J Antimicrob Chemother 2016; 71 Suppl 1: i103 – i109

doi:10.1093/jac/dkw076

Antibiotic susceptibility in Streptococcus pneumoniae, Haemophilus

influenzae and Streptococcus pyogenes in Pakistan: a review of results
from the Survey of Antibiotic Resistance (SOAR) 2002–15
A. Zafar1, R. Hasan1, S. Nizamuddin2, N. Mahmood2, S. Mukhtar2, F. Ali3, I. Morrissey4, K. Barker5 and D. Torumkuney5*

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1
Aga Khan University Hospital, Department of Pathology and Laboratory Medicine, Section of Microbiology, Karachi, Pakistan; 2Shaukat
Khanum Memorial Cancer Hospital and Research Center, Department of Microbiology, 7A, Block R-3, Johar Town, Lahore, Pakistan;
3
GlaxoSmithKline Pakistan, 35 Dockyard Road, West Wharf, Karachi 74000, Pakistan; 4IHMA Europe Sàrl, 9a route de la Corniche, Epalinges
1066, Switzerland; 5GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK

*Corresponding author. Tel: +44-20-8047-1671; E-mail: didem.x.torumkuney@gsk.com

Objectives: To investigate changes in the antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus

influenzae and Streptococcus pyogenes from the Survey of Antibiotic Resistance (SOAR) in community-acquired
respiratory tract infections (CA-RTIs) between 2002 and 2015 in Pakistan.
Methods: This is a review based on previously published studies from 2002 –03, 2004– 06 and 2007– 09 and also
new data from 2014–15. Susceptibility was determined by Etestw or disc diffusion according to CLSI and phar-
macokinetic/pharmacodynamic (PK/PD) breakpoints.
Results: A total of 706 isolates from CA-RTIs comprising 381 S. pneumoniae, 230 H. influenzae and 95 S. pyogenes
were collected between 2002 and 2015 and tested against a range of antibiotics. Antibiotic resistance in
S. pneumoniae rose steeply from 2002 to 2009, with isolates non-susceptible to penicillin and macrolides increas-
ing from 10% to 34.1% and from 13% –14% to 29.7%, respectively. Susceptibility to amoxicillin/clavulanic acid
(and by inference amoxicillin) remained between 99.4% and 100% from 2002 to 2015. Over the years, the preva-
lence of susceptibility to cefuroxime was 98% – 100% among S. pneumoniae. Resistance in S. pneumoniae
to some older antibiotics between 2007 and 2009 was high (86.8% for trimethoprim/sulfamethoxazole
and 57.2% for tetracycline). Between 2002 and 2015, ampicillin resistance (b-lactamase-positive strains)
among H. influenzae has remained low (between 2.6% and 3.2%) and almost unchanged over the years
(H. influenzae was not tested during 2004–06). For S. pyogenes isolates, macrolide resistance reached 22%; how-
ever, susceptibility to penicillin, amoxicillin/clavulanic acid and cefuroxime remained stable at 100%.
Conclusions: In S. pneumoniae from Pakistan, there has been a clear reduction in susceptibility to key antibiotics
since 2002, but not to amoxicillin/clavulanic acid (amoxicillin) or cefuroxime. However, susceptibility in
H. influenzae has remained stable. Local antibiotic susceptibility/resistance data are essential to support
informed prescribing for CA-RTIs and other infections.

