Harvard ProMed: PHARYNGEAL GONORRHOEA.(NG-MAST genogroup 1407) resistant to monotherapy

GONOCOCCAL DISEASE - SWEDEN: PHARYNX, TREATMENT FAILURE, 2013-2014
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Date: Thu 31 Jul 2014
Source: Eurosurveillance Edition 2014, 19(30) [edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20862>


Four treatment failures of pharyngeal gonorrhoea with ceftriaxone (500
mg) or cefotaxime (500 mg), Sweden, 2013 and 2014
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[Authors: Golparian D, Ohlsson AK, Janson H, Lidbrink P, Richtner T,
Ekelund O, Fredlund H, Unemo M]

Abstract
--------
We describe 4 cases in Sweden of verified treatment failures of
pharyngeal gonorrhoea with ceftriaxone (500 mg; n=3) or cefotaxime
(500 mg; n=1) monotherapy [2013-2014]. All the ceftriaxone treatment
failures were caused by the internationally spreading
multidrug-resistant gonococcal NG-MAST genogroup 1407 clone. Increased
awareness of treatment failures is crucial particularly when
antimicrobial monotherapy is used. Frequent test of cure and
appropriate verification/falsification of suspected treatment
failures, as well as implementation of recommended dual antimicrobial
therapy are imperative.

_Neisseria gonorrhoeae_ has developed resistance to all antimicrobials
previously used as 1st-line treatment for gonorrhoea [1-4]. Clinical
resistance is now emerging to the extended-spectrum cephalosporins
(ESCs), that is, cefixime (oral) and the more potent ceftriaxone
(injectable). Many treatment failures with cefixime have been verified
in Japan, Europe, Canada, and South Africa. No failure to treat
urogenital gonorrhoea with ceftriaxone (250 mg-1 g), the last
remaining option for 1st-line empiric antimicrobial monotherapy, has
been detected as yet. However, some few failures to treat pharyngeal
gonorrhoea with ceftriaxone have been verified in Japan (n=1),
Australia (n=3), Sweden (n=1) and Slovenia (n=1) [4-10]. In recent
years, extensively drug-resistant (XDR) gonococcal strains with
high-level ceftriaxone resistance were also reported from Japan,
France and Spain [2,9-11].

Case descriptions
-----------------
>From February to May 2013, 3 cases of suspected failure to treat
pharyngeal gonorrhoea with ceftriaxone 500 mg intramuscularly were
reported from 2 clinics for sexually transmitted infections (STIs) in
Sweden (Table). All 3 patients reported having had unprotected oral
and vaginal sex with heterosexual contacts in Stockholm. Case A was a
woman in her 30s, with pharyngeal symptoms including pharyngitis.
Cases B and C, both in their 50s, were asymptomatic. Pharyngeal and
urogenital samples were taken and all patients had a positive
gonococcal pharyngeal culture. Furthermore, the urogenital samples
from the Cases B and C were positive in a nucleic acid amplification
test (NAAT) (BD ProbeTec GC Qx Amplified DNA Assay, Becton Dickinson).
All 3 patients were administered a single dose of 500 mg ceftriaxone
intramuscularly (Day 1). When returning for follow-up after 7 to 22
days, all patients were asymptomatic but had persistent positive
gonococcal pharyngeal cultures. All urogenital samples were negative.
Finally, all 3 patients were successfully treated with a single dose
of 1 g ceftriaxone intramuscularly between Day 7 and 27, which was
confirmed at follow-up visits with negative pharyngeal cultures
between Day 22 and 48 (Table).

In May 2014, 1 case of suspected failure to treat pharyngeal
gonorrhoea with cefotaxime 500 mg intramuscularly was reported from an
STI clinic in Karlskrona, Sweden. This patient (Case D), a man in his
30s, attended the clinic because he had had unprotected oral and
vaginal sex with a woman diagnosed with gonorrhoea. On Day 1, the
patient was asymptomatic and sampled from the pharynx, urethra, and
rectum. The pharyngeal sample was positive for gonococci in culture
and he was treated with a single dose of 500 mg cefotaxime
intramuscularly. At the follow-up visit (Day 7), the patient was still
asymptomatic, however, a pharyngeal sample remained positive in
culture. The patient was treated with a single dose of 250 mg
ceftriaxone intramuscularly plus a single oral dose of 1 g
azithromycin (day 14). On Day 26, the patient returned for test of
cure and the pharyngeal culture was negative for gonococci (Table).

