Date: Thu 21 Jun 2012
Source: Eurosurveillance Edition 2012, 17(25) [edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20200>

Treatment failure of pharyngeal gonorrhoea with internationally recommended first-line ceftriaxone verified in Slovenia, September 2011
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[Authors: Unemo M, Golparian D, Potocnik M, Jeverica S]

We describe the 2nd case in Europe of verified treatment failure of pharyngeal gonorrhea, caused by an internationally occurring multidrug-resistant gonococcal clone, with recommended 1st-line ceftriaxone 250 mg in Slovenia. This is of grave concern since ceftriaxone is last remaining option for empirical treatment. Increased awareness of ceftriaxone failures, more frequent test-of-cure, strict adherence to regularly updated treatment guidelines, and thorough verification/falsification of suspected treatment failures are essential globally. New effective treatment options are imperative.

Background
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_Neisseria gonorrhoeae_ has developed resistance to all antimicrobial drugs previously used as 1st-line treatment (1). Resistance to currently recommended 1st-line 3rd-generation cephalosporins, cefixime, and ceftriaxone, is emerging (1-3), and treatment failures with cefixime have been verified in Japan (4) and several European countries, namely Norway (5), the UK (6), Austria (7), and France (8). One failure to treat pharyngeal gonorrhea with ceftriaxone, the last remaining option for empiric treatment, has also been verified in Europe (Sweden) (9). It is likely that treatment failures with ceftriaxone will initially accumulate for pharyngeal gonorrhea because these infections are harder to treat than urogenital infections (1,10,11). It is of grave concern that during the past year, the 1st 3 extensively drug-resistant (XDR) (1) _N. gonorrhoeae_ strains that also had high-level ceftriaxone resistance were reported from Japan, France and Spain (8,12,13).

In this emergent situation of fear that gonorrhoea may become untreatable (1,8,12), the European Centre for Disease Prevention and Control (ECDC) has prepared a response plan for the European Union (14). The WHO has published the 'Global Action Plan to Control the Spread and Impact of Antimicrobial Resistance in _Neisseria gonorrhoeae_' (15).

This report describes a ceftriaxone treatment failure of pharyngeal gonorrhea in Slovenia in 2011, which is the 2nd one strictly verified in Europe (and possibly globally).

Case description
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In early September 2011, a Slovenian bisexual woman in her early 30s visited a dermatovenereologist in Ljubljana, Slovenia (day 1). She had no symptoms of gonorrhea, however, she was sampled and administered the internationally recommended 1st-line treatment of 1Ã--250 mg ceftriaxone intramuscularly (table [for tables, see source URL above. - Mod.LL]), based on the fact that she had had unprotected oral and vaginal sex with gonorrhea-positive casual male partner in late August 2011 in Belgrade, Serbia. The partner could later not be traced in Serbia.

Microscopy of Gram stained smear of a cervical specimen was negative for _N. gonorrhoeae_. However, 2 days later (day 3), a pharyngeal culture was shown to be positive for _N. gonorrhoeae_, while the cervical culture was negative. _Chlamydia trachomatis_ DNA was identified in an additional cervical sample, using the COBAS TaqMan CT Test v2.0 (Roche Diagnostics). During a follow-up visit 7 days after the initial visit (day 8), a test-of-cure (TOC) pharyngeal culture was taken and examination showed no signs or symptoms of pharyngeal gonorrhea, and she was given doxycycline at a dosage of 100 mg twice a day, for 7 days, for a concomitant chlamydial infection. However, 2 days later (day 10) the TOC culture confirmed gonococci in a pharyngeal sample. About 3 weeks later (day 30), the patient returned with symptoms of acute pharyngitis (pain, inflammation and fever) and was given a dose of 250 mg ceftriaxone intramuscularly and an oral dose of 1 g azithromycin. Finally, a follow-up examination after about 4 months (day 173) showed no signs of infection, and a pharyngeal TOC culture was negative for _N. gonorrhoeae_. The patient repeatedly reassured that she had not had any sexual contacts between the ceftriaxone therapy and the TOC.

Characterisation of _N. gonorrhoeae_ isolates
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The pre- and post-treatment _N. gonorrhoeae_ isolates were species-confirmed by sugar utilisation test and Phadebact Monoclonal GC Test (Pharmacia Diagnostics). The isolates were indistinguishable using serovar determination (Bpyut), full-length porB gene sequencing, multilocus sequence typing (MLST; ST1901 (12), and _N. gonorrhoeae_ multiantigen sequence typing (NG-MAST; ST1407 [16]). Using Etest (AB bioMerieux), both isolates showed a ceftriaxone minimum inhibitory concentration (MIC) of 0.125 mg/L (Table), and overall indistinguishable antibiograms (cefixime 0.25 mg/L, spectinomycin 16 mg/L, azithromycin 0.5 mg/L, and ciprofloxacin more than 32 mg/L) and were beta-lactamase-negative. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (17), the MIC of ceftriaxone for these isolates were equal to the resistance breakpoint ( greater than 0.125 mg/L). Sequencing of resistance determinants for 3rd-generation cephalosporins (1,8,12,18,19) showed that both isolates contained an identical penA mosaic allele XXXIV (12), which has been correlated with decreased susceptibility or resistance to 3rd-generation cephalosporins and treatment failure with cefixime (5,20,21). In addition, they contained mtrR and penB alterations that further increase the MICs of 3rd-generation cephalosporins (1,8,12,19).

Discussion
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This study describes the 2nd verified case in Europe (possibly globally) of treatment failure of pharyngeal gonorrhea with the internationally recommended 1st-line treatment of 250 mg ceftriaxone, the last remaining treatment option. The failure was strictly verified in accordance with WHO recommendations (1,15), that is, detailed clinical records were obtained, reinfection was excluded as much as possible, pre- and post-treatment isolates were indistinguishable using highly discriminatory typing, ceftriaxone MICs were elevated, and the isolates contained well-known cephalosporin resistance determinants. The reporting of the case was unfortunately delayed because it took several months before the patient returned for follow-up examination and TOC after the 3rd antimicrobial treatment (to prove successful eradication of infections).

This case shows that ceftriaxone at a dosage of 1Ã--250 mg may in rare cases not be enough for treatment of pharyngeal gonorrhea caused by gonococcal strains with ceftriaxone MICs of 0.125 mg/L. A 250 mg ceftriaxone dose also results in median times of free ceftriaxone above the MIC of only 24.1 h (range: 10.5-52.2 h) for the detected MIC of 0.125 mg/L (22), and rare treatment failures may happen in the lower range. Nevertheless, these cases are likely to be treatable with enhanced ceftriaxone doses or dual antimicrobial treatment that has already been introduced as 1st-line empiric treatment in the USA (10) and the UK (23). It may be crucial to promptly revise also other national and regional treatment guidelines, and a revision of the European guidelines from the International Union against Sexually Transmitted Infections (IUSTI) and WHO (2) are currently in progress.

It is worrying that the gonococcus causing this treatment failure was assigned to MLST ST1901 and NG-MAST ST1407, which is a multidrug-resistant gonococcal clone that also shows decreased susceptibility and resistance to cefixime and is spreading worldwide (5,7,8,13,20,21,24-28). The previously reported treatment failures with cefixime in Norway (5), Austria (7), France (8), and likely in the UK (6), were caused by this gonococcal clone or its evolving subtypes. This clone has also shown its capacity to develop high-level resistance to ceftriaxone (8,13).

In conclusion, the 2nd case in Europe (possibly worldwide) of clinical failure using standard ceftriaxone treatment for pharyngeal gonorrhea, caused by an internationally occurring multidrug-resistant gonococcal clone, has been strictly verified in Slovenia. An increased awareness of treatment failures with ceftriaxone, more frequent TOC (all cases of pharyngeal cases may be crucial), strict adherence to appropriate treatment guidelines, which need to be regularly updated based on antimicrobial resistance surveillance data, and thorough verification/falsification of suspected treatment failures (including subsequent tracing of sexual contacts of the index case with the treatment failure) are essential globally. A stronger focus on pharyngeal gonorrhea, including increased sampling of pharyngeal specimens and promotion of condom use also when practising oral sex, is also crucial because pharyngeal infection is harder to treat than urogenital infection, relatively common, and is frequently an asymptomatic reservoir for infection and emergence of resistances (1,5). Ultimately, new options for effective treatment of gonorrhea are imperative.

References
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2. Bignell C, IUSTI/WHO: 2009 European (IUSTI/WHO) guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2009; 20: 453-7.
3. Cole MJ, Unemo M, Hoffmann S, et al: The European gonococcal antimicrobial surveillance programme, 2009. Euro Surveill. 2011;16(42): pii=19995. Available from <http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19995>.
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13. Camara J, Serra J, Ayats J, et al: Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother. 2012 May 7. [Epub ahead of print].
14. European Centre for Disease Prevention and Control (ECDC): Response plan to control and manage the threat of multidrug-resistant gonorrhoea in Europe. Stockholm: ECDC; 2012. p. 1-23. Available from <http://www.ecdc.europa.eu/en/publications/Publications/1206-ECDC-MDR-gonorrhoea-response-plan.pdf>.
15. WHO: Global Action Plan to Control the Spread and Impact of Antimicrobial Resistance in _Neisseria gonorrhoeae_. Geneva: WHO; 2012. p. 1-36. Available from <http://www.who.int/reproductivehealth/publications/rtis/9789241503501>.
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17. European Committee on Antimicrobial Susceptibility Testing(EUCAST). Breakpoint tables for interpretation of MICs and zone diameters. Version 2.0. Basel: European Society of Clinical Microbiology and Infectious Diseases; 1 Jan 2012. Available from <http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_2.0_120221.pdf>.
18. Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J: Phenotypic and genetic characterization of the 2008 WHO _Neisseria gonorrhoeae_ reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J Antimicrob Chemother. 2009; 63: 1142-51.
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20. Buono S, Wu A, Hess DC, et al: Using the _Neisseria gonorrhoeae_ Multiantigen Sequence-Typing Method to Assess Strain Diversity and Antibiotic Resistance in San Francisco, California. Microb Drug Resist. 2012 Jun 11. [Epub ahead of print].
21. Heymans R, Bruisten SM, Golparian D, et al: Clonally related _Neisseria gonorrhoeae_ isolates with decreased susceptibility to the extended-spectrum cephalosporin cefotaxime in Amsterdam, the Netherlands. Antimicrob Agents Chemother. 2012;56: 1516-22.
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23. Bignell C, Fitzgerald M, Guideline Development Group: UK national guideline for the management of gonorrhoea in adults, 2011. Int J STD AIDS. 2011; 22: 541-7.
24. Golparian D, Hellmark B, Fredlund H, Unemo M: Emergence, spread and characteristics of _Neisseria gonorrhoeae_ isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden. Sex Transm Infect. 2010; 86: 454-60.
25. Pandori M, Barry PM, Wu A, et al: Mosaic penicillin-binding protein 2 in _Neisseria gonorrhoeae_ isolates collected in 2008 in San Francisco, California. Antimicrob Agents Chemother. 2009; 53; 4032-4.
26. Tapsall JW, Ray S, Limnios A: Characteristics and population dynamics of mosaic penA allele-containing _Neisseria gonorrhoeae_ isolates collected in Sydney, Australia, in 2007-2008. Antimicrob
Agents Chemother. 2010; 54: 554-6.
27. Tanaka M, Koga Y, Nakayama H, et al: Antibiotic-resistant phenotypes and genotypes of _Neisseria gonorrhoeae_ isolates in Japan: identification of strain clusters with multidrug-resistant phenotypes. Sex Transm Dis. 2011; 38: 871-5.
28. _Neisseria gonorrhoeae_ Multi Antigen Sequence Typing (NG-MAST). Query global sequence and ST database. London: Department of Infectious Disease Epidemiology, Imperial College London and are funded by The Wellcome Trust. Available from <http://www.ng-mast.net/sql/allelicprofile.asp>.
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[For a discussion of reduced cephalosporin susceptibility among _N. gonorrhoeae_ isolates in the United States, see CDC Morbidity and Mortality Weekly Report (MMWR) 8 Jul 2011; 60(26): 873-7 (<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6026a2.htm>). - ProMed Mod.LL]

[A HealthMap/ProMED-mail map can be accessed at:
<http://healthmap.org/r/2E3k>.]
Date: Tue, 13 Mar 2012 12:35:15 +0100 (MET)

BRATISLAVA, March 13, 2012 (AFP) - Two boys trying to smoke cigarettes started a blaze which destroyed parts of a 14th century castle in eastern Slovakia at the weekend, police said Tuesday. "Two boys, aged 11 and 12, were trying to light up a cigarette and because of their careless use of matches the grass at the castle hill caught fire," police spokeswoman Jana Mesarova said. "Police have not pressed charges yet due to the young age of the suspects," Interior Minister Daniel Lipsic said.

In Slovakia, children under 15 cannot be criminally prosecuted. Police originally said the fire was started by locals burning dry grass. The medieval castle of Krasna Horka suffered extensive damage to the roof as well as parts of its interior. The culture ministry said the damage was severe but did not indicate how much repairs would cost. Nobody was injured but several tourists had a narrow escape as their tour of the castle finished just before the fire broke out.
Date: Wed, 7 Dec 2011 15:32:11 +0100 (MET)

BRATISLAVA, Dec 7, 2011 (AFP) - Slovak hospitals resumed normal service on Wednesday after over a thousand doctors who had resigned in protest over low pay returning to work after agreeing a pay deal with the government. "As of today, all the doctors should be in hospitals and the situation is stabilised," Marian Kollar, head of the Medical trade union, told journalists in Bratislava. According to the wage deal, the government will raise the basic monthly salary of junior doctors to at least 807 euros (1,088 dollars) as of 2012 while specialists will earn 1,230 euros. As of 2013, their salaries will increase to 961 euros for the beginners and 1,769 euros for the specialists. Now the monthly pay of a young doctor in Slovakia is between 550 and 600 euros.

The government also said that as of Thursday it would cancel a state of emergency declared last week amid the labour action and that 30 doctors from the neighbouring Czech Republic who were helping understaffed Slovak hospitals would return home. Slovak doctors struck a deal Friday night with the outgoing government ensuring higher wages and better working conditions, but more than 1,220 doctors who had handed in their notice did not return to hospitals until Wednesday. The protest closed entire hospital departments and forced some hospitals to cancel operations and provide only emergency care.
Date: Sat, 3 Dec 2011 09:07:23 +0100 (MET)

BRATISLAVA, Dec 3, 2011 (AFP) - Slovak doctors will end their protest after striking a deal overnight with the outgoing government ensuring higher wages and better working conditions, local media said Saturday. "We reached a deal after very tough and long talks," the SITA news agency quoted outgoing Prime Minister Iveta Radicova as saying after 3:00 am (0200 GMT). "I firmly believe the doctors will now return to their patients," she added. Doctors' union leader Marian Kollar said this would happen but did not say when more than 1,220 doctors who have handed in their notice and others who failed to show up for work would return to hospitals.

The protest closed entire hospital departments and forced some hospitals to cancel operations and provide only emergency care. It also led the government to declare a state of emergency to force doctors back to work. The protest inspired a wave of solidarity in neighbouring countries, with the Czech Republic offering to send army doctors and Poland and Austria ready to take Slovak patients.

The doctors were asking the health ministry to increase their salaries to between 1,140 and 2,280 euros ($1,537-3,075) a month against the national average of 760 euros, but the increase will be much lower in the end. The monthly pay of a young doctor in Slovakia is between 550 and 600 euros. The doctors and the government also agreed on better compliance with the Labour Code to keep the working week at a maximum of 48 hours, and on halting the privatisation of state-run hospitals as joint-stock companies. Slovakia's centre-right government was toppled in a parliamentary no-confidence motion in October. The country will hold early elections on March 10.
Date: Fri, 2 Dec 2011 14:53:24 +0100 (MET)

BRATISLAVA, Dec 2, 2011 (AFP) - Slovak hospitals cancelled most planned surgeries and were providing only emergency healthcare on Friday, a day after more than 1,000 doctors quit in protest at low pay and poor working conditions. "The situation is serious, but we are still providing emergency healthcare," said Danica Lehocka, spokeswoman for the Bratislava Teaching Hospital, which was missing 358 out of its 1,400 doctors on Friday. Other hospitals across Slovakia were closing entire departments as hundreds of doctors did not show up at work, local media reported.

The neighbouring Czech Republic's government said Friday it was sending 30 specialists to help Slovakia's understaffed hospitals, while hospitals in areas of southern Poland bordering Slovakia said they were prepared for Slovak patients. Austria also put its hospitals on stand-by to take in Slovak patients in cases of emergency, depending on capacity, the health ministry in Vienna told the Austria Press Agency.  "Out of 2,400 doctors that initially threatened to quit as of Thursday, only about 1,220 actually resigned but more are expected to quit as of the end of the year," Katarina Zollerova, spokeswoman for the health ministry told AFP.

Bitter over what they consider low pay and poor working conditions, Slovak doctors are asking the ministry to increase their salaries to between 1,140 and 2,280 euros ($1,537-3,075). The monthly salary of a young doctor in Slovakia is between 550 and 600 euros, well below the national average of 760 euros, while experienced specialists earn between 1,000 and 1,200 euros, according to the medical trade union association (LOZ). The unions also complain that doctors have to work more than the 48 hours a week set down in the Labour Code, and are asking the government to halt privatisation of state-run hospitals into joint-stock companies.

Earlier this week, physicians refused a health ministry proposal to raise the average salary by 300 euros -- the most it said it could offer given a bleak economic outlook.  "Hospitals are understaffed (and) there are not enough young doctors because the job isn't attractive to young people. One-third of medical students don't want to stay in Slovakia after they graduate," deputy chairman of the medical trade unions Peter Visolajsky told AFP.

Lucia Hippova, a 27-year old Slovak doctor left for Germany after working three months in a small Slovak hospital. "The main reason was money. In Slovakia, my basic monthly salary was approximately 430 euros.  In Germany, I started with 1,890 euros a month. After three years, my salary reached 3,200 euros," she said. While the unions and politicians struggle for a compromise, patients like 70-year-old Anna were worried. "I'm supposed to undergo surgery next week. My pre-surgery examination was cancelled today, I don't know what to expect," the pensioner told AFP in Bratislava Friday.

The labour action comes as the outgoing cabinet of Prime Minister Iveta Radicova has been struggling to keep public finances under control as growth slows. The export-driven economy is expected to slow next year to 1.7 percent growth compared to this year's 3.0 percent in line with the forecast economic downturn across Europe. A eurozone member since 2009, Slovakia has adopted austerity spending in a drive to cut its public deficit, expected to reach 4.9 percent of gross domestic product this year, to under 3.0 percent of GDP in 2013 in order to meet the eurozone deficit ceiling.
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