Introduction Like many other Asian countries, in Pakistan antimicrobial

Worldwide, there are concerns about rising levels of antibiotic
resistance and fears that the efficacy of antimicrobial therapy
may be compromised, resulting in treatment failure and reduced
utility of older antibiotics.1
Streptococcus pneumoniae, Haemophilus influenzae and
Streptococcus pyogenes are all commonly carried in the naso-
pharynx and implicated in community-acquired respiratory tract
infections (CA-RTIs). These infections account for significant
morbidity and mortality, including severe life-threatening infec-
tions such as pneumonia and meningitis (S. pneumoniae and
H. influenzae) and rheumatic fever with risk of cardiac sequelae
(S. pyogenes).2 – 7
therapeutic choices for RTIs are usually empirical due to the lim-
ited availability of laboratory identification and antibiotic suscep-
tibility testing of bacterial isolates. Even when available, the cost
of laboratory testing in this setting can often prove inhibitive.8 The
increasing prevalence of resistant organisms threatens the cur-
rent and future treatment of CA-RTIs.4,9 – 11 Surveillance studies,
therefore, provide an important tool for determining local and
regional susceptibility patterns and guiding empirical antimicro-
bial therapy.12
The Survey of Antibiotic Resistance (SOAR) studies have been
undertaken in Pakistan during 2002 – 03, 2004 – 06, 2007 – 09
and 2014 – 15, as well as elsewhere in Asia, the Middle East,
Africa, Latin America, Asia Pacific and the Commonwealth of

