Review ISSN 1975-7425(Print) / ISSN: 2288-016X(Online) http://dx.doi.g/10.14777/kjutii.2015.10.1.12 Kean J Urogenit Tract Infect Inflamm 2015;10(1):12-18 다제내성시대의임균치료 채지윤, 오미미 고려대학교의과대학비뇨기과학교실 Treatment of Neisseria gonrhoeae in the Era of Multidrug Resistance Ji Yun Chae, Mi Mi Oh Department of Urology, Kea University College of Medicine, Seoul, Kea Neisseria gonrhoeae (NG) is becoming increasingly less susceptible to the extended spectrum cephalospin (ESC), which has been recommended f first-line treatment, and cases of treatment failure are being repted globally. An era of untreatable gonrhea may have started, and it calls f novel treatment strategies. Essential actions should include use of higher doses of ceftriaxone administered as part of dual therapy and further development of alternative drug combinations. This review focuses on the global spread of ESC resistant NG and potential treatment options f the future. Keywds: Neisseria gonrhoeae; Drug resistance; Cephalospins Copyright 2015, Kean Association of Urogenital Tract Infection and Inflammation. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.g/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the iginal wk is properly cited. Received: 28 February, 2014 Revised: 18 March, 2014 Accepted: 25 March, 2014 Crespondence to: Mi Mi Oh http://cid.g/0000-0002-1232-2598 Department of Urology, Kea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 152-703, Kea Tel: +82-2-2626-3203, Fax: +82-2-2626-1321 E-mail: mamah@hanmail.net 서 론 임균은두번째로흔한박테리아성성매개감염병인임질의원인균으로대개성적접촉을통해감염되어남성에서는요도염을, 여성에서는자궁경내막염을유발한다. 임질을제대로치료하지않는경우여성의골반염, 불임, 자궁외임신, 남성의부고환 / 고환염및 human immunodeficiency virus 감염등의합병증이발생할수있다. 1,2 가장최근발표된 Wld Health Organization의통계에따르면임질의유병률은빠르게증가하고있으며 2008년집계당시그해새로감염된환자수가전세계적으로 1억 6천만명에이르는것으로나타났다. 3 한편, 지난 30년동안임균은임질의치료제로쓰였던 penicillin, tetracyclines, fluoquinolones 등에내성을획득하였으며, 이에 1990년대부터는 3세대 extended-spectrum cephalospins (ESCs) 가임질의일차치료제로권장되어사 용되어왔다. 4 그러나최근다양한 3세대 cephalospin 제제들의치료실패사례들이보고되면서임질의치료는새로운국면을맞이하게되었다. 5-8 세계각국에서 ESCs 에대한임균의내성보고가잇따름에따라 2012 년 8월, 미국질병예방통제센터 (Centers f Disease Control and Prevention, CDC) 는세계동향과미국내임균분리감시체계 (Gonococcal Isolate Surveillance Project) 결과에따라임질치료지침을개정발표하였다. 2013년 8월국내에서또한임균감염치료에대한부분개정안을마련하여, 기존단일제제로투여되던 cefixime 혹은 ceftriaxone의사용대신 ceftriaxone 및 azithromycin 혹은 doxycycline의병합요법을권장하고있다. 이에저자들은변경된임질의치료지침에맞추어다제내성임균의출현과현황, 이의새로운치료지침및항생제내성시대의임질의치료방안에대하여알아보고자하였다. 12
