East African Medical Journal Vol. 82 No. 12 December 2005DRUG SUSCEPTIBILITY PATTERN OF HELICOBACTER PYLORI IN PATIENTS WITH DYSPEPSIA AT THE KENYATTA NATIONAL HOSPITAL,NAIROBIL. Lwai-Lume, MBChB, (MUK), MMed (UON), Senior House Officer, E. O. Ogutu, MBChB, MMed (UON), Consultant Physician/Gastroenterologist,E. O. Amayo, MBChB, MMed (UON), Consultant Physician/Neurologist, Senior Lecturer (at time of study), Department of Medicine, College of Health Sciences,University of Nairobi, P.O. Box 19676, Nairobi, Kenya and S. Kariuki, BVMed. (UON) MSc (Nor.) PhD (UK), Consultant Microbiologist, Senior Researcher,Centre for Microbiology Research, Kenya Medical Research Institute, P. O. Box 43610, Nairobi, Kenya
Request for reprints to: Dr. L. Lwai-Lume, Department of Medicine, College of Health Sciences, University of Nairobi, P.O. Box 19676, Nairobi, Kenya
DRUG SUSCEPTIBILITY PATTERN OF HELICOBACTER PYLORI IN PATIENTS WITH DYSPEPSIA AT THE KENYATTA NATIONAL HOSPITAL, NAIROBI
L. LWAI-LUME, E. O. OGUTU, E. O. AMAYO and S. KARIUKI
ABSTRACT Objective: To determine drug susceptibility pattern of Helicobacter pylori to metronidazole, clarithromycin, amoxicillin and tetracycline in patients presenting with dyspepsia at the Kenyatta National Hospital. Design: Cross-sectional descriptive study. Setting: Kenyatta National Hospital, Nairobi. Subjects: Two hundred and sixty-seven patients aged 15 to 85 years, presenting with dyspepsia and referred for upper gastro-intestinal endoscopy were recruited into the study. Results: Between October 2003 and April 2004, 138 male and 129 female patients aged 15-85 years, with a mean age of 45.4 years were studied. Gastritis was the most common endoscopic finding, occurring in 55%, followed by normal-looking mucosa in 27% and peptic ulcer disease in 16% of the patients. The rapid urease test was positive in 184 patients (69%). The culture yield was 62% of these CLO (Campylobacter like organisms) positive biopsies. The MIC (minimum inhibitory concentration) was 256 mg/l for metronidazole, 1.5mg/l for clarithromycin, 1.5mg/l for tetracycline and 0.75 mg/l for amoxicillin. The MIC values for amoxicillin were significantly higher in the female patients (p = 0.02) but showed no significant variation for age. The MIC values for metronidazole, tetracycline and clarithromycin showed no significant difference for age or gender. MIC values for tetracycline were significantly higher for patients with duodenitis and duodenal ulcer p = 0.009 and 0.02, respectively. Conclusion: All isolated H. pylori organisms were resistant to metronidazole. The susceptibility of the H. pylori isolates was 93.6% for clarithromycin, 95.4% for amoxicillin and 98.1% for tetracycline. The MIC90 for amoxicillin and clarithromycin were found to be close to the upper limit of the susceptibility range. There was a rising MIC90 for tetracycline and metronidazole compared to that found in a previous study in 1991.
gastric outlet obstruction. A local study by Lule et alin 1989 reported a 90% prevalence of H. pylori in
Helicobacter pylori (H. pylori) is a gram-negative,
peptic ulcer disease (3), while Ogutu et al in 1994
spiral, flagellate bacilli affecting more than one billion
isolated H. pylori in 100% of patients presenting to the
people worldwide. Warren and Marshall, two Australian
Kenyatta National Hospital with peptic ulcer disease
investigators, first described the organisms in 1983, in
(4). H. pylori is classified as a group 1 (or definite)
gastric mucosal biopsies of patients with chronic active
carcinogen by the World Health Organisation's
gastritis (1). The gastric antrum is the most favoured
International Agency for Research on Cancer. Infected
site, but any part of the stomach may be colonised.
persons have an increased risk of developing gastric
About 80% of those who are infected are asymptomatic.
cancer and mucosa-associated lymphoid type (MALT)
However H. pylori can cause acute gastritis, chronic
active, chronic persistent and chronic atrophic gastritis.
