanisms, including Ξ²-lactamases, porin loss, efflux pump, and alteration of target
proteins, complicates treatment options.
Clinical approach usually entails empiric coverage with a Ξ²-lactam, which has the best local in
vitro activity against Pseudomonas, with or without a second antipseudomonal agent. Therapy
could be de-escalated to a monotherapy with the narrowest spectrum on availability of AST results.
Ceftolozane/tazobactam is a novel Ξ²-lactam/Ξ²-lactamase inhibitor antimicrobial with enhanced
activity against P. aeruginosa.