Successful treatment of extreme drug resistant Acinetobacter baumannii infection following a liver transplant

Orthotopic liver transplantation is a life-saving procedure for patients with end-stage liver failure. However, Acinetobacter baumannii infections and acute rejection are important causes of morbidity and mortality following transplants. Here we present a case report of a cadaveric donor liver transplantation with infectious complications detected after transplantation. The patient was a 64-year-old female. Because of non-alcoholic steatohepatitis due to hepatic insufficiency (model for end-stage liver disease (MELD): 12; Child-Pugh: 9B), liver transplantation from a cadaveric donor was performed. Following the transplantation, the patient developed a blood stream infection, urinary tract infection (UTI) and postoperative wound infection from biliary leakage. A. baumannii was isolated from blood, urine and wound cultures. Imipenem (4×500 mg), tigecycline (2×50 mg) and phosphomycin (4×4 g) were administered intravenously (IV). On the 14th day of treatment, the bile fistula closed and there was no bacterial growth in blood and urine cultures. The patient was discharged with full recovery. The duration of a transplant patient’s hospital stay, intensive care unit stay, invasive interventions, blood transfusions and immunosuppressive treatments cause an increased risk of extensively drug-resistant (XDR) A. baumannii infections, and a high mortality rate is seen despite antibiotic treatment. Phosphomycin, used in combination therapy, may be an alternative in the treatment of XDR pathogens in organ transplant patients, due to its low side effect profile and lack of interaction with immunosuppressives.


Introduction
Orthotopic liver transplantation is a life-saving procedure for patients with end-stage liver failure. In patients undergoing liver transplantation, 80% of postinfectious complications occur in the first year [1]. The incidence of infections due to Acinetobacter baumannii is 1.4-6.1% in patients who undergo liver transplantation, with a mortality rate of 39-80% for those infected [2].
On the 23rd day of the antibiotic therapy, bile leakage continued at the wound site. XDR A. baumannii was found in blood and urine cultures and lab tests showed WBCs = 6770/mm 3 , CRP = 10.3 mg/dL and procalcitonin = 1 ng/mL. Imipenem (4×500 mg) and phosphomycin (4×4 g IV) were started. After 48 hours, due to CRP increase (CRP = 17.6 mg/dL), tigecycline (50 mg/q12h IV) was added after 100 mg loading. On the 14th day of treatment, the bile fistula closed, and there was no bacterial growth in blood and urine cultures. Laboratory tests showed WBCs = 5320/mm 3 , CRP = 2.9 mg/dL and procalcitonin = 0 ng/mL. The patient was discharged with full recovery.

Discussion
The risk of infection with multidrug-resistant (MDR)/XDR bacteria is increased in solid organ transplantation (SOT) recipients because of long-term hospitalization (especially in intensive care), invasive procedures, comorbidities and immunosuppressives. As a result, mortality risk was increased, graft survival was reduced, and antibiotic use in SOT recipients was investigated in 54%, and it was found that this resulted in a 3.5-fold increase in mortality [1,2]. Early treatment can reduce bacteraemic infections by 15% and severe sepsis and septic shock-related mortality by 50% [3].
The risk of biliary complications after liver transplantation has been reported in the range of 5-30%. Biliary leaks cause opportunistic infections, bile duct necrosis and prevention of arterial collateralisation [3,4]. Metallo-beta-lactamase-, oxacillinase-and carbapenem-resistant MDR and XDR A. baumannii species are increasing [5]. Bacterial resistance to betalactams, aminoglycosides, fluoroquinolones and tetracyclines, such as broad-spectrum antibiotics, has also increased. Colistin is the cornerstone of carbapenemase-producing Acinetobacter treatment [5,6]. Combinations with tigecycline, sulbactam, aminoglycosides, rifampicin, phosphomycin and/or carbapenems have been tried because of the increasing number of MDR and XDR pathogens and the lack of new antibiotics [6,7].
Phosphomycin is a phosphonic acid derivative that inhibits UDP-N-acetyl glucosamine (MurA). Thus, it inhibits the first step of bacterial cell wall synthesis [8,9]. It has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. It prevents bacterial invasion into the urinary and respiratory epithelium. Phosphomycin has an immunomodulating effect, effective on a biofilm structure, that increases neutrophilic phagocytosis even in patients with chronic renal failure and in transplant patients [8]. In vitro studies with XDR A. baumannii producing OXA-23 demonstrated the combinations of imipenem+phosphomycin, meropenem+amikacin, imipenem+amikacin and imipenem+colistin had synergistic effects of 65.2%, 46.2%, 30.8% and 17.4%, respectively [10,11]. In another study, aminoglycoside, sulbactam or colistin and phosphomycin were found to be synergistic combinations [10,11]. In addition, the combinations prevented the development of resistance to phosphomycin [10][11][12]. In 94 patients infected with carbapenem-resistant A. baumannii, when colistin and colistin + phosphomycin treatments (7-14 days) were compared, there was a significantly better microbiological response and better clinical outcome compared to monotherapy [13]. In the meta-analysis results of clinical studies using the results of 128 studies and including 5527 patients and using phosphomycin +colistin combination was found to be more effective for carbapenem-resistant A.baumannii than colistin treatment alone [14]. According to meta-analysis of 23 studies examining pneumonia due to resistant Acinetobacter, clinical cure rate was found to be more effective in combination of inhaler colistin+IV colistin+sulbactam, and microbiological eradication rate in phosphomycin+intravenous colistin+sulbactam combination compared to colistin treatment alone [15]. The risk of renal toxicity is increased in patients undergoing solid organ transplantation due to reduced glomerular perfusion and the use of nephrotoxic agents (such as calcineurin inhibitors). In these patients, aminoglycosides and colistin used in the treatment of infections with resistant microorganisms due to increase the risk of renal toxicity. In animal studies, histamine release from aminoglycoside-associated mast cells was inhibited by phosphomycin and was shown to be protective against nephrotoxic effect [9]. No interactions related to immunosuppressives have been described. The most common side effects of intravenous phosphomycin-disodium are hypernatremia and hypokalemia, resulting in edema, acid and heart failure [15]. No side effects were seen in our case. As a result; In the treatment of infections in solid organ transplant recipients, treatment decision should be made according to the place of infection, liver and kidney function values, comorbidities and resistance profile of regional strains. phosphomycin may be an alternative in the treatment of XDR pathogens in organ transplant patients, in combination therapy due to its low side effect profile and lack of interaction with immunosuppressives.