Ji Yun Chae and Mi Mi Oh. Treatment of Neisseria gonrhoeae in the Era of Multidrug Resistance 13 본 론 1. Penicillin, Tetracycline 및 Fluoquinolone에의내성 1940년대 penicillin의도입이후이는사실상임질의첫번째주치료제가되었으며이후 40 년이상효과적인치료제로사용되었다. 하지만 50년대부터 penicillin의최소억제농도 (minimum inhibity concentration, MIC) 가꾸준히증가함에따라 penicillin 의임질치료용량은지속적으로상승하였다. 여러유전자의변이로인한염색체매개 penicillin 내성에서부터시작하여 1970 년대에는플라스미드매개로 penicillinase 를분비하는임균균주가발견되면서 penicillin 내성이점차확산되어갔고, 따라서 1970 년대말에는더이상 penicillin 을임질치료제로쓸수없게되었다. 9 거의비슷한시기에 tetracycline 의경우도마찬가지로임균의유전자변이로인한저항성획득으로 tetracycline 에의감수성이점차감소하기시작했다. 1980년대에는플라스미드매개 tetracycline resistance protein (TetM) 결정인자의발현으로 tetracycline 에높은저항성을갖는임균이발견되었으며이들은빠른속도로전세계적으로확산되었다. 이들 TetM을암호화하는플라스미드는 penicillinase 를분비하는임균균주에서흔히발견되는것으로나타났다. 10 1980년대들어서 fluoquinolone은부작용이거의없으면서단회투여로치료가능한임균의치료제로부상하였고, 1980년대말에는 3세대 cephalospin 과함께임균의일차치료제로권장되었다. 그러나 1990년대초반 fluoquinolone 에의내성을결정짓는유전자인 gyra와 parc의변이가발생하면서치료실패사례들이보고되기시작했으며, 1990년대아시아-태평양지대를시작으로유럽과북미, 다음아프리카와남미순서로전세계적으로확산되었다. 9 이에 2000 년대중반이후부터 fluoquinolone은임질의권장치료제에서제외되었다. 2. Extended-Spectrum Cephalospins에의내성이렇듯임균은지난 70-80년간 penicillins, tetracyclines, spectinomycin, macrolides, fluoquinolones 등모든가능한임균의치료항생제에내성을획득해왔으며따라서현재는 ESCs인주사용 ceftriaxone, 경구용 cefixime만이유일한단일치료제로선택가능하게되었다. 하지만대부분의국가에서 3세대 ESCs를임질의일차치료제로사용하기시작하면서여러경구용 ESCs가낮은용량으로사용되었고, 이에따라억제농도보다는낮은 ESCs가지속적으로축적되면서 ESCs 내성균주들출현에기여하였을것으로생각된다. 11 특히경구용 ESCs 중가장강력한 cefixime만이인두임질을효과적으로치료할수있는것으로알려지면서 cefixime (400 mg) 은전세계적으로임질의주된치료제로서사용되어왔지만, 10 2001년일본을시작으로한아시아에서경구용 ESCs에의감수성이 떨어지는임균균주들이출현하면서치료실패로이어졌다. 1999 년과 2002 년사이일본중심부의 6개병원통계에따르면 cefixime과 ceftriaxone에저하된감수성 (MIC 0.5 g/ml) 을갖는임균의비율이각각 0% 에서 30.2% 로, 0% 에서 0.9% 로증가한것으로나타났다. 12 경구용 ESCs 에의감수성이떨어지는임균균주들은대개 penicillin 결합단백질인 penicillin-binding protein 2를인코딩하는 pena 유전자의변이를나타냈으며이들과구강인두에흔히존재하는공생 Neisseria 종들의 pena 유전자간의수평적유전자이동으로인해구강인두내저항성임균감염이호발하는것으로생각된다. 초반의내성균주들은일반적으로 penicillin과 fluoquinolone에는저항성을보였고, ceftriaxone 의 MIC가상승되어있었지만근주용 ceftriaxone 에는감수성을갖는것으로나타났다. 12 일본을시작으로하여 2000년대후반호주, 중국, 홍콩, 대만, 미국, 캐나다등전세계적으로 3세대 ESCs에내성을갖는임균균주들이확산되었다. 