Abstract

Here we report a 75-year-old female resident of nursing home with several illnesses, who came to our hospital due to dyspnea for 2 days. She was hospitalized for suspected pneumonia caused by gram negative organisms, but sputum sample with satisfied quality for culture test couldn't draw because the patient was too weak. She was treated empirically by second-generation cephalosporins, ertapenem, and then piperacillin-tazobactam, but the clinical responses of these agents were not quite well. Sputum culture with good quality was received at day 18. It showed positive for carbapenem resistant Acinetobacter baumannii（CRAB）, and physicians changed antibiotic agents to meropenem + sulbactam. Afterward, symptoms of infection declined significantly, and patient didn't need further treatment after completion of 15 days of meropenem-sulbactam combination therapy.

Several literatures had pointed out that sulbactam is one of the most important additive agents in treating carbapenem resistant Acinetobacter baumannii infections, especially in regional hospitals where colistin and tigecycline are not always available. Our success in treating this case could be one of the examples.

Key words: Carbapenem resistant Acinetobacter baumannii, sulbactam, health-care associated pneumonia

Introduction

Nowadays, the control of expense in the hospitals for medicine is getting stricter. How to do not only an efficient management but also keep a smooth supply to ensure a prompt provision of medicine have become one of the most inevitable challenges. According to the healthcare executive and financial concerns, regional hospitals cannot enlist all kinds of antibiotics to be their routine supplement, especially those used for resistant pathogens. It would help hospitals to reduce its prime costs, but, on the other hand, clinical practitioners should know how to use current available agents to treat patients well.

Acinetobacter baumannii is a common cause of nosocominal infections worldwide. Recently, bloodstreams or lower respiratory tract infections（LRTIs）with high mortality rates caused by multiple-drug resistant Acinetobacter baumannii（MDRAB）or carbapenem resistant Acinetobacter baumannii（CRAB）are becoming more prevalent¹. Polymyxin（includes polymyxin B and colistin）based regimen is the most active treatment, but it is not one of the regular storage of medicine in regional hospitals.

This study case is a nursing home resident who was admitted for pneumonia in 2008. Sputum culture was positive for growth of CRAB at Day 18, and it remained susceptible only to colistin. We reported the whole course of treatment, the selection of antibiotics and the result of therapy, and also made a brief literature review of pharmacotherapy of CRAB.

Case report

A 75 years old female resident of nursing home was admitted due to dyspnea for 2 days at 2008. She has a medical history of hypertension, chronic renal failure（CRF）and chronic obstructive pulmonary disease（COPD）. She was bed-ridden after a stroke event 20 years ago, and accepted an operation of tracheotomy because of respiratory failure for 2 years. Her baseline serum creatinine was 3.0 ~ 3.5 mg/dL. Other lab data were shown as Table 1. Since her refusal of dialysis therapy, treatment with oral medicine and low nitrogen diet were given.

Physician's first impression was pneumonia caused by gram negative organisms after discussing the results of X-ray and sputum smear. Cefuroxime 1.5 g qd was empirically given, then changed to ertapenem 1g qd（day 8~ 17）and Pipercillin + Tazobactam（Tazocin）2.25 g q8h（day 18~ 23）because of unsatisfied clinical response or results of susceptibility tests. Sputum culture drawn at day 18 showed positive for Acinetobacter baumannii bacteria which was not susceptible（resistant or intermediate）to all cephalosporins、ß-lactam + ß-lactamase inhibitors（ex. Unasyn、Tazocin）、levofloxacin、and carbapenems, remaining susceptible only to colistin（Table 2-3）. Day 23, antibiotic therapy was replaced with meropenem 500 mg qd + sulbactam 1 g qd. Afterward, the patient's fever was subsided and clinical symptoms were significantly improved. Antibiotic treatment was completed 15 days after being shifted to meropenem + sulbactam.

Literature review

Acinetobacter spp. is one of the gram negative bacteria strains. It distributes mostly in watery area, and is one of the normal flora in the throat and skin of health adults. During the past three decades, Acinetobacter spp. has became one of the most common pathogens causing the nosocominal hospital infections, especially pneumonia. The organism's ability to accumulate diverse mechanisms of resistance, the emergence of strains that are resistant to many commercially available antibiotics and the lack of new antimicrobial agents in development are the most alarming problems worldwide^1,2.

