Editorial

Cephalosporin resistant
Neisseria gonorrhoeae: time
to consider gentamicin?
J D C Ross,1 D A Lewis2,3
The pattern of antimicrobial resistance in
Neisseria gonorrhoeae is depressingly
predictable. An antibiotic is chosen and
used for a few years but resistance
develops, so the dose is increased to
maintain efcacy before the drug nally
fails irrevocably. For penicillin, this process
took a number of decades but with the
subsequent use of tetracyclines, macrolides and uoroquinolones, the cycle has
shortened, and the utility of oral cephalosporins is now threatened within a few
short years of their introduction as
preferred therapy in many countries.1
Following the emergence of N gonorrhoeae strains with decreased susceptibility
to oral cephalosporins, clinical treatment
failures soon appeared in Japan and Hong
Kong;2e4 more recently, similar outcomes
have reported from other regions of the
world, including Europe. There still exists
some debate as to the minimum inhibitory
concentration (MIC) breakpoint for oral
cephalosporins that correlates with clinical
failure. However, data from Deguchi et al
suggest that clinical failures may occur
with MICs of 0.125 mg/l or higher.3 Pharmacodynamic modelling with Monte
Carlo simulations highlighted the fact
that, for reliable efcacy, cephalosporins
require a free drug level above the MIC for
20e24 h (compared to 7e10 h in the case
of penicillin G).5 These analyses predicted
that failures with standard doses of
cexime
(400 mg)
and
ceftriaxone
(250 mg) become likely around MICs of
0.125 mg/l and 0.25 mg/l respectively. The
clinical practice of treating patients with
gonorrhoea with an additional agent for
presumptive Chlamydia trachomatis infec-

Birmingham University Hospital, Birmingham, UK;

Centre for HIV and STIs, National Institute for
Communicable Diseases, National Health Laboratory
Service, Sandringham, South Africa; 3Department of
Internal Medicine, Faculty of Health Sciences, University
of the Witwatersrand, Johannesburg, South Africa
2

Correspondence to Professor J D C Ross, University

Hospital Birmingham, Whittall Street Clinic, Whittall
Street, Birmingham B4 6DH, UK;
jonathan.ross@uhb.nhs.uk
6

tiondparticularly azithromycin and, to

a lesser extent, doxycyclinedmay have
prevented the appearance of treatment
failures in those individuals infected with
N gonorrhoeae strains possessing high
cephalosporin MICs.
The mechanism of resistance to oral
cephalosporins involves changes in the
structure and function of a number of key
proteins, notably the penA-encoded
penicillin binding protein 2 and the
MtrC-MtrD-MtrE multiple transferable
resistance efux pump. The latter is
important as those strains with decreased
susceptibility to oral cephalosporins also
have high MICs to penicillins, tetracyclines and macrolides.2 Gonococci tend to
retain resistance phenotypes and genotypes to those antibiotics used earlier for
treatment, even when their use has been
discontinued, which generally rules out
reintroducing them in the current era of
multidrug-resistant gonorrhoea.6 It is,
therefore, not too surprising to note that
the majority of circulating gonococcal
strains with decreased susceptibility to
oral cephalosporins are also resistant to
uoroquinolones.2
The worlds rst extensively drug-resistant N gonorrhoeae strain (H041), dened
by criteria put forward by Tapsall et al,
was recently described in detail.6 7 This
H041 strain has a ceftriaxone MIC of
2e4 mg/l, which is fourfold to eightfold
higher than previously reported, as well as
a cexime MIC of 8 mg/l. In addition, the
H041 strain was determined to be resistant to b-lactams (with the possible
exception of carbapenems and piperacillintazobactam, for which breakpoints are
not available), tetracyclines, macrolides,
uoroquinolones, trimethoprim-sulphamethoxazole and chloramphenicol. The
same strain was susceptible to both
rifampicin and spectinomycin, and had
low MICs to gentamicin and kanamycin,
although these MIC values were difcult
to interpret as breakpoints do not exist for
these two antimicrobial agents.
If we are facing the imminent failure of
cephalosporins for treating gonorrhoea,

then what are the options for the future

and how can we use antibiotics more
effectively to prolong their efcacy?
Combining two or more antibiotics
together is one logical approach, if slightly
more expensive and with a greater
potential to cause side effects than
monotherapy. A combination of drugs
generally provides wider antimicrobial
coverage and is particularly valuable when
giving empirical treatment before the
resistance pattern for an organism is
known, as is often the case when treating
gonorrhoea. Unfortunately, the number of
effective drugs available is now extremely
limited, but azithromycin is frequently
combined with ceftriaxone to cover
possible coinfection with chlamydia8e10
and this combination may also be more
effective against N gonorrhoeae.8
We have been fortunate in the past in
having effective single dose treatments for
gonorrhoea which were simple for
patients to take and could be directly
observed to ensure adherence, but the
drug levels attained with this approach
and the length of time that they are
maintained above the organisms MIC are
necessarily limited. Increasing the drug
dose or giving multiple doses will increase
the length of time that the drug concentration exceeds the MIC and will increase
the peak MIC concentration, and thus
may extend the utility of individual drugs.
This was the rationale for the recent
increase in the recommended dose of
ceftriaxone to 500 mg in the UKs gonorrhoea treatment guidelines.8
Another option to prevent the emergence of resistance would be to regularly
rotate the antibiotics which are recommended for empirical therapy, thus
reducing the selective pressure arising
from any single agent. However, this
would present a number of practical
problems around coordinated implementation, and remains of unproven value
in preventing the emergence of resistance.
Whatever approach is taken, we need to
identify alternative antibiotics which can
be used in patients with gonorrhoea who
either fail or are intolerant to cephalosporin
treatment, and have coexisting resistance
to penicillin, uoroquinolones, tetracyclines and macrolides. Gentamicin has
been used in many developing countries,
and has the advantages of low cost and,
at least anecdotally, high efcacy. What
place should it have in our therapeutic
repertoire?
Gentamicin is an aminoglycoside antibiotic with concentration-dependent
bactericidal
activity
against
Gram
Sex Transm Infect February 2012 Vol 88 No 1