Treatment of the diseases associated with H. pylori
The organism is also strongly associated with peptic
involves eradication of the organism as the cornerstone
ulcer disease (2), and ensuing complications of upper
for disease clearance. The recommendations for
gastrointestinal bleeding, iron deficiency anaemia and
(i) Triple therapy regimens with a combination
Ethical considerations: The study was carried out with the
of any proton pump inhibitor (PPI) with two antibiotics
approval of the Kenyatta National Hospital Scientific and Ethical
or ranitidine bismuth citrate in combination with two
Review Committee. The patient or parent/ guardian (if the patient
antibiotics. The former option has been adopted in
was under 18 years old) gave informed, written consent.
most countries due to better efficacy and tolerability. Clinical procedures and laboratory methods: All patients
The antibiotics used include tetracycline, amoxicillin,
completed a questionnaire on demographic features and were
clarithromycin, metronidazole (or other nitroimidazole),
and more recently rifabutin (a semi synthetic
The patients underwent upper gastrointestinal endoscopy
ansamycin). The drug regimens are recommended for
using an Olympus gastro intestinal fibreoptic scope Q20, Q40
or XQ20 (Olympus Keymed, Southend-on-Sea, Essex, U.K.).
(ii) Quadruple therapy, which combines a PPI
Six biopsies were taken, two from each of the following sites:
with a bismuth-based regimen including any two of
gastric body, the incisura and the antrum.
the recommended antibiotics. The duration of
One biopsy specimen from each site was used for the
CLO test (a rapid urease test), which is a marker of the
treatment is again 7-14 days, with eradication rates
presence of viable H. pylori organisms and detects the
of over 95% being achieved, although the amoxicillin-
conversion of urea to ammonia by bacterial urease. The three
based regimens have not been as effective (6, 7).
biopsies for culture (one from each site) were immersed in
This is mainly used as second line treatment in
tryptone soy broth with 15% glycerol, for transportation to
patients with failed response to triple therapy. Audit
the laboratory at the Kenya Medical Research Institute
standards for eradication of H. pylori have been set
(KEMRI). To increase the concentration of the organisms,
variously at 80% for intention-to-treat results
only 1ml of broth was used. The CLO test was read up to
(Maastricht consensus meeting, 1996), and 90% for
six hours post biopsy, which enabled us to include some of
the low yielders of H. pylori. The CLO positive specimenswere cultured within six hours of harvesting (11).
(iii)There are other antibiotics being recommended
Brain heart infusion agar (Oxoid, Basingstoke, U.K.),
for resistance to the above two regimes. These include
supplemented with 7% defibrinated horse blood was used for
levofloxacin, furazolidone, and an amoxicillin-
culture. The modified Thayer- Martin's recommended antibiotics
for Campylobacter (vancomycin 3mg/l, trimethoprim 5mg/l,
The prevalence of H. pylori drug resistance varies
colistin 7.5 mg/l and nystatin 12.50 IU/I) were added to enhance
in different countries. Metronidazole resistance varies
selectivity (11). The culture plates were pre-warmed to 37° C
from 10-30% in the United States and Western Europe
and 1ml of broth was then poured onto the agar. A sterile swab,
(2), to 73% in Hong Kong (9) and 74% in Malawi (10).
moistened with some of the transport broth, was used to spread
Culture studies are not routinely done in any part of
the sample over the 90mm plate for culture. Thc culture plateswere covered and placed in a moistened jar.
the world. They are expensive and require a high degree
Microaerophilic conditions were obtained by the candle
of expertise. Local research laboratories need to keep
extinction method and were maintained by use of a Campy
surveillance of the susceptibility pattern of H. pylori
pack (B.D.L, USA). Once opened, the Campy pack released
so as to be able to recommend treatment regimens. Data
hydrogen radicals. These formed water molecules from the
on the susceptibility of H. pylori in our local population
ambient oxygen, ensuring a persistent moist yet microaerophilic
were only available up to 1991. There was no reported
environment. The plates were incubated at 37°C for a
resistance to the recommended antibiotics at that time.
