救急・集中治療 バンコマイシン耐性 毒素産生型MRSAにおけるリファンピシン

MRSA感染症におけるリファンピシンを用いたコンビネーション治療

名古屋大学大学院医学系研究科

救急・集中治療医学分野

松田直之

　バンコマイシンやテイコプラニンに抵抗性を持つMRSA（メチシリン耐性黄色ブドウ球菌）に，毒素産生タイプを認めことがあります。このようなMRSAに対して，例えば高濃度カテコラミンが投与されている場合にはバイオフィルム形成を促進させるために，カテコラミンの適正使用指導に入る場合があったり，リネゾリドに切り替えます。さらに短期的に，リファンピシンを併用することを考慮するのですが，MRSAのリファンピシンに対する薬剤耐性は比較的獲得されやすいために，使うべきではないという指摘があります。
　結核症でリファンピシンを使用している患者さんでは，リファンピシン耐性MRSAが検出されやすいことが知られています。米国のHCAPではリファンピシン耐性MRSAの増加が散見されるようですし，逆に日本では結核既往患者さん以外にはリファンピシンの使用が控えられているために，リファンピシン耐性MRSAの検出が少ないのかもしれません。弁膜症でMRSAを起炎菌として疑う場合やMRSAディバイス感染症などにおいては，リファンピシン 450 mg 1日2回投与を加えることでMRSAが消えやすい傾向があることは知られています。MRSAによる重篤ななディバイス感染や敗血症性ショックにおいて，リファンピシンの位置づけをどうするか悩ましいところです。ダプトマイシンにも期待したいところです。このようなリファンピシンの併用を考える論文を，以下に紹介しますので，参考とされて下さい。

文献 1　ガイドライン　Liu C, Bayer A, Cosgrove SE, et al. Clin Infect Dis 2011;52:e18-e55.

Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.

Infective Endocarditis, Prosthetic Valve

27.　IV vancomycin plus rifampin 300 mg PO/IV every 8 h for at least 6 weeks plus gentamicin 1 mg/kg/dose IV every 8 h for 2 weeks (B-III).

28.　Early evaluation for valve replacement surgery is recommended (A-II).


What is the management of MRSA bone and joint infections?
Osteomyelitis

36.　Surgical debridement and drainage of associated soft-tissue abscesses is the mainstay of therapy and should be performed whenever feasible (A-II).

37.　The optimal route of administration of antibiotic therapy has not been established. Parenteral, oral, or initial parenteral therapy followed by oral therapy may be used depending on individual patient circumstances (A-III).

38.　Antibiotics available for parenteral administration include IV vancomycin (B-II) and daptomycin 6 mg/kg/dose IV once daily (B-II). Some antibiotic options with parenteral and oral routes of administration include the following: TMP-SMX 4 mg/kg/dose (TMP component) twice daily in combination with rifampin 600 mg once daily (B-II), linezolid 600 mg twice daily (B-II), and clindamycin 600 mg every 8 h (B-III).

39.　Some experts recommend the addition of rifampin 600 mg daily or 300–450 mg PO twice daily to the antibiotic chosen above (B-III). For patients with concurrent bacteremia, rifampin should be added after clearance of bacteremia.

40.　The optimal duration of therapy for MRSA osteomyelitis is unknown. A minimum 8-week course is recommended (A-II). Some experts suggest an additional 1–3 months (and possibly longer for chronic infection or if debridement is not performed) of oral rifampin-based combination therapy with TMP-SMX, doxycycline-minocycline, clindamycin, or a fluoroquinolone, chosen on the basis of susceptibilities (C-III).

41.　Magnetic resonance imaging (MRI) with gadolinium is the imaging modality of choice, particularly for detection of early osteomyelitis and associated soft-tissue disease (A-II). Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) level may be helpful to guide response to therapy (B-III).

Septic Arthritis

42.　Drainage or debridement of the joint space should always be performed (A-II).

43.　For septic arthritis, refer to antibiotic choices for osteomyelitis (recommendation 37 above). A 3–4-week course of therapy is suggested (A-III).

Device-related osteoarticular infections

44.　For early-onset (3 weeks) of symptoms (A-II).

45.　For early-onset spinal implant infections (≤30 days after surgery) or implants in an actively infected site, initial parenteral therapy plus rifampin followed by prolonged oral therapy is recommended (B-II). The optimal duration of parenteral and oral therapy is unclear; the latter should be continued until spine fusion has occurred (B-II). For late-onset infections (>30 days after implant placement), device removal whenever feasible is recommended (B-II).