Editorial

negative bacteria. It binds at the 30S

bacterial ribosomal subunit, and results in
mRNA
misreading
during
protein
synthesis, permeabilisation of the cell
membrane, inhibition of the initiation of
DNA replication and loss of cell viability.11
As aminoglycosides are hydrophilic and
highly lipophobic, they are rapidly
distributed after parenteral injection but
are poorly absorbed from the gastrointestinal tract. The peak concentration of an
intramuscular dose is seen in about
30e90 min. Gentamicin is excreted almost
exclusively through the kidney and very
little is reabsorbed after glomerular ltration. Gentamicin, like other aminoglycosides, exhibits a post-antibiotic effect
(PAE) in terms of suppressing bacterial
growth for a period of time after drug
administration. During the period of PAE,
bacteria are less likely to take up further
amounts of the drug, which is one of the
arguments in favour of dosing once a day.
Several mechanisms have been proposed
for aminoglycoside resistance, including
decreased antibiotic uptake and accumulation, modication of the ribosomal
target, efux and enzymatic modication.11 The major mechanism of resistance
in most bacteria is enzymatic modication
of aminoglycosides, with the resultant
effect of impaired ribosomal binding.
However, based on early studies, this does
not appear to be the mechanism in N
gonorrhoeae. Within gonococci, resistance
has been observed in the case of kanamycin (aminoglycoside) and spectinomycin (aminocyclitol). Resistance
appears to be due to mutations in
linked loci which result in altered sensitivity of the 30S ribosomal subunit of N
gonorrhoeae.12 To the best knowledge of
the authors, there are no published
reports of conrmed clinical resistance to
gentamicin.
The efcacy of gentamicin has been
reported in a number of small observational and controlled (although not randomised) trials. Most of the studies date
from the 1970s and 1980s, and many are
methodologically weak by modern
comparison.13e22 The most common dose
of gentamicin used was 240 mg given once
by intramuscular injection, which equates
to about 6 ml of uid. This volume is near
to the maximum that patients can
tolerate as a single injection, so the choice
of a higher dose would probably require
two separate injections. Clinical and
microbiological cure rates range from 89%
to 100% following gentamicin, although,
in one study, a lower cure rate of around
65% was reported in the gentamicin and
Sex Transm Infect February 2012 Vol 88 No 1

comparator arms.20 Reassuringly, no

adverse events were reported in these
studies.
Perhaps the most important data
concerning long-term use of gentamicin to
treat gonorrhoea come from Malawi,
where a single intramuscular dose of
gentamicin (240 mg) was adopted in 1993
as the preferred antibiotic to treat
presumptive gonorrhoea within the
context of syndrome management treatment algorithms. Although regular gonococcal antimicrobial susceptibility surveys
have not been undertaken on a nationwide basis in Malawi during the last
18 years, there are periodic data from
Lilongwe for microbiological MIC determinations among N gonorrhoeae isolates
and clinical response.13 23 The last
published survey from 2007 conrms the
continued susceptibility of gonococci to
gentamicin, with all isolates having
gentamicin MIC values of #4 mg/l. In
comparison, slightly higher gentamicin
MICs have been recently reported from
a multinational European survey (MIC
range: 1e16 mg/l; modal MIC: 8 mg/l).23 24
Brown et al reported the challenge they
faced in trying to obtain clinical in vitro
correlates within Malawi, although such
an approach was not possible in the
European survey as gentamicin is not used
routinely for treatment of gonorrhoea in
the participating countries.23 Such correlates are urgently needed for gentamicin
and should be the focus of further
research.
The main toxicity of gentamicin relates
to the kidney and the inner ear, where
gentamicin concentrations may be higher,
but the potential for damage is usually
linked to the duration of exposure above
a
toxicity
threshold
(traditionally
measured by trough monitoring). The use
of a relatively low single intramuscular
dose reduces the potential for harm to
occur. The risk of ototoxicity following
aminoglycoside exposure is also higher in
those with pre-existing hearing problems
or impaired renal function, and a ribosomal RNA polymorphism (A1555G) has
been associated with ototoxity, although
the linkage is not strong enough to be
used as a screening test.25
Further information on the efcacy and
safety of gentamicin for the treatment of
gonorrhoea will emerge from an ongoing
randomised comparative trial of gentamicin plus azithromycin against gemioxacin plus azithromycin (http://
clinicaltrials.gov, accessed 25 August 2011)
but this study is not expected to report
fully for a further 2e3 years. In terms of

a research agenda, especially given the

importance of extragenital gonorrhoea in
the emergence of novel gonococcal antimicrobial resistance determinants, it will
also be important to determine the effectiveness of gentamicin to cure pharyngeal
or rectal gonococcal infections.
In summary, the available options for
treating multi-resistant N gonorrhoeae
remain limited. However, the efcacy and
safety data we currently possess for gentamicin, although several decades old, are
encouraging and gentamicins use as a single
intramuscular dose of 240 mg would be
appropriate when there is resistance, allergy
or intolerance to penicillins, macrolides,
tetracyclines and uoroquinolones.
Competing interests None.
Contributors JR and DL jointly wrote and edited this
article.
Provenance and peer review Commissioned;
externally peer reviewed.
Accepted 27 November 2011
Sex Transm Infect 2012;88:6e8.
doi:10.1136/sextrans-2011-050362

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