13-20 2009년부터 2010년까지 European Union/European Economic Area에서발견된 cefixime에의감수성저하혹은내성을보이는임균균주들의비율이 4% 에서 9% 로상승하였으며, 이내성을갖는표현형은총 17개국가에서발견되었다. 21 3. Multidrug Resistant Neisseria gonrhoeae 및 Extensively Drug Resistant N. gonrhoeae 임균에대한 ESCs의 MIC 상승과함께감수성이저하된임균이지역과집단을초월하여전세계적으로높은비율로보고되고있으며이는해마다증가하고있다. 이들은 fluoquinolone 등다른항생제들에도저항성을보이는데, 가장문제가되는것은성매매업종사자와동성애자들에서발견되고있는 extensively drug resistant (XDR) 임균들로, 높은 ceftriaxone 의 MIC를갖는것이특징이다. 7,22,23 Ceftriaxone의치료에내성을보인첫균주는 2009 년일본교토의성매매업종사여성의인두에서발견된 H041로, 이는사실상임균으로써의첫 superbug로생각되며, ceftriaxone MIC가 2-4 mg/l, cefixime MIC가 8 mg/l로나타났다. 23 다음으로프랑스의남성동성애자의요도에서높은 ceftriaxone MIC (2 mg/l) 를갖는 2번째 superbug 임균균주 F89 가발견되었으며, 7 스페인의동성파트너인두남성의요도와직장에서 MIC 1.5 mg/l 를갖는임균균주가이어서발견되었다. 22 H041의출현후일본에서는 XDR-임균균주의감시를강화하여확산범위파악에힘썼으나, 아직까지 H041 균주는처음출현한지역외에서는발견되지않았다. 하지만이후세유럽인에서분리된균주들은같은임균 multiantigen sequence typing인 sequence type (ST) 1407을공유하고있는것으로밝혀졌고이는현재전세계적으로발견되고있는 ST 1901 에속한다. 16,18,24 따라서프랑스의 F89의경우스페인의동성애자인두남성에게전파되었던
14 Ji Yun Chae and Mi Mi Oh. Treatment of Neisseria gonrhoeae in the Era of Multidrug Resistance 것으로생각되며, 이는 ceftriaxone 에높은내성을갖는임균의첫국제적전파라할수있다. 한편, ceftriaxone을투여한구강인두임질의치료실패사례들이다수보고되고있으며이들에대한 ceftriaxone의 MIC는상대적으로낮은편이다. 25-27 MIC 가낮은균주들에서는약물역동학적인요인들이치료실패에주요하게작용하였을것으로보이며, ceftriaxone의임질치료실패는구강인두임질의치료에서처음시작된것으로생각된다. 4. 현재임질의치료지침현재미국 CDC 및변경된국내임질치료지침에따르면모든단순임질의경우 ceftriaxone 250 mg의단회근육주사와함께경구 azithromycin 1 g 단회경구투여혹은 doxycycline 100 mg 1일 2회씩 7일경구투여를일차적으로권장하고있다. 28-30 Ceftriaxone을사용할수없는경우, 대체요법으로 spectinomycin 2 g 근육주사단회요법 ( 인두임균감염은제외 ), 또는 cefixime 400 mg 단회경구투여및 azithromycin 1 g 단회경구투여 (7일내검사 ), 또는 cefixime 400 mg 단회경구투여및 doxycycline 100 mg 1일 2회 7일경구투여 (7일내검사 ) 를권장하고있으며알레르기로 cephalospin 계항생제를사용할수없는경우에는 spectinomycin 2 g 근육주사단회요법 ( 인두임균감염은제외 ) 또는 azithromycin 2 g 단회경구투여 (7일내검사 ) 를권장하고있다 (Table 1). 30 2012년부터 cefixime 400 mg의단회경구투여와 azithromycin 혹은 doxycycline 의병합요법은일차가아닌대체치료법으로권장되고있는데, 이는 cefixime의높은 MIC 농도와치료실패율, 또한흔히놓치기쉬운인두임질의치료에 cefixime이부적합하다고판단되었기때문이다. 28 이렇듯임 질의일차치료약제를 cefixime에서고용량의주사용 ceftriaxone 으로교체함으로써경구용 ESCs 에내성을갖거나감수성이저하된임균의전파속도를늦추는효과를기대하고있다. 또한, 임질에대한보다적극적인치료가필요하게되면서, 각나라의임질치료실패율이 5% 를상회하기전에권장일차치료제를빠르게변화시킬것을요구하고있다. 31 5. 새로운치료법다제내성임균및 XDR 임균의효과적인치료를위해서는기존과는다른새로운치료전략이필요하다. 이로는 ESCs 의투여용량및기간증가, 이차치료제의병합투여, 오래된항생제들의재사용, 대체치료약제개발등을들수있다. 1) 고용량의 Extended-Spectrum Cephalospins 기존사용되던 ESCs, 특히 ceftriaxone 의용량을증가해서투여하는치료는대개의나라에서시행되고있다. 