46.　Long-term oral suppressive antibiotics (eg, TMP-SMX, a tetracycline, a fluoroquinolone [which should be given in conjunction with rifampin due to the potential emergence of fluoroquinolone resistance, particularly if adequate surgical debridement is not possible should be given in conjunction with rifampin], or clindamycin) with or without rifampin may be considered in selected cases, particularly if device removal not possible (B-III).

Pediatric considerations

47.　For children with acute hematogenous MRSA osteomyelitis and septic arthritis, IV vancomycin is recommended (A-II). If the patient is stable without ongoing bacteremia or intravascular infection, clindamycin 10–13 mg/kg/dose IV every 6–8 h (to administer 40 mg/kg/day) can be used as empirical therapy if the clindamycin resistance rate is low (eg,
48.　Alternatives to vancomycin and clindamycin include the following: daptomycin 6 mg/kg/day IV once daily (C-III) or linezolid 600 mg PO/IV twice daily for children ≥12 years of age and 10 mg/kg/dose every 8 h for children


Rifampin for MRSA

Rifampin has bactericidal activity against S. aureus and achieves high intracellular levels, in addition to penetrating biofilms [67–69]. Because of the rapid development of resistance, it should not be used as monotherapy but may be used in combination with another active antibiotic in selected scenarios. The role of rifampin as adjunctive therapy in MRSA infections has not been definitively established, and there is a lack of adequately powered, controlled clinical studies in the literature [120]. The potential use of rifampin as adjunctive therapy for MRSA infections is discussed in various sections throughout these guidelines. Of note, rifampin dosing is quite variable throughout the literature, ranging from 600 mg daily in a single dose or in 2 divided doses to 900 mg daily in 2 or 3 divided doses [70–74]. The range of rifampin dosing in these guidelines is suggested on the basis of the limited published data and is considered reasonable on the basis of expert opinion. Additional study is needed to define the role and optimal dosing of rifampin in management of MRSA infections.

67.↵ Blaser J, Vergeres P, Widmer AF, et al. In vivo verification of in vitro model of antibiotic treatment of device-related infection. Antimicrob Agents Chemother 1995;39:1134-9.
68. Widmer AF, Frei R, Rajacic Z, et al. Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. J Infect Dis 1990;162:96-102.
69.↵ Zimmerli W, Frei R, Widmer AF, et al. Microbiological tests to predict treatment outcome in experimental device-related infections due to Staphylococcus aureus. J Antimicrob Chemother 1994;33:959-67.
70.↵ Nau R, Prange HW, Menck S, et al. Penetration of rifampicin into the cerebrospinal fluid of adults with uninflamed meninges. J Antimicrob Chemother 1992;29:719-24.
71. Euba G, Lora-Tamayo J, Murillo O, et al. Pilot study of ampicillin-ceftriaxone combination for treatment of orthopedic infections due to Enterococcus faecalis. Antimicrob Agents Chemother 2009;53:4305-10.
72.↵ Zimmerli W, Widmer AF, Blatter M, et al. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 1998;279:1537-41.
73.↵ Norden CW, Bryant R, Palmer D, et al. Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin-rifampin therapy. South Med J 1986;79:947-51.
74.↵ Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394-434.
100. Kim SH, Kim KH, Kim HB, et al. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2008;52:192-7.
120.↵ Perlroth J, Kuo M, Tan J, et al. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature. Arch Intern Med 2008;168:805-19.

文献 ２　Perazzi B, Bello N, Mollerach M, Vay C, Lasala MB, Famiglietti A.

J Med Case Reports. 2011 Jul 7;5(1):292.
Endocarditis caused by methicillin-susceptible Staphylococcus aureus with reduced susceptibility to vancomycin: a case report.

INTRODUCTION:
Staphylococcus aureus is the most common cause of acute infective endocarditis. Recent reports have described heteroresistance to vancomycin associated with methicillin-resistant S. aureus. We present the first case report in Argentina of the failure of treatment with vancomycin in endocarditis caused by methicillin-susceptible S. aureus containing subpopulations with reduced susceptibility to vancomycin.
CASE PRESENTATION:
We report the case of a 66-year-old Hispanic man with infective endocarditis complicated by septic emboli in the lumbosacral spine and the left iliopsoas muscle. This disease was caused by methicillin-susceptible Staphylococcus aureus containing subpopulations with reduced susceptibility to vancomycin. The patient was initially treated with cephalothin and gentamicin but developed a rash caused by beta-lactams and interstitial nephritis. For that reason, the treatment was subsequently switched to vancomycin but the patient failed to respond. The infection resolved after administration of vancomycin in combination with gentamicin and rifampin.
CONCLUSION:
This study provides important evidence for the existence of subpopulations of methicillin-susceptible S. aureus that have reduced susceptibility to vancomycin which would account for treatment failure in this case. Furthermore, this work raises an alert about the existence of these strains and highlights the need to determine the vancomycin minimum inhibitory concentration (MIC) of S. aureus to screen for the presence of strains that have reduced vancomycin susceptibility at different infection sites.


