Case of the Month

September 2018

Case presentation

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:

  • Timely antibiotic therapy management
    • &Reduce “hang-time”, in order to ensure prompt initiation of antibiotics
  • Ensure appropriate selection of antibiotic
    • Ensure proper antibiotic regimen selected for specific clinical syndrome and infection
    • Use antibiograms of antibiotics and clinical guidelines to optimize antibiotic selection
    • Discontinue unnecessary antibiotics for Gram negative and/or anaerobic bacterial infections
  • Appropriate administration and de-escalation of antibiotic therapy
    • Ensure proper dosing, frequency and duration
    • Peer review of antibiotic use 48-72 hours after initiation (should antibiotic be continued, changed or discontinued)
    • Monitor serum therapeutic levels if required
  • Monitor side effects/adverse effects reactions
    • Both amikacin and vancomycin will increase chance for oto-and nephro toxicity
    • Vancomycin: “red man syndrome” – Rapid IV administration may cause histamine release causing hypotension, palpitations and rash
    • Amikacin: Dose and duration related toxic effect on the renal proximal tubular cells.
  • Perform regular handwashing/hygiene
    • Wet hands with clean and warm running water.
    • Apply a small amount of soap
    • Rub your palms together, away from the water
    • Rub your fingers and thumbs and the skin in between them
    • Scour your palms with your nails
    • Rub the back of each hand
    • Rinse with clean running water
    • Dry with a clean towel or paper towel

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.


  • Amikacin dose can be changed to 820 mg 24 hourly, Patient MM has a k value (elimination rate constant) of 0.07, t1/2 (half-life) = 10.02 hours, true peak level of 48.22 (normal MIC 40 mcg/ml), true trough level of 9.18 (normal <10 mcg/ml), VD of 24.57 L and vd/l/kg of 0.45 (normal 0.25-0.4 L/kg). Then at a dose of 820 mg administered 24 hourly, a peak level of 40.06 mcg/ml and a trough level of 8.07mcg/ml will be achieved
  • Vancomycin
    Based on the patient’s weight and creatinine clearance the dose of vancomycin can be changed to 750 mg every 48 hours. AUC (area under the curve) (mg/L·hr) Target AUC / MIC goal is 400 400 / 1 = 400 AUC = Daily dose / Clearance 400 = 750 mg 48 hourly Trough levels: 15-20mcg/ml

    On the fifth day she remained pyrexial, with temperatures persistently above 38 °C. At this point, a second blood culture taken during the sepsis screen, yielded a pure culture of oxidase-negative, non-fermenting Gram-negative bacilli on primary blood agar plates. The A. baumannii blood isolate was resistant to all antimicrobial agents tested (amikacin, ampicillin-sulbactam, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, piperacillin-tazobactam, tobramycin, and trimethoprim-sulfamethoxazole), with zone sizes greater than 6 mm by disk diffusion, susceptibility testing for colistin and tigecycline was indicated – however tigecycline was not available at the time.

    Due to the continued pyrexia with temperatures above 38°C with the follow-up positive blood cultures for XDR Acinetobacter baumannii (showing resistance to most antibiotics) the treatment regimen was changed to include combination therapy consisting of colistin with meropenem.

    The patient received a colistin loading dose (LD) of 12 Million Units (MU) despite the renal impairment. A maintenance colistin dose of 2 MU every 24 hours was started after the LD. The meropenem dose according to renal function was initiated at 500mg 12-hourly.

    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 outcome

    The 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.

    To illustrate the issues involved, we focus only on the choice of drug(s) and consider the options available for the treatment of the A.baumannii and MRSA infection when the patient was admitted to the hospital.

    Based on the resistance profiles of the A.< i > baumannii isolated from blood, the drug options were(i) continuing a carbapenem such as meropenem, (ii)combination therapy with meropenem and colistin.

    Combination therapy can reduce the probability of resistance mutations arising because the probability of multiple resistance mechanisms arising de novo in the same bacterium is low.

    Clinicians at a patient’s bedside must weigh treatment options with respect to ultimate outcomes.Despite a comprehensive search of the literature, we concluded that it was impossible to make even crude estimates of the evolutionary risks associated with the different treatment options.Unfortunately after colistin therapy was initiated, the patient rapidly succumbed to the sepsis.


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