11,32,33 일본과중국에서는 1 g ceftriaxone 의단회투여가권장되고있으며지역사회획득폐렴의치료에사용되는용량에근거하여 ceftriaxone 2 g 단회투여도안전한것으로보고있다. 32,34-36 그러나증량된 ceftriaxone 의투여는단기적인해결책일뿐이다. 현재존재하는다른어떤경구혹은주사용 cephalospine 제제도 ceftriaxone 이나 cefixime을능가하는약동학 / 약물역동학적인효과를나타낼수없으며, 더구나인두임질에서의효과는말할것도없다. 37,38 2) 병합요법 영국에서는 2011 년부터단순항문직장임질에서 ceftriaxone 500 mg 단회근주투여및 azithromycin 1 g 단회경구투여를 Table 1. Revised regimens of treatment in gonococcal infection Classification Recommended regimens Alternative regimens Uncomplicated gonococcal infections of the cervix, urethra and rectum Uncomplicated gonococcal infections of the pharynx in a single dose+azithromycin 1 g PO in a single dose in a single dose+doxycycline 100 mg PO twice a day f 7 days in a single dose+azithromycin 1 g PO in a single dose in a single dose+doxycycline 100 mg PO twice a day f 7 days IM: intramuscular, PO: per os. Ceftriaxone (Hoffmann-La Roche, Basel, Switzerland). <In case that Ceftriaxone cannot be used> - Spectinomycin 2 g IM in a single dose - Cefixime 400 mg PO in a single dose + azithromycin 1 g PO in a single dose (in 1 week) - Cefixime 400 mg PO in a single dose + Doxycycline 100 mg PO twice a day f 7 days (in 1 week) <In case of showing allergy to cephalospins> - Spectinomycin 2 g IM in a single dose - Azithromycin 2 g PO in a single dose (in 1 week) <In case that Ceftriaxone cannot be used> - Cefixime 400 mg PO in a single dose+azithromycin 1 g PO in a single dose (in 1 week) - Cefixime 400 mg PO in a single dose +doxycycline 100 mg PO twice a day f 7 days (in 1 week) <In case of showing allergy to cephalospins> - Azithromycin 2 g PO in a single dose (in 1 week)
Ji Yun Chae and Mi Mi Oh. Treatment of Neisseria gonrhoeae in the Era of Multidrug Resistance 15 권장하고있으며, 38 미국의경우 ceftriaxone 250 mg 단회근주투여및 azithromycin 1 g 단회경구투여혹은 doxycycline 100 mg 하루 2회 7일간경구투여하는것을권장하고있다. 29,39 이렇듯 ESCs와 azithromycin 을병합하여투여하는것은, 인두임질의치료에상승효과가있으며, Chlamydia trachomatis 감염의동시치료가가능하고, 나아가서임균의다제내성획득을예방할수있을것으로생각된다. 실제임질과함께 Chlamydia trachomatis 동시감염이있는경우가흔하기때문에, 이들병합요법은여러곳에서보편적으로시행되어왔고, 따라서임균의 ceftriaxone 에의감수성이저하, doxycycline 및 azithromycin 에의내성출현이문제가되고있다. 최근 23S rrna gene의변이로 azithromycin 에고도의내성을보이는 (MIC 256 g/ml) 임균균주들이몇몇나라에서보고되고있다. 