maximum of seven days. Suspected colonies of H. pylori were
This study was therefore designed to determine the
gram stained and further identified by standard catalase,
current H. pylori drug susceptibility pattern and to make
oxidase and urease tests (11). The H. pylori isolates wereimmersed in 20% glycerol and stored at -70°C until further
appropriate recommendations for eradication treatment
Sensitivity testing: The isolated strains of H. pylori were
thawed and subcultured on Mueller-Hinton agar plates. Bacterial suspensions of approximately 107-109 cfu/ml were
Study design: The study design was a cross-sectional,
prepared according to the McFarland turbidity standard (the
test strains) (12). These were then inoculated into the plateswith a multi-point inoculator delivering 7µl. The final
Study population: The study was carried out between
inoculums on the agar surface were 106 cfu/ml. Epsilometer-
October 2003 and April 2004 at the Kenyatta National
test strips (E-test) were used to determine the minimum
Hospital, a teaching and referral hospital in Nairobi, Kenya.
inhibitory concentration (MIC in mg/l) of the antibiotics:
Patient recruitment: Consecutive patients with past or present
clarithromycin, metronidazole, amoxicillin, and tetracycline
history of dyspepsia, and having been referred for upper
(13). The plates were incubated under microaerophilic
gastrointestinal tract (GIT) endoscopy were included in the
study. Also included were patients with a complication
The lowest concentration of antimicrobial agent that
relating to a disease state known to cause dyspepsia. Patients
inhibited growth in 90% of the isolates is the MIC90.
were excluded if they were found to have predominantly
Resistance was considered with an MIC90 > 8mg/l for
reflux symptoms or if they failed to give written consent.
metronidazole, > 2mg/l for clarithromycin, > 2mg/l for
The minimum sample size was 92 H. pylori positive isolates.
amoxicillin and > 2mg/l for tetracycline (13). Data collection and analysis: Data were collected and
culture yield from CLO positive biopsies was 62% in
coded. It was verified, cleaned and entered into the social
sciences software package (SPSS Version 12), beingsummarised into means and standard deviations. The data
Susceptibility testing/minimum inhibitory
were presented in histograms, tables, and pie charts. The chi-
concentration of anti-microbial: One hundred and eight
square test was used to analyse categorical variables and the
strains were tested for susceptibility to metronidazole,
student's t-test for continuous variables. A p-value < 0.05 wasconsidered significant.
amoxicillin, clarithromycin and tetracycline. There wasequal distribution of isolates between male and female
Metronidazole: The isolated strains of H. pylori
Two hundred sixty seven consecutive patients with
showed no susceptibility to metronidazole. The MIC
dyspepsia and having been referred for upper GIT
was ≥ 256mg/l for all isolates. An MIC ≥ 8mg/l
endoscopy at the Kenyatta National Hospital were
indicates resistance: There was no significant variation
in MIC values for age, gender or upper GIT endoscopic
The age range was 15 to 85 years, with a mean
age of 45.4 years (SD ± 17.6 years). There were 138
male (52%) and 129 female (48%) patients, giving a
clarithromycin ranged from 0.016 mg/l to 2mg/l.
There was no statistically significant difference between
The most frequent upper GIT endoscopic finding
MIC values for clarithromycin with regards to
was gastritis (55%) (Table 1). Several patients with
endoscopic findings. This also applied to gender. The
gastritis also had reflux oesophagitis. Those patients
older age groups (45 - 74 years) had MIC values >
whose sole upper GIT endoscopic finding was
1.5mg/l for clarithromycin (p<0.05). The MIC values
gastro-oesophageal reflux were not included in this
for the H.pylori isolates showed susceptibility to
clarithromycin. The MIC50 was 0.38mg/l. The MIC90was 1.5mg/l (Figure 1).An MIC > 2mg/l indicates
resistance. The isolates showed 93.6% susceptibilityto clarithromycin. Endoscopic findings of 267 patients with dyspepsia at theMIC values for clarithromycin (mg/l) in patients withdyspepsia at the Kenyatta National HospitalAntibiotic/ other drugs used prior to endoscopy:
Antibiotic or other drug use, in the four weeks priorto upper GIT endoscopy, was noted in 158 patients(59%). Of the 158 patients 87 were male (55%) and71 were female (45%). Amoxicillin was the most
Amoxicillin: The MIC values for amoxicillin ranged
commonly used antibiotic (41%), followed by
from 0.016mg/l to 2mg/l. There were significantly more
metronidazole (28%), clarithromycin (25%) and
female with an MIC of over 0.38 mg/l, (p=0.02). The
tetracycline (6%). PPI use was noted in 25%, H
MIC values did not show significant variation for upper
receptor antagonists in 20% and antacids in 32%.
