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A combination regimen of meropenem, cefoperazone-sulbactam, and minocycline for
extensive burns with pan-drug resistant Acinetobacter baumannii infection
Ning Fang-Gang1, Shen Yu-Ming1, Chen Xu1, Zhao Xiao-Zhuo1, Wang Cheng1, Rong Yan-Hua1, Du
Wei-Li1, Wen Chun-Quan1, Zhang Guo-An1
1.Department of Burn, Beijing Jishuitan Hospital, 4th Medical College of Peking University, No. 31,
Xinjiekou East Street, Xi Cheng District, Beijing, 100035, China
Correspondence to:
Zhang GA
Department of Burns, Beijing Jishuitan Hospital, No. 31, Dongjie, Xinjiekou, Xicheng District, Beijing
100035, China
Abstract
Background: Pan-drug resistant Acinetobacter baumannii (PDRAB) infection has become a serious
medical problem. The current study summarized the experience of treating extensive burns with PDRAB
infection during the last 2 years, with the purpose of developing a feasible treatment option. Methods:
From February 2011 to March 2013, nine adult patients with extensive burns complicated by PDRAB
infection were treated using high doses of meropenem, cefoperazone-sulbactam, and minocycline, and
their clinical data were retrospectively reviewed. Results: All nine patients developed PDRAB infection in
the respiratory system initially. In six patients (66.7%), wound infection with PDRAB occurred
subsequently. In four of these six patients, PDRAB was later cultured from the blood. All patients were
treated with meropenem, cefoperazone-sulbactam, and minocycline. The treatment was effective for all the
patients, and the symptoms improved significantly 3 days after starting the medication. All nine patients
were discharged after complete recovery. Conclusion: Combined administration of meropenem,
cefoperazone-sulbactam, and minocycline appears to be an option for the treatment of extensive burns
infected with pan-drug resistant A. baumannii. However, the sample size was small, and many
confounding factors could have affected the results.
Keywords: Acinetobacter baumannii, burns, meropenem, cefoperazone-sulbactam, minocycline
1. Introduction
Pan-drug resistant Acinetobacter baumannii (PDRAB) is resistant to all currently-available
antimicrobials (including carbapenems), with the exception of colistin (polymyxin).1 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.2,3 Multidrug-resistant A. baumannii
(MDRAB; ie, strains with resistance to ≥3 classes of drugs) strains are being increasingly reported
worldwide.1,4–9 Infections due to such resistant microbes are associated with increased morbidity and
mortality.5,7,10-12 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.
1,2,13–15
. 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 9 PDRAB infections were successfully treated with high doses of
meropenem, cefoperazone-sulbactam, and minocycline.
2. Methods
2.1. 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, cefoperazone-sulbactam, 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.
2.2. Diagnosis of infection
The diagnosis of infection was made by two attending dictors 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 out A. baumannii that was
resistant to all antibiotics except polymyxin B were labeled PDRAB.
2.3. Antibiotic administration
When patients were diagnosed with PDRAB infection in the blood or in the lungs, meropenem,
cefoperazone-sulbactam, and minocycline were administered. Meropenem was administered IV four times
per day (6g/day total). Cefoperazone-sulbactam was administered by twice a day (12g/day total;
cefoperazone 8g and sulbactam 4g). 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 every 6 hours thereafter.
2.4. 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.
2.5. Other treatment measures
Mechanical ventilation was used for all 9 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 utilized as needed.
2.6. Statistical analysis
Data were summarized in frequency (percentage) for the categorical variables and mean ± standard
deviation (SD) and range for continuous variables.
3. Results
Two-thirds (6/9) of the patients were men. The mean age was 38.2±10.7years (range, 23-57 yr). 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 7 of the 9 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 6 patients. However, the wound eventually healed with active wound
dressing and skin grafting.
In 2 of the 9 patients, blood cultures were positive for methicillin-resistant Staphylococcus aureus,
and turn negative after theated by 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.16,17
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 extended-spectrum
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 astructure 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.18-20 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 (8g/day). Moreover, A. baumannii drug resistance increases rapidly. It
was reported that 53.3% of A. baumannii strains are not susceptible to the sulbactam in Spain21, and 70%
of the strains are not susceptible to the ampicillin-sulbactam in Taiwan.22 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. In the animal model of A. baumannii
pneumonia, meropenem has a better antibacterial effect than imipenem.23 It was reported that the combined
administration of sulbactam and meropenem can improve the outcome of A. baumannii infection.24,25
Some scholars also successfully treated serious PDRAB infection using a combined administration of
sulbactam and meropenem.20 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.26-28 However, no large-sample, randomized controlled study has verified the accuracy of these
studies.
In order to ensure the maximal effect from each antibiotic, how 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.29-31 In a meta-analysis of 730 episodes of infection, it was
shown that when the total daily antibiotic dose was the same, clinical failure was significantly lower in the
continuous infusion group compared with the intermittent infusion group.32 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 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.33
Conclusion
The combined application of meropenem, cefoperazone-sulbactam, 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.
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