40-42 Gemifloxacin은 ciprofloxacin에내성을갖는임질에서그효과가있는것으로알려져있으며임상연구결과경구용 gemifloxacin 320 mg와경구용 azithromycin 2 g을병합하여투여한것과경구용 azithromycin 2 g과 gentamicin 240 mg을근주하여투여한것을비교하였을때양쪽모두에서치료율이 99.5%, 98.5% 로높게보고되었다. 43 3) 대체치료제 임질의대체단일치료제로는 spectinomycin, gentamicin, azithromycin, ertapenem, tigecycline 등이고려되고있으나이들각각에는제한점이있다. 먼저 spectinomycin (2 g, 근주 ) 의경우이에대한내성은전세계적으로드물지만, 고가의비용문제가있다. 또한유전자의단일염기다형성등의기전으로인해 spectinomycin 에대한저항성이빠르게증가하는것또한문제가된다. 그예로 1980 년대주한미군들에서 spectinomycin 이임질의일차치료제로널리사용되었을때이에높은내성을갖는임균균주들이빠르게출현했다는보고가있다. 44 이는 16S rrna 유전자에위치한 C1192T의단일염기다형성때문인것으로밝혀졌다. 45 더불어 spectinomycin은구강인두임질에낮은치료효과를보여성매매업종사자나동성애자의치료에제한이있는것으로밝혀졌으며, 아직몇몇나라에는도입이되지않아일차치료제로사용되기에는어려움이있다. Gentamicin 의경우현재몇몇나라에서임질의치료제로고려되고있다. Gentamicin 240 mg 단회근주투여는 Malawi 에서 1993 년부터 20년넘게성기분비물등증상이있는임질의심환자의일차치료로사용되어왔으며, 아직까지특별한내성균주의보고가없었다. 그러나국제적인감수성보고결과가부족한상태로, 임질의단일치료제로서의 gentamicin 의안전성과효과에관해서는추가임상연구가필요한실정이다. 최근시행된 1,300명의유럽임질환자를대상으로한 연구결과상 gentamicin 에의감수성이높은것으로나타났으나, 46 또다른메타분석결과는임질환자에서 gentamicin 일회투여의치료율이낮은것 (91.5%) 으로보고하였다. 47 이는현재권장되고있는효과적인임질치료율인 95% 에못미치는것으로, 무엇보다구강인두및항문직장임질의치료에있어서 gentamicin의효과에대한추가연구가필요하다. 48 경구용 azithromycin 일회투여는여러임상연구를통해 ESCs에감수성이있는지역에서임질의치료에효과가있는것으로밝혀졌으며, 49 ESCs 에내성을갖는임균은 azithromycin 에도감수성이저하되거나내성을갖기쉬운것으로나타났다. Azithromycin에내성을갖는임균균주에대해서도이미수많은연구결과가보고되었다. 40-42 Ertapenem은 in vitro 연구결과 ESCs에내성을갖는임균의치료에효과가있는것으로나타났으며, 안전하고, 요로감염의치료에도효과적인장점이있다. 50 그러나 ceftriaxone 에내성을갖는균주들이상대적으로낮은 ertapenem 의 MIC를가짐에도불구하고 ESCs 내성과관련한변이가있는경우 ertapenem 의 MIC가증가하는것으로밝혀졌다. 50 이는 pena 유전자에추가변이가발생하는경우 ertapenem의치료효과가없을수있음을암시한다. Ertapenem 은또한 carbapenemase, TEM-1 -lactamase 의획득으로인해그감수성이저하될가능성이있어, 미래임질의일차치료제로적절하지않을것으로생각된다. 한편 tigecycline은광범위주사용 glycylcycline로, in vitro 연구상 tetracycline 에내성을갖는임균에서도높은효과를갖는것이밝혀졌다. 하지만다제내성임균에대한연구나생체내연구는미미한실정이며, 간으로배설되기때문에소변으로의배출량이적어, 요로감염에의효과에대한부분은명백히밝혀진바가없다. 4) 새로운치료제 현재 cephalospin에저항성을갖는임질의치료로임상단계까지들어간항생제는 solithromycin 하나로 macrolide 형태의하나인경구용 fluoketolide 이다. Solithromycin 은 azithromycin 에비해서적게는 4배, 많게는 32배이상효과가강력한것으로드러났으며, 다른여러항생제들보다우월한것으로알려져있다. 51 이는여타 macrolides 와는달리박테리아리보솜의세결합부위에결합하기때문으로생각되며따라서내성의획득도더딜것으로기대할수있다. 52,53 In vitro 실험결과 solithromycin은 cephalospin에내성을갖는임균의치료에효과가있는것으로밝혀졌으며몇몇의낮은 azithromycin 내성을갖는임균의치료에도효과가있었다. Solithromycin은또한 Chlamydia trachomatis와 Mycoplasma genitalium에도치료효과를보이는것으로나타나, 성매개감염병의치료에도적용가능한것이장점이다.
16 Ji Yun Chae and Mi Mi Oh. Treatment of Neisseria gonrhoeae in the Era of Multidrug Resistance 결론 임질은지역과인구집단을막론하고만연한성매개전염성질환이며, 임균의지속적인항생제내성획득과이에대한적절한치료의실패로다제내성임균의감염은전세계적으로심각한공중보건문제로대두되고있다. 항생제내성시대의임균치료전략은높은용량의 ceftriaxone과효과적인이차치료제를병합하여투여하는것과함께, 요로계및구강인두임질모두에적용할수있는새로운대체치료약제를개발하는것이병행되어야한다. 이에더하여, 적절하고시기적인임질환자및파트너의치료, 항생제내성에대한적극적감시체계의구축및궁극적으로는임균백신개발을위한꾸준한노력이필요할것으로생각된다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was repted. REFERENCES 1. Marrazzo JM, Handsfield H, Sparling F. Neisseria gonrhoeae. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier, 2010. 2. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999;75:3-17. 3. Wld Health Organization. Global incidence and prevalence of selectable curable sexually transmitted infections: 2008. Geneva, Switzerland: WHO, 2012. 4. Unemo M, Shafer WM. Antibiotic resistance in Neisseria gonrhoeae: igin, evolution, and lessons learned f the future. Ann N Y Acad Sci 2011;1230:E19-28. 5. Yokoi S, Deguchi T, Ozawa T, Yasuda M, Ito S, Kubota Y, et al. Threat to cefixime treatment f gonrhea. Emerg Infect Dis 2007;13:1275-7. 6. Lo JY, Ho KM, Leung AO, Tiu FS, Tsang GK, Lo AC, et al. Ceftibuten resistance and treatment failure of Neisseria gonrhoeae infection. Antimicrob Agents Chemother 2008; 52:3564-7. 7. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonrhoeae in France: novel pena mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012;56:1273-80. 8. Allen VG, Mitterni L, Seah C, Rebbapragada A, Martin IE, Lee C, et al. Neisseria gonrhoeae treatment failure and susceptibility to cefixime in Tonto, Canada. JAMA 2013;309:163-70. 9. Lewis DA. Global resistance of Neisseria gonrhoeae: when they becomes reality. Curr Opin Infect Dis 2014;27:62-7. 10. Lewis DA. The Gonococcus fights back: is this time a knock out? Sex Transm Infect 2010;86:415-21. 11. Deguchi T, Yasuda M, Yokoi S, Ishida K, Ito M, Ishihara S, et al. Treatment of uncomplicated gonococcal urethritis by doubledosing of 200 mg cefixime at a 6-h interval. J Infect Chemother 2003;9:35-9. 12. Ito M, Yasuda M, Yokoi S, Ito S, Takahashi Y, Ishihara S, et al. Remarkable increase in central Japan in 2001-2002 of Neisseria gonrhoeae isolates with decreased susceptibility to penicillin, tetracycline, al cephalospins, and fluoquinolones. Antimicrob Agents Chemother 2004;48:3185-7. 13. Barry PM, Klausner JD. The use of cephalospins f gonrhea: the impending problem of resistance. Expert Opin Pharmacother 2009;10:555-77. 14. Bolan GA, Sparling PF, Wasserheit JN. The emerging threat of untreatable gonococcal infection. N Engl J Med 2012;366: 485-7. 15. Centers f Disease Control and Prevention (CDC). Cephalospin susceptibility among Neisseria gonrhoeae isolates-- United States, 2000-2010. MMWR Mb Mtal Wkly Rep 2011;60:873-7. 16. Chisholm SA, Alexander S, Desouza-Thomas L, Maclure- Webster E, Anderson J, Nichols T, et al; GRASP Collabative Group. Emergence of a Neisseria gonrhoeae clone showing decreased susceptibility to cefixime in England and Wales. J Antimicrob Chemother 2011;66:2509-12. 17. Cole MJ, Unemo M, Hoffmann S, Chisholm SA, Ison CA, van de Laar MJ. The European gonococcal antimicrobial surveillance programme, 2009. Euro Surveill 2011;16. 18. Golparian D, Hellmark B, Fredlund H, Unemo M. Emergence, spread and characteristics of Neisseria gonrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalospins in Sweden. Sex Transm Infect 2010;86:454-60. 19. Kirkcaldy RD, Ballard RC, Dowell D. Gonococcal resistance: are cephalospins next? Curr Infect Dis Rep 2011;13:196-204. 20. Kubanova A, Frigo N, Kubanov A, Sidenko S, Lesnaya I, Polevshikova S, et al. The Russian gonococcal antimicrobial susceptibility programme (RU-GASP)--national resistance prevalence in 2007 and 2008, and trends during 2005-2008. Euro Surveill 2010;15. 21. European Centre f Disease Prevention and Control. Gonococcal antimicrobial susceptibility surveillance in Europe 2010. London, United Kingdom: European Centre f Disease Prevention and Control, 2012. 22. Cámara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D, Andreu A, et al. Molecular characterization of two high-level ceftriaxoneresistant Neisseria gonrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother 2012;67:1858-60.
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