GIT endoscopic findings or age. The MIC values for
Increased antibiotic use was noted in those patients in
the H. pylori isolates showed susceptibility to
the 35-44 year age group (clarithromycin 31%,
amoxicillin. The MIC50 was 0.38mg/l. The MIC90 was
amoxicillin 25%, metronidazole 20%).
0.75mg/l. (Figure 2). An MIC ≥ 2mg/l indicates
Culture: Of the total patient population, 133
resistance. The isolates showed 95.4% susceptibility to
patients (50%) had positive H. pylori cultures. The
Minimum inhibitory concentrations (MIC's) of four antimicrobial agents tested against 108 H. pylori isolatesMIC values for amoxicillin (mg/l) in patients with
Eradication of H.pylori remains the cornerstone
dyspepsia at Kenyatta National Hospital
for reduction of morbidity and mortality associated withdyspepsia and the ensuing complications.
Drug resistance has now emerged as the most
limiting factor to H. pylori eradication.
Becx et al reported metronidazole resistance as
early as 1990, predominantly in females (14). et al reported 27% metronidazole resistance
in Belgium in the same year (15). Harries et al reporteda 74% metronidazole resistance in Malawi in 1992 (10)
and Ling et al reported resistance at 73.2% in HongKong (9). Perez Aldana et al reported a significant rise
in metronidazole resistance from 6.6% (1997- 98) to
12% (1999-2000) (p=0.02). The prevalence ofmetronidazole and clarithromycin resistance in this
Tetracyclin: The MIC values for tetracycline ranged
study was related to the annual consumption of these
from 0.016mg/l to 2mg/l.The MIC values for tetracycline
did not show a statistically significant variation for age
Using the E-test for 62 isolates, Garza-Gonzalez
group or gender. Higher MIC values (over 0.5mg/l)
et al reported metronidazole resistance at 38% (17). A
showed association with duodenitis (p=0.009) and
recent Iranian study reported a 75.4% metronidazole
duodenal ulcer (p=0.02). The MIC values for the H.
resistance for 120 H. pylori strains by the disk diffusion
pylori isolates showed susceptibility to tetracycline. The
test (18). The observed in vitro resistance to
metronidazole can however be overcome when this
50 was 0.5mg/l. The MIC90 was 1.5mg/l. An MIC
≥ 2mg/l indicates resistance (Figure 3).The isolates
drug is used in combination therapy regimes. Longer
showed 98.1% susceptibility to tetracycline.
eradication courses have also been found to lead toincreased clinical response (19). The overuse ofmetronidazole in the treatment of amoebiasis and other
anaerobic infections has greatly contributed to the risein drug resistance in populations where these infections
MIC values for tetracycline (Mg/l) in patients withdyspepsia at Kenyatta National Hospital
Resistance to clarithromycin, metronidazole and
amoxicillin can decrease rates of cure by up to 62%
(20), 36% (7) and 20% (8) respectively. Resistance to
tetracycline and bismuth salts have not been reported
There was no statistically significant difference
between MIC values for clarithromycin as regardsgender or upper GIT endoscopic findings. However, the
older age groups (45 - 74 years) had MIC values
> 1.5mg/l for clarithromycin (p<0.05). Clarithromycin
is used to treat atypical pneumonia, which is more
common in the older age group. Our study could
suggest increased exposure to clarithromycin in this age
group or may be an indicator of primary resistance,
since clarithromycin is a relatively recent antibiotic on
selection and transmission of resistant organisms.
the Kenyan market. Cross-resistance with erythromycin
We recommend that metronidazole should not
be considered as first line drug therapy in triple
There were significantly more females with
regimens for H. pylori eradication in Nairobi and it's
H. pylori isolates with an MIC of over 0.38 mg/l for
environments. This could probably be extrapolated
amoxicillin, p=0.02. This could be due to increased use
to most of the Kenyan population. We should still
of this antibiotic in the female population especially
incorporate amoxicillin, clarithromycin and
in the treatment of pelvic inflammatory disease and
tetracycline in H. pylori eradication regimens. Future
other gynaecological conditions. The MIC values did
studies are required to evaluate in vivo susceptibility
not show significant variation for upper GIT endoscopic
of H. pylori to metronidazole in the Kenyan population
findings or age. Perez Aldana et al reported growing
and to determine H. pylori susceptibility to the newer
drug resistance, albeit to metronidazole and
recommended antibiotics, which were not included
clarithromycin, and related it to the annual consumption
There were a number of limitations of our study.
