Mrs. MM, a known epileptic patient, was admitted to the burns unit of an Academic Public-Sector facility on the 26th of October 2017, for the treatment of 40% burns that she sustained during an epileptic seizure. She was 26 years old and weighed 55 kg on admission. Her condition rapidly deteriorated (over two days) and she was admitted to the intensive care unit (ICU) on the 28th of October 2017 with a severe sepsis syndrome for which she received empiric intravenous antibiotic therapy.
Her medication on day 5 of ICU admission was as follows:
Therapeutic drug monitoring was performed:
Microbiology report (Blood culture performed on 29th of October 2017):
Acinetobacter baumanni (sensitive only to amikacin, gentamicin and tobramycin); colistin and tigecycline susceptibilities were not reported
Methicillin-Resistant Staphylococcus aureus (MRSA) - vancomycin Minimum Inhibitory Concentrations (MIC) determined by an E-test was 1 mg/L (susceptibility breakpoint 2 mg/L).
Further investigations for disseminated MRSA were not conducted.
The following antimicrobial stewardship principles were considered:
The following issues were considered to optimize the antibiotic dosing:
Both antibiotics are concentration dependent antibiotics and several pathophysiological changes may impact on therapeutic levels. E.G. The ratio of Creatinine:urea - hydration status - is 1:22 – impact on volume of distribution - patient may be edematous and have a large volume of distribution (VD) for water-soluble drugs e.g. amikacin and vancomycin. This may imply that larger doses are needed for a therapeutic peak concentration (but longer dosing intervals due to the renal dysfunction). Principle of the creatinine: urea ratio measurement is that urea and creatinine are both freely filtered at the glomerulus, creatinine is not reabsorbed and urea reabsorbed by tubules via regulation so the ratio can be used as an indicator of the likely cause of renal failure. The patient has a low albumin which will affect highly protein-bound antibiotics which fortunately is not applicable to amikacin and vancomycin. The correct dose for the patient’s condition can be calculated with the assistance of a clinical pharmacist.
Reason for loading dose of colistin:
Critically ill patients have increased capillary leakage, increasing the volume of distribution 4-15 fold. This fact, combined with the long half-life of formed colistin, may result in a time interval of 2-3 days to reach an adequate therapeutic plasma concentration, in the absence of a loading dosage. The high LD does not affect the renal function; only the subsequent maintenance dosages would need to be adjusted.
Tigecycline has activity against the multidrug-resistant Acinetobacter species. Tigecycline’s mechanism of action involves binding to the 30S ribosomal subunit and blocking protein synthesis. Tigecycline has a 7 to 9 L/kg volume of distribution and a half-life of approximately 42 hours. A loading dose of 100 mg is recommended, with a maintenance dose of 50 mg every 12 hours. No dose adjustment is required for patients with renal impairment or mild-to-moderate hepatic impairment.
The Laboratory did not provide an interpretation of ‘susceptible’, ‘intermediate,’ and ‘resistant’ for susceptibility to tigecycline because of a lack of correlating clinical data.
High-level resistance to tigecycline has been detected among some MDR Acinetobacter isolates and there is concern that the organism can rapidly evade this antimicrobial agent by upregulating chromosomally mediated efflux pumps. Studies have documented overexpression of a multidrug efflux pump in Acinetobacter isolates with decreased susceptibility to tigecycline. Given these findings and concerns about whether adequate peak serum concentrations can be achieved, tigecycline is best reserved for salvage therapy, with administration determined in consultation with an infectious diseases specialist.
Tigecycline showed synergism with levofloxacin, amikacin, imipenem, and colistin. Antagonism was observed for the tigecycline / piperacillin-tazobactam combination. Synergism was detected only among tigecycline non-susceptible strains. Time-kill assays confirmed the synergistic interaction between tigecycline and levofloxacin, amikacin, imipenem, and colistin. No antagonism was confirmed by time-kill assays.
Colistimethate sodium was used clinically because of its proven ability to treat infections caused by MDR A. baumannii and other MDR organisms. Many studies have reported cure rates or improvement with colistin of 57 –77% among severely ill patients with MDR Acinetobacter species infections, including bacteremia, pneumonia, sepsis, CNS infection, and intra-abdominal infection. Although in-depth pharmacokinetic data is lacking, colistin is reported to have relatively poor lung and CSF distribution and the clinical outcomes vary for different types of infections.
A lack of controlled clinical trials makes it difficult to evaluate the role of synergy or combination therapy for XDR and PDR Acinetobacter infection. The most readily available data are from uncontrolled case series, animal models, or in vitro studies. Many studies describe different combinations of antimicrobials including rifampicin, sulbactam, aminoglycoside agents, colistin, and carbapenems for the management of XDR and PDR Acinetobacter infections. However, studies have found conflicting results with the same antimicrobial combinations. However, the use of a similar combination of rifampicin plus imipenem for the treatment of carbapenem-resistant Acinetobacter infection has been cautioned due to a high failure rate, and the emergence of rifampicin resistance in 70% of the patients who were treated with this regimen has been documented.
Most results of the combination therapy are comparable to the cure rates reported for parenteral colistin alone and the wide variety of other agents used limits the ability to draw any conclusions with regard to combination therapy. Synergistic effects when used in combination with the carbapenems in 77% of A. baumannii strains with an increase in the bactericidal effect. Combination is used for maximum antimicrobial activity and to decrease the chances of resistance. Controlled clinical studies are needed to determine whether any antimicrobial combinations translate into useful therapeutic strategies.
Summary of treatment and patient outcomeThe goal of treatment was to identify a regimen that gave an immediate improvement in the patient’s health and at the same time maximally delayed the emergence of resistance.Decisions had to be made concerning choice of drug(s), dose, infusion time and dosing frequency and about whether to maintain a regimen until it failed and then switch to another, or whether to change treatment after some fixed interval, perhaps rotating treatments.
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