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Zafar et al.
Independent States countries, to provide detailed and compara-
tive information on resistance trends among strains from docu-
mented CA-RTIs caused by S. pneumoniae, H. influenzae and
S. pyogenes.13 – 16
Materials and methods
Collaborating centres
Isolates were collected from two sites in Pakistan: Aga Khan University
Hospital (for the 2002 – 09 study period) Karachi and Shaukat Khanum
Memorial Cancer Hospital and Research Centre, Lahore (for the 2014– 15
study period).
Clinical isolates (from outpatients who attended
the university hospitals)
Between 2002 and 2015, a total of 381 S. pneumoniae, 230 H. influenzae
and 95 S. pyogenes isolates were obtained from a range of clinical samples
including sputum, blood, bronchoalveolar lavage, middle ear effusion and
tracheal aspirate taken from adult and paediatric patients with a con-
firmed CA-RTI using routine clinical collection methods. All S. pyogenes iso-
lates were from the throat. Duplicate isolates from the same patient were
not accepted.
S. pneumoniae isolates were collected during 2002 – 03, 2004 – 06,
2007 – 09 and 2014 – 15. H. influenzae isolates were collected over the
same time periods, except none were collected in 2004 –06. S. pyogenes
isolates were collected only during 2007 –09.
The isolates were identified using conventional methods (optochin sus-
ceptibility for S. pneumoniae, X and V factor requirement for H. influenzae
and bacitracin antibiotic disc susceptibility for S. pyogenes strains).
Isolates were stored at 2708C until tested. b-Lactamase production of
H. influenzae isolates was determined by a chromogenic cephalosporin
(nitrocefin) disc method.17 b-Lactamase-negative ampicillin-resistant
(BLNAR) isolates were defined as those organisms having a negative
b-lactamase result and an ampicillin MIC of ≥4 mg/L.18
Susceptibility testing
w
MICs were determined using Etest susceptibility testing methods accord-
ing to the manufacturer’s instructions [AB BIODISK (Solna, Sweden) for
2002 – 09 and bioMérieux (Marcy-l’Etoile, France) for 2014 – 15] and
interpreted using CLSI guidelines and pharmacokinetic/pharmacody-
namic (PK/PD) breakpoints (for 2002 – 03, M100-S1419; for 2004 – 06,
CLSI M100-S1518; for 2007 – 09, M100-S1920; and for 2014 – 15,
M100-S2421). For isolates collected during 2007 – 09, susceptibility to
erythromycin, tetracycline, trimethoprim/sulfamethoxazole and chloram-
phenicol was also determined using the CLSI disc diffusion method.22
Briefly, for Etestw MIC testing, S. pneumoniae isolates were subcultured
twice on blood-supplemented Mueller–Hinton agar and H. influenzae iso-
lates were cultured on Haemophilus Test Medium before susceptibility
testing was performed. Inocula were prepared by direct colony suspension
to give a 0.5 McFarland standard dilution and inoculated onto appropriate
agar plates to produce a confluent lawn of growth. Etestw and antibiotic
discs were applied and plates incubated for 20 – 24 h (16 – 17 h for
H. influenzae agar disc diffusion) at 358C in a 5% CO2 atmosphere. For
azithromycin and clarithromycin Etests, S. pneumoniae and S. pyogenes
isolates were incubated in ambient air due to the adverse effect of CO2
on the activity of macrolide antibiotics. Etestw MICs and inhibition zone
diameters were read in accordance with bioMérieux’s instructions and
CLSI guidelines for disc susceptibility testing, respectively.
The number of antibiotics tested varied at the different timepoints.
Between 2002 and 2009, S. pneumoniae strains were tested against peni-
cillin, amoxicillin/clavulanic acid (data from which can be used to deduce
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susceptibility to amoxicillin alone), cefixime, cefuroxime, cefaclor, cefpro-
zil, clarithromycin, azithromycin, erythromycin, ciprofloxacin, trimetho-
prim/sulfamethoxazole, tetracycline, chloramphenicol and clindamycin.
S. pyogenes strains were tested against penicillin, amoxicillin, cefaclor, cef-
ixime, erythromycin, azithromycin, clarithromycin, clindamycin, tetracyc-
line and chloramphenicol. Finally, susceptibility of H. influenzae was
assessed against ampicillin, amoxicillin/clavulanic acid, cefaclor, cefixime,
cefprozil, cefuroxime, clarithromycin, azithromycin, ciprofloxacin, levofloxa-
cin, trimethoprim/sulfamethoxazole, tetracycline and chloramphenicol.
For the 2014 –15 isolates, susceptibility testing was carried out using a
more limited range of antibiotics. S. pneumoniae susceptibility was tested
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against amoxicillin/clavulanic acid (amoxicillin), cefaclor, cefuroxime,
chloramphenicol, erythromycin and penicillin. H. influenzae was tested
against amoxicillin/clavulanic acid, ampicillin, azithromycin, cefaclor, cefu-
roxime, chloramphenicol and levofloxacin using the same CLSI break-
points as for 2009 isolates.
Quality control and data analysis
Quality control strains S. pneumoniae ATCC 49619, H. influenzae ATCC
49247, H. influenzae ATCC 49766, Escherichia coli ATCC 25922 and E. coli
ATCC 32518 were included on each day of testing. Results of susceptibility
testing were accepted if the results of the control strains were within pub-
lished limits.
Any Etestw MIC results that were between doubling dilutions were
rounded up to the next doubling dilution MIC for data analysis. MICs and
zone diameters were interpreted qualitatively using CLSI interpretive stan-
dards; MICs were also analysed using PK/PD breakpoints established to
predict the clinical and bacteriological efficacy of antimicrobial dosing regi-
mens. 11,19,23 To interpret azithromycin and clarithromycin MICs for
H. influenzae, revised breakpoints were used to account for incubation in
a CO2 atmosphere (using the Etestw susceptibility method according to
the manufacturer’s instructions; bioMérieux, Marcy-l’Etoile, France). The
respective PK/PD breakpoints were adjusted accordingly, i.e. raised by
one doubling dilution for interpretation of H. influenzae susceptibility
because of incubation under 5% CO2.
Results
From 2002 to 2009, CLSI breakpoint interpretations for
S. pneumoniae were unchanged for all of the study drugs except
penicillin. PK/PD breakpoints were also in good agreement with
the ‘susceptible’ category, except for cefaclor and azithromycin.
For both of these antibiotics, the susceptible breakpoint from
PK/PD data was lower than the CLSI breakpoint—by one dilution
for cefaclor and three dilutions for azithromycin, reflecting the
relatively low blood level attainable with this antibiotic.
Table 1 shows the breakpoints used to interpret Etestw MICs for
strains isolated in the period 2002 –15. During the course of the
studies, S. pneumoniae with raised penicillin MICs were being
reported with increasing frequency worldwide. The original break-
points for penicillin of susceptible (S) ≤0.06 mg/L, intermediate (I)
0.12– 1.0 mg/L and resistant (R) ≥2.0 mg/L had been appropriate
for use of oral penicillin V and for injectable penicillin used in men-
ingitis treatment. However, with an increasing prevalence of
penicillin-intermediate S. pneumoniae (PISP) strains, the use of
penicillin was questioned for treatment of S. pneumoniae infections
other than meningitis and particularly for pneumonia. This concern
was addressed by CLSI and new penicillin breakpoints were applied
for S. pneumoniae from non-meningeal