A combination regimen of meropenem, cefoperazone-sulbactam and minocycline for extensive burns with pan-drug resistant Acinetobacter baumannii infection.

Pan-drug resistant Acinetobacter baumannii (A. baumannii) (PDRAB) is resistant to all currentlyavailable antimicrobials (including carbapenems), with the exception of colistin (polymyxin). Recently, PDRAB infection has become a serious medical problem. The mechanisms of A. baumannii drug resistance include low permeability of the outer membrane to antibiotics, an antibiotic efflux pump, and an extended-spectrum β-lactamase, etc. In addition, drug resistance can be easily acquired by incorporating genetic elements such as plasmids, transposons, and integrons. Multidrug-resistant A. baumannii (MDRAB; ie, strains with resistance to ≥3 classes of drugs) strains are being increasingly reported worldwide. Infections due to such resistant microbes are associated with increased morbidity and mortality. Carbapenems, which used to be the antimicrobials of choice, have become increasingly ineffective against such multi-resistant strains and no longer constitute salvage therapy for A. baumannii infections. In the last few years, PDRAB infections have been encountered several times during the treatment of patients with extensive burns. A. baumannii is susceptible to polymyxin B, which is not available in China. Therefore, the nine PDRAB infected patients were successfully treated with high doses of meropenem, cefoperazone-sulbactam and minocycline. METHODS Clinical data From February 2011 to March 2013, nine adult patients with extensive burns complicated by PDRAB infection were treated by slow intravenous (IV) infusion of high doses of meropenem and cefoperazone-sulbactam together with oral minocycline. Retrospective analysis was performed on the collected data: patients’ demographics; length of stay; total burn surface area (total and full-thickness); cause of injury; duration of mechanical ventilation; infection data; APACHE II score; duration of meropenem, cefoperazonesulbactam, and minocycline therapy; serum creatinine and aminotransferase levels before and after treatment; peak values of serum creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and patient outcomes. Infection data included chest X-ray, changes in the white blood cell (WBC) count and neutrophil levels, timing and results of bacterial cultures, location and method of sampling, and the results of antimicrobial susceptibility testing. Diagnosis of infection The diagnosis of infection was made by two attending doctors based on the clinical symptoms and bacterial data, imaging data, WBC count, and procalcitonin level. Specimens for blood cultures were collected mainly via arterial catheter and central venous catheter (CVC). Sputum for culture was harvested from the airway with a sputum collection device. Wound cultures were obtained with sterile swabs. Bacterial cultures and antibiotic sensitivity tests were carried out according to the reference standards of the Microbiology Laboratory of Beijing Jishuitan Hospital. Cultures that grew A. baumannii that was resistant to all antibiotics except polymyxin B were labeled PDRAB. Antibiotic administration When patients were diagnosed with PDRAB infection in the blood or in the lungs, meropenem, cefoperazonesulbactam, and minocycline were administered. Meropenem was administered IV four times per day (6 g/day total). Cefoperazone-sulbactam was administered twice a day (12 g/day total; cefoperazone 8 g and sulbactam 4 g). The antibiotic infusion time was prolonged to 1.5–2 hours every time. The first dose of minocycline was 200 mg orally and was given 50 mg every 6 hours thereafter. Outcome evaluation Outcome evaluation was carried out by two attending doctors according to symptom improvement and the results of sputum and blood cultures. The timing of antibiotic withdrawal was then decided. Other treatment measures Mechanical ventilation was used for all nine patients with respiratory failure. Burn wounds were repaired aggressively by micro-skin grafts, allogeneic skin grafts, mesh skin grafts, and stamp skin grafts. Additional therapies such as nutritional support were provided as needed. Statistical analysis Data were summarized in frequency (percentage) for the categorical variables and mean ± standard deviation (SD) and range for continuous variables. RESULTS Two-thirds (6/9) of the patients were men. The mean age was (38.2±10.7) years (range, 23–57 years). The mean APACHE II score on admission was 24.2±6.4 (range, 15–32). All patients had moderate or severe inhalation injuries. The mean total burn surface area was 70.0%±22.5% (range, 30%-95%). PDRAB infection first occurred in the respiratory system in all nine patients— before mechanical ventilation in four patients (44.4%) and after mechanical ventilation in the other five patients (55.6%). Wound PDRAB infection occurred in six patients (66.7%), and 4 of those patients demonstrated blood cultures positive for PDRAB. In seven of the nine patients, A. baumannii was susceptible to meropenem or ciprofloxacin initially. However, after initial treatment, A. baumannii turned into PDRAB, which then was treated with meropenem, cefoperazone-sulbactam, and minocycline. The treatment was effective in all nine patients, and the symptoms improved significantly 3 days after starting the 3-drug regimen. The drugs were withdrawn after negative blood cultures and sputum cultures in eight of the patients (88.89%). In one patient, a few PDRAB grew in the sputum 28 days after treatment. However, the body temperature, WBC count, and procalcitonin levels were normal, and the chest X-ray showed resolution of inflammation. The antibiotics were stopped, and there was no recurrent infection. The sputum culture became negative 14 days after stopping the antibiotics. A. baumannii was found in the wound after antibiotic withdrawal in six patients. However, the wound eventually healed with active wound dressing change and skin