A tetracycline MIC > 0.5 mg/l showed a
The study population may not have been representative
significant association with duodenitis (p= 0.009)
of the general Kenyan population. The Kenyatta
and duodenal ulcer (p= 0.02) but did not show
National Hospital is a referral hospital, drawing
statistical significance for gender or age group. H.
patients from all over the country, but the majority
pylori infection is specific for gastric mucosa and
of the patients are however from the greater Nairobi
areas of gastric metaplasia. Our study could suggest
area and may not be representative of the general
that H. pylori isolates that have higher MlC's for
population. Patients living in the environments of a
tetracycline are more likely to induce gastric
hospital or pharmacy may have had greater exposure
metaplasia within the duodenum. It is now known
to antibiotics, which may have a bias on the drug
that the virulence of H. pylori is affected more by
resistance profile. Patients with recurrent dyspepsia
the vacuolating cytotoxin (VacA) and the cag
are more likely to be referred to a tertiary facility.
pathogenicity island (CagA) evidenced by genotypic
These may represent a select group of patients with
markers, than it is by the presence of drug resistance
a high rate of drug resistance, which may not be
(2,21-22). Drug resistance as evidenced by a rise in
reflective of the resistance pattern in the general
MIC90 level could not clearly be related to the
population. Screening for H. pylori is usually on the
severity of disease expression at upper GIT endoscopy.
strength of two tests such as histology and CLO
Histology may have answered this more appropriately.
testing. The CLO test is 85-90% sensitive if read up
The future for therapy is uncertain. There are
to 24 hours. This was the only screening test in our
no new antimicrobials that would have a major
study and was read up to six hours post-biopsy. We
impact on the current position. Predictions that
may therefore have missed many H. pylori positive
knowledge of the genome would lead to more
patients. Further delay in reading the CLO tests
appropriate therapy have not materialised. Drugs
would not have been beneficial, as it would have
under investigation to try and increase the
increased the chances of overgrowth of oral and
susceptibility of H. pylori to antibiotics include the
stomach contaminants and hence reduced the
use of aspirin, but the results are controversial and
sensitivity of the culture results. However, the major
the benefits have not been noted in vivo (23).
objective of this study was susceptibility testing and
Prolonging therapy to 10 to 14 days should be
not H. pylori prevalence; the latter would have been
greatly affected by the use of one screening test. This
In conclusion all our isolates showed in vitro
was an in vitro study, which may not be fully
resistance to metronidazole, MIC > 256mg/ml, but
reflective of the in vivo situation
showed susceptibility to clarithromycin (93.6%),amoxicillin (95.4%) and tetracycline (98.1%). Higher
MIC values for tetracycline were significantly
associated with duodenitis and duodenal ulcer. H.
Microbiology laboratory for the culture and sensitivity
pylori showed a rising MIC90 for metronidazole and
testing; Mr Waweru, Department of Medicine, KNH
tetracycline as compared to a similar study carried
and the endoscopy room nurses for their technical
out in Kenyatta National Hospital by Sang et al in
assistance; Dr. Mutie, Dr. Kioko, Dr. Musau, (KNH),
Dr. Lodenyo (KEMRI) and Mr. Okumu (Department
metronidazole of 4.0mg/l, for tetracycline 0.12mg/l,
of Surgery, KNH) for the upper GIT endoscopies and
for ampicillin 0.03mg/l and for erythromycin 0.25mg/
Lords Pharmaceuticals and AstraZeneca for financial
l. A rising MIC90 is a good indicator of growing
assistance. Funds from these companies were used
to purchase E-test strips from an independent
In this light, all attempts should be made to
company, AB BIODISK (Solna, Sweden).
effectively eradicate H. pylori so as to avoid the
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