Treatment of infections with Acinetobacter baumannii

Selection of antibiotics in treating Acinetobacter baumannii infections is generally based on the result of antibiotic susceptibility tests. Favorable antibiotics include broad-spectrum cephalosporins, ß-lactam- ß-lactamase inhibitor combinations（ex. Unasyn, Tazocin）and carbapenems, used alone or in combination of aminoglycosides¹. The duration of treatment is generally similar to that for infections caused by other gram-negative bacilli, for example, Escherichia coli or Klebsiella pneumonia. It is largely empirical and depends on the site of infections. However, the appearance of multiple-drug resistant strains（defined as strains which are resistant to more than three different categories of antibiotics）keeps on increasing its ratio in recent years³. Risk factors of infections caused by multiple drug resistant Acinetobacter baumannii,（MDRAB）of patients include history of hospitalization in the intensive care unit（ICU）, long duration of hospitalization, greater disease severity, previous antibiotics exposure or invasive treatments, etc. Residents of long-term care facilities have a higher risk of MDRAB infections usually because of their high frequency of receiving invasive and/or antibiotic treatments.^4,5

Carbapenems are one of the most important and efficient agents in treating Acinetobacter baumannii, especially to those which are resistant to ß-lactam- ß-lactamase inhibitor combinations or broad spectrum cephalosporins. But, the statistic researchers of the United States CDC found that the prevalence of carbapenem resistant Acinetobacter baumannii（CRAB）has developed from 9%（1995）to 40%（2004）⁶. Taiwan TSAR data also demonstrates that Acinetobacter's drug-resistance to imipenem has rapidly elevated from below 5%（2002）to 16% （2004）⁷. For infections caused by CRAB, the choice of antibiotics is generally limited. High recommendations are polymyxin-based therapy, such as: polymyxin B and polymyxin E, or in combination with imipenem、rifampim、ampinillin-sulbactam, etc. Tigecycline, a newly marketed glycylcyline antibiotic, is also a probable alternative agent^1,8,9. However, systemic use of polymixin B in Taiwan is not commercially available, and regional hospitals do not keep colistin （polymyxin E） and tigecylcine as a routine supplement. On the other hand, both drugs have significant shortcomings. Colistin is associated with several adverse reactions, such as nephrotoxicity, neurotoxicity, and neuromuscular blockage. Pathogens can easily develop resistance to tigecycline during therapy, too.

Role of sulbactam and its combinations

Some combinations of antibiotic agents showed good synergic or additive effects in CRAB treatment. Sulbactam with its unique antibiotic effects and inherent activity against Acinetobacter baumannii, has become one of the drug of choice for treating CRAB. Sulbactam is chemically a penicillanic acid sulphone, showing particular activity against C, A and D enzyme. It can irreversibly inhibit the hydrolytic activity of ß-lactams, and avoid the decomposition of ß-lactam agents by bacteria strains. Parenteral sulbactam / ß-lactams combination has been widely used in cases of community and/or hospital-acquired pneumonia, and in several mixed infections, including intra-abdominal infections, diabetic foot infections, staphylococcal bacteraemia, etc¹⁰. On the other hand, researchers discovered that sulbactam can bind to the PBP2 of Acinetobacter baumannii, Bacteroides fragilis, demonstrating a direct antibiotic effect, and is helpful in overcoming the resistance of ß-lactams including penicillins, cephalosporins and carbapenems.

Reports about the mechanism and efficacy of sulbactam in treating Acinetobacter baumannii have been increasing recently, and it makes clinicians be more confidential when using it. For example, one research report in 2006 pointed out that treating CRAB with cefepime + sulbactam would reduce the MIC₅₀ of carbapenem and sulbactam from 32μg/mL to 8μg/mL¹¹. In-vitro study published in Korea in 2007 discovered that the CRAB strain with intermediate sensitivity to sulbactam when treated with imipenem + sulbactam would effectively achieve the doubling effect of bactericidal action¹². N.Y Lee et al. at National Cheng Kung University Hospital of Taiwan¹³ also described four critically ill patients with MDRAB bacteremia. The pathogens were resistant to commonly available antibiotics, including carbapenem and sulbactam. However, combination therapy with a carbapenem and sulbactam led to favorable clinical outcomes and decreasing of MIC of carbapenem in all four patients.

Discussion

This study case is a hospitalized patient of a health care institution, who suffers multiple diseases. There are a lot of risk factors for MDRAB infection, such as: long duration of hospitalization, previous antibiotic and invasive therapy, and greater disease severity. She accepted cefuroxime、ertapenem、piperacillin- ticarcillin, but all were failed to achieve ideal treatment effects. Physicians had no evidence of the accurate pathogens of the pneumonia because the patient was too weak to make a satisfying sputum sample. On the 18^th day, nurses got a sputum sample with better quality for culture testing, and the laboratory report showed CRAB strain positive. According to the susceptibility test report, there were more than 3 categories of antibiotics ineffective, including the penicillins, 3^rd and 4^th generation of cephalosporins, carbapenems, sulbactam and aminoglycosides. Physicians changed the antibiotic agents to meropenem 500mg qd + Sulbactam 1g qd. Symptoms had been significantly improved and no other signs of infection followed after treated with meropenem + sulbactam during the 15 days.