grafting. In two of the nine patients, blood cultures were positive for methicillin-resistant Staphylococcus aureus, and turn negative after treatment with vancomycin. Comparison of the laboratory results before and after treatment showed that the serum creatinine, ALT, and AST levels did not significantly elevate. The ALT and AST were elevated in five patients during the time of antibiotic therapy, but all due to other express reasons such as operation and infection. No renal replacement therapy was performed, and no liver failure occurred. Supportive treatments were carried out after admission, and the wounds were covered by allogeneic skin graft, micro-skin graft, mesh graft, and/ or stamp skin graft. Micro-skin grafting failed in 1 patient and serious wound sepsis occurred. The conditions of this patient became extremely critical; however, all nine patients were eventually discharged after complete healing. DISCUSSION PDRAB infection has become a critical problem in the intensive care unit (ICU). A. baumannii is susceptible to polymyxin, but this antibiotic is not available in China. Tigecycline, another antibiotic possibly effective for PDRAB, has just obtained marketing authorization in China. However, its efficacy is still controversial, and the drug resistance of PDRAB against it has increased rapidly.1 When effective antibiotics cannot be obtained, the approach to successful treatment of PDRAB infection revolves around increasing the effective blood drug concentration and the combined application of various antibiotics according to the drug resistance mechanisms of the bacteria. In addition, some unconventional drugs were used in the current study. Drug resistance mechanisms of PDRAB include low permeability of the outer membrane to antibiotics, an antibiotic efflux pump, and an extendedspectrum β-lactamase. Although in vitro antibiotic susceptibility testing showed that PDRAB is not susceptible to carbapenem, this class of β-lactams is not totally ineffective against PDRAB. Increasing the dosage and prolonging the administration time may compensate for the low permeability of the outer membrane to antibiotics and overcome the antibiotic efflux pump to some extent. For the extended-spectrum β-lactamase, the combined application of carbapenem and high doses of enzyme inhibitors can theoretically improve the outcome. Sulbactam is an Ambler class A-lactamase inhibitor with a structure similar to β-lactams that carries intrinsic activity against A. baumannii by binding to its penicillin-binding protein 2. Sulbactam showed an encouraging efficacy during the treatment of A. baumannii infections and is widely used in clinical practice now.2 However, there is no single sulbactam product available in many countries including China. Therefore, only ampicillin-sulbactam (2:1 ratio) or cefoperazone-sulbactam (2:1 ratio) can be utilized. Due to the limitations of permissible dosage of ampicillin and cefoperazone, the dosage of sulbactam can hardly reach the recommended dose (8 g/day). Moreover, A. baumannii drug resistance increases rapidly. Therefore, the administration of sulbactam alone against PDRAB infection in critically-ill patients is a poor therapeutic choice. Although PDRAB is not susceptible to the carbapenem antibiotics in antimicrobial susceptibility tests, they play an important role in the treatment of PDRAB. The administration of a large dose of carbapenem combined with other antibiotics can be effective for some patients. It was reported that the combined administration of sulbactam and meropenem can improve the outcome of A. baumannii infection.3 Some scholars also successfully treated serious PDRAB infection using a combined administration of sulbactam and meropenem.2 However, like the current study, most studies are not large-sample, randomized controlled trials, and some are only animal models. Minocycline is a semi-synthetic tetracycline antibiotic, which can prevent bacterial protein synthesis and has been applied in clinical practice since the 1960s. Recently, its efficacy against MDRAB has attracted attention. Minocycline has strong penetration; its concentration in the blood and tissues is high; and it can reach the central nervous system. A number of studies reported its excellent effect on PDRAB.4 However, no large-sample, randomized controlled study has verified the accuracy of these studies. In order to ensure maximum effect from each antibiotic, the way the drug is administered is also very important, especially for those time-dependent antibiotics. Studies have shown that prolongation of the infusion time for the carbapenem antibiotics has the ability to achieve drug concentrations above the MIC for a greater time for less susceptible organisms. Therefore, the maximum permissible dose of meropenem was given during the treatment and was slowly infused four times a day to improve its efficacy. This study had several limitations. First, a large-sample, randomized controlled study was impossible due to the critically-ill condition of the patients. Hence, our study is only a small-sample clinical experience. Second, many factors affect the incidence of infection, especially in burn patients, and antibiotic administration is just one aspect of the treatment. Toxin absorption due to wound discharge and infection causes severe physiological damage and compromises immunity. Infection was controlled in our nine patients after most parts of the wounds were covered by micro-skin grafts, allogeneic skin grafts, mesh skin grafts, and stamp skin grafts. Antibiotic administration only plays a role of “buying time” for wound repair and an improvement in the general condition.5 The combined application of meropenem, cefoperazonesulbactam, and minocycline in the treatment of extensive burns with pan-drug resistant A. baumannii infection represents a feasible treatment option. However, since the sample size is small and there are many confounding factors, this treatment recommendation should be used cautiously.