文献 3　Walvick MD, Amato M.　J Community Health. 2011 Apr 17.

Ophthalmic Methicillin-resistant Staphylococcus aureus Infections: Sensitivity and Resistance Profiles of 234 Isolates.

Source
Internal Medicine Resident, University of California San Francisco-Fresno, 155 N. Fresno St, Fresno, CA, 93701, USA, mwalvick@gmail.com.

Abstract
To identify the sensitivity and resistance profiles of ophthalmic Methicillin-resistant Staphylococcus aureus (MRSA) in a large, diverse demographic. The electronic database of a large health maintenance organization was searched for patients who had an ophthalmic bacterial culture performed from 2002 to 2008 which grew MRSA. Data collected included culture source, sensitivity and resistance profiles, and whether the infection was community or nosocomially-acquired. In this retrospective study, not all isolates were tested for all the antibiotics. All isolates tested for vancomycin, trimethoprim/sulfamethoxazole, and rifampin were sensitive to these antibiotics and none were resistant. Gentamycin and chloramphenicol had the next highest sensitivity to resistance ratios, followed by tetracycline and trimethoprim (without sulfamethoxazole). Community acquired MRSA is becoming more frequent and the most common ophthalmic manifestation is eyelid involvement. The sensitivities to antibiotics of the ophthalmic MRSA isolates in this study are consistent with that seen in the literature.


急性期臨床データ
文献 ４　Mercieri M, Di Rosa R, Pantosti A, De Blasi RA, Pinto G, Arcioni R.　Anesth Analg. 2010 Mar 1;110(3):852-4.

Critical pneumonia complicating early-stage pregnancy.

Source
Università Sapienza di Roma, II Facoltà di Medicina e Chirurgia, Ospedale Sant'Andrea, via di Grottarossa 1035, Rome, Italy. mamerx@gmail.com

Abstract
We present a case of community-acquired methicillin-resistant Staphylococcus aureus necrotizing pneumonia, Panton-Valentine leukocidin positive, in a woman at 14 weeks of pregnancy. To our knowledge, this is the first case reporting this critical lung infection occurring during an early phase of pregnancy. This case study alerts physicians to the increasing worldwide spread of these uncommon yet virulent and potentially lethal infections. In our patient, antibiotic therapy with linezolid plus rifampin started at 14 weeks of pregnancy had a successful outcome without inducing toxicity or teratogenesis in the fetus.


日本のデータ
文献 5 Yamamoto T, Dohmae S, Saito K, Otsuka T, Takano T, Chiba M, Fujikawa K, Tanaka M.　Antimicrob Agents Chemother. 2006 Dec;50(12):4077-86. Epub 2006 Oct 16.

Molecular characteristics and in vitro susceptibility to antimicrobial agents, including the des-fluoro(6) quinolone DX-619, of Panton-Valentine leucocidin-positive methicillin-resistant Staphylococcus aureus isolates from the community and hospitals.

Source
Division of Bacteriology, Department of Infectious Disease Control and International Medicine, Niigata University Graduate School of Medical and Dental Sciences, 757 Ichibanchou, Asahimachidori, Niigata 951-8510, Japan. tatsuoy@med.niigata-u.ac.jp

Abstract
Highly virulent, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strains with Panton-Valentine leucocidin (PVL) genes have been found increasingly worldwide. Among a total of 2,101 MRSA strains isolated from patients in hospitals in Japan, two were positive for PVL genes. One strain was identified as a community-acquired MRSA strain with genotype sequence type 30 (ST30) and spa (staphylococcal protein A gene) type 19 from Japan and was resistant only to beta-lactam antimicrobial agents. The other strain was closely related to PVL+ multidrug-resistant, hospital-acquired MRSA strains (ST30, spa type 43) derived from nosocomial outbreaks in the 1980s to 1990s in Japan but with a divergent sequence type, ST765 (a single-locus variant of ST30). Twenty-two PVL+ MRSA strains, including those from Japan and those from other countries with various sequence types (ST1, ST8, ST30, ST59, and ST80) and genotypes, were examined for susceptibility to 31 antimicrobial agents. Among the agents, DX-619, a des-fluoro(6) quinolone, showed the greatest activity, followed by rifampin and sitafloxacin, a fluoroquinolone. The data suggest that DX-619 exhibits a superior activity against PVL+ MRSA strains with various virulence genetic traits from the community as well as from hospitals.