Characterisation of _N. gonorrhoeae_ isolates
---------------------------------------------
The pre- and post-treatment gonococcal isolates were species-confirmed
by sugar utilisation test, Phadebact Monoclonal GC Test (Pharmacia
Diagnostics), and MaldiTOF MS (Bruker Daltonics). The paired isolates
from each case were indistinguishable using _N. gonorrhoeae_
multi-antigen sequence typing (NG-MAST [12]) and the isolates from
Cases A, B, and C belonged to the NG-MAST genogroup 1407 clone [4,13]
(Table). Using Etest (AB bioMerieux), the isolates from Cases A, B,
and C (ceftriaxone treatment failures) showed elevated minimum
inhibitory concentrations (MICs), that is, 0.064-0.125 mg/L, which is
equal to the European resistance breakpoint (greater than 0.125 mg/L)
[14]. In Case D (cefotaxime treatment failure), according to the
European resistance breakpoints [14], the paired isolates were
resistant to cefotaxime (MIC: 0.5 mg/L) and the pre-treatment isolate
also to ceftriaxone (MIC: 0.25 mg/L) (Table).

Sequencing of ESC resistance determinants [1,3,4,6,9,10,15] showed
that all the paired isolates belonging to Cases A, B and C contained
the penA mosaic allele XXXIV, which has been correlated with NG-MAST
genogroup 1407, decreased susceptibility or resistance to ESCs and ESC
treatment failures [1,4-6,9,11]. The isolates from Case D contained
the penA mosaic allele XIII [10]. In addition, all isolates contained
mtrR and penB alterations that further increase the ESC MICs
[1,3-6,9-11,15].

Discussion
----------
This paper reports 4 cases of verified pharyngeal gonorrhoea treatment
failure in Sweden using injectable ESCs, that is, ceftriaxone (n=3)
and cefotaxime (n=1). The failures were verified in accordance with
international recommendations [2,4], that is, clinical records were
obtained, reinfection was excluded, pre- and post-treatment isolates
were identical using highly discriminatory molecular epidemiological
typing, and the isolates had elevated ESC MICs and well recognised ESC
resistance determinants. Reinfection was considered to be excluded as
much as possible for all cases. Accordingly, all patients were
strongly advised to abstain from any sexual contacts before their
follow-up visit and all 4 patients repeatedly assured that they had
not had any unprotected sexual contacts between the
ceftriaxone/cefotaxime treatment and test of cure. Furthermore, Case D
was infected by a casual sexual contact.

In the current emergent situation of fear that gonorrhoea may become
untreatable [1-3,10], recommendations of using dual antimicrobial
therapy (mainly ceftriaxone plus azithromycin) have been introduced in
the United States [16] and Europe [17]. No appropriate well-designed
international study has yet assessed the implementation of dual
antimicrobial therapy. However, as observed by the authors in many
international projects the implementation of these guidelines appears
suboptimal in several European countries and monotherapy with
ceftriaxone remains frequently used.

No failure to treat urogenital gonorrhoea with ceftriaxone (250 mg-1
g) monotherapy has been verified to date. However, the observed
initial accumulation of failures treating pharyngeal gonorrhoea was
not unexpected, because these infections are substantially harder to
eradicate with most antimicrobials than urogenital gonorrhoea
[1-4,6,18]. As shown in the present study, ceftriaxone 500 mg
monotherapy can be sufficient to eradicate urogenital gonorrhoea but
not the concomitant pharyngeal gonorrhoea in the same patient. The
pharyngeal gonorrhoea of the patients was instead successfully treated
with 1 g ceftriaxone monotherapy or 250 mg ceftriaxone plus 1 g
azithromycin. Unfortunately, 1 g ceftriaxone monotherapy may only
provide a short-term solution [1,2,4,19,20] judging from the failure
to treat the pharyngeal gonorrhoea caused by the 1st gonococcal XDR
strain with 1 g ceftriaxone [10], ceftriaxone MICs of all the
identified gonococcal XDR strains [9-11], emergence of ceftriaxone
resistance and its anticipated trend, and
pharmacodynamic/pharmacokinetic simulations showing that the benefits
of increasing the ceftriaxone dose from 500 mg to 1 g are limited when
taking into account the high ceftriaxone MICs detected recent years
[19]. Consequently, dual antimicrobial therapy, such as 500 mg
ceftriaxone intramuscularly plus 2 g azithromycin orally, as
recommended by the European gonorrhoea guideline [17], should ideally
be implemented. It remains unknown if ceftriaxone and azithromycin act
synergistically in vivo. However, most importantly, there are no
indications, in vitro or in vivo, that they act antagonistically.
According to a review from 2010, 99 percent of urogenital and 98
percent of pharyngeal gonorrhoea cases may be treatable with 2 g
azithromycin monotherapy [21]. Consequently, nearly all gonorrhoea
cases (ceftriaxone-resistant or not) are treatable with even 2 g
azithromycin monotherapy. Nevertheless, azithromycin monotherapy is
not recommended due to the spread of gonococcal strains with
high-level resistance to azithromycin and the anticipated rapid
selection of azithromycin resistance [1,17,20].

All ceftriaxone treatment failures in the present study (Cases A, B,
and C) were caused by the internationally spreading
multidrug-resistant gonococcal NG-MAST genogroup 1407 clone, which has
caused many ESC treatment failures internationally [4-6,9,15].
However, the cefotaxime treatment failure was caused by the unrelated
NG-MAST ST4539, which shows that clinical resistance to injectable
ESCs is emerging also in other gonococcal clones.

In conclusion, increased awareness of treatment failures particularly
with antimicrobial monotherapy, improved implementation of recommended
dual antimicrobial therapy (such as 500 mg ceftriaxone plus 2 g
azithromycin [17]), frequent test of cure (ideally for all cases, and
at least for all cases of pharyngeal gonorrhoea), and appropriate
verification/falsification of suspected treatment failures (including
subsequent tracing of sexual contacts of the index case with the
treatment failure) are essential internationally. An enhanced focus on
pharyngeal gonorrhoea is also crucial, with increased sampling and
prevention, such as promotion of condom use also when practising oral
sex. Ultimately, novel options for effective treatment of gonorrhoea
are imperative.

[Table and references can be accessed at the source URL
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20862>.]

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[In 2012 US CDC updated its recommendations for treatment of
uncomplicated urogenital, anorectal, and pharyngeal gonorrhea to
combination therapy with a single intramuscular dose of ceftriaxone
250 mg plus either a single dose of azithromycin 1 g orally or
doxycycline 100 mg orally twice daily for 7 days
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a3.htm>). The CDC
considers that the 250 mg dose of ceftriaxone is sufficient to treat
gonococcal infection at all anatomic sites caused by strains currently
circulating in the United States
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a3.htm>).

The updated European gonorrhea guideline, however, recommends a 500 mg
intramuscular dose of ceftriaxone plus azithromycin 2 g oral dose for
uncomplicated gonorrhea
(<http://dx.doi.org/10.1177/0956462412472837>).

Pharyngeal gonococcal infections are known to be substantially harder
to eradicate with most antimicrobials than urogenital gonorrhea (Moran
JS: Treating uncomplicated _Neisseria gonorrhoeae_ infections: is the
anatomic site of infection important? Sex Transm Dis. 1995; 22(1):
39-47;
<http://journals.lww.com/stdjournal/Abstract/1995/01000/Treating_Uncomplicated_Neisseria_gonorrhoeae.7.aspx>.)
The Eurosurveillance report above describes 4 cases in Sweden of
verified treatment failures of pharyngeal gonorrhea with ceftriaxone
(500 mg; n=3) or cefotaxime (500 mg; n=1) monotherapy.

Although sufficient to eradicate urogenital gonorrhea in 2 of the 4
patients, ceftriaxone 500 mg monotherapy failed to eradicate gonococci
in concomitant pharyngeal gonorrhea in the same patients. The
ceftriaxone MICs (0.064-0.125 mg/L) of the gonococcal isolates from
the 3 ceftriaxone pharyngeal gonorrhea treatment failures were
actually below both the Clinical Laboratory Standards Institute (CLSI)
resistance breakpoint MIC (equal to or greater than 0.5 micrograms per
mL) and the European resistance breakpoint MIC (equal to or greater
than 0.25 micrograms per mL)
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a3.htm> and
<http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_4.0.pdf>).

The cefotaxime MICs (0. 5 micrograms per mL) of the 2 isolates from
the one cefotaxime pharyngeal gonorrhea treatment failure were above
the European resistance breakpoint MIC (equal to or greater than 0.25
micrograms per mL). Thus it seems that gonococci persisted in the
pharynx despite having MICs in several instances in the susceptible
range, perhaps because in the doses used, the pharyngeal antibiotic
concentrations were too low or less active than at other infected
sites. Pharyngeal gonorrhea in the 4 patients was subsequently
successfully treated with 1 g ceftriaxone monotherapy or 250 mg
ceftriaxone plus 1 g azithromycin.

Most gonococcal infections of the pharynx are asymptomatic and can be
relatively common in some populations
(<http://www.cdc.gov/std/treatment/2010/gonococcal-infections.htm>).
Culture of the pharynx in patients presenting with gonococcal disease,
even in the absence of pharyngeal symptoms, and, as the authors of the
Eurosurveillance report emphasize, supplemented by use of recommended
combined antimicrobial therapy with azithromycin, which might enhance
treatment efficacy for pharyngeal infection, and test of cure for
pharyngeal gonorrhea
(<http://www.cdc.gov/std/treatment/2010/gonococcal-infections.htm>),
are essential to control the continued spread of this disease. -
Mod.ML