The frequency of CRAB infections among critically ill patient is rising. With the effect of decreasing MIC of ß-lactams, and its intrinsic antibiotic property of sulbactam, we could treat patients who infected by CRAB with sulbactam and carbapenems; especially when the number of available antimicrobial agents is limited. We observed a favorable clinical outcome in this case, and expect more experience of CRAB treatment to be discussed in future.

References:

1. Munoz-Price LS, Weinstein RA, Munoz-Price LS, Weinstein RA. Acinetobacter infection. N Engl J Med 2008; 358: 1271-81.

2. Luna CM, Aruj PK, Luna CM, Aruj PK. Nosocomial Acinetobacter pneumonia. Respirology 2007; 12: 787-91.

3. Giamarellou H, Antoniadou A, Kanellakopoulou K, Giamarellou H, Antoniadou A, Kanellakopoulou K. Acinetobacter baumannii: a universal threat to public health? Int J Antimicrob Agents 2008; 32: 106-19.

4. Navon-Venezia S, Ben-Ami R, Carmeli Y, Navon-Venezia S, Ben-Ami R, Carmeli Y. Update on Pseudomonas aeruginosa and Acinetobacter baumannii infections in the healthcare setting. Curr Opin Infect Dis 2005; 18: 306-13.

5. Karageorgopoulos DE, Falagas ME, Karageorgopoulos DE, Falagas ME. Current control and treatment of multidrug-resistant Acinetobacter baumannii infections. Lancet Infect Dis 2008; 8: 751-62.

6. Munoz-Price LS, Weinstein RA, Munoz-Price LS, Weinstein RA. Acinetobacter infection.[see comment]. N Engl J Med 2008; 358: 1271-81.

7. 劉伯瑜、施智源：多重抗藥性鮑氏不動桿菌的相關危險因子及感染管制策略。感染控制雜誌 2007；17卷1期。

8. 8.Perez F, Hujer AM, Hujer KM, et al: Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2007; 51: 3471-84.

9. Rahal JJ, Rahal JJ. Novel antibiotic combinations against infections with almost completely resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis 2006; 43 Suppl 2: S95-9.

10. Akova M. Sulbactam-containing beta-lactamase inhibitor combinations. Clin Microbiol Infect 2008; 14 Suppl 1: 185-8.

11. Tong W, Wang R, Chai D, et al: In vitro activity of cefepime combined with sulbactam against clinical isolates of carbapenem-resistant Acinetobacter spp. Int J Antimicrob Agents 2006; 28: 454-6.

12. Song JY, Kee SY, Hwang IS, et al: In vitro activities of carbapenem/sulbactam combination, colistin, colistin/rifampicin combination and tigecycline against carbapenem-resistant Acinetobacter baumannii. J Antimicrob Chemother 2007; 60: 317-22.

13. Lee NY, Wang CL, Chuang YC, et al: Combination carbapenem-sulbactam therapy for critically ill patients with multidrug-resistant Acinetobacter baumannii bacteremia: four case reports and an in vitro combination synergy study. Pharmacotherapy 2007; 27: 1506-11.

摘要

本案例報告為一名75歲女性病患，長期居住於養護機構，患有多重疾病。本次因呼吸急促持續兩日前來就診，醫師診斷為疑似葛蘭氏陰性菌引起之肺炎，收入住院。住院時，因病患虛弱無法採集合適的痰液檢體供細菌培養使用，故先後給予第二代cephalosporins、ertapenem和puperacillin-tazobactam治療。但是，病患狀況未有明顯改善。住院第十八天時，採得可供細菌培養之病患痰液，檢驗發現菌株為carbapenem-resistant Acinetobacter baumannii（CRAB）。因此，醫師將抗生素改為meropenem和sulbactam並用。病患用藥後症狀明顯改善，完成15天抗生素療程後，不再出現感染徵候、也不再需要抗生素治療。

目前許多文獻已指出，sulbactam是CRAB感染治療中，最重要具有的治療效果加乘性的抗生素之一。其特殊角色，在一些缺乏colistin、tigecycline的區域醫院中更形重要。我們此次成功的治療經驗，即是一項可供參考的案例。

作者
台北市立聯合醫院陽明院區藥劑部藥師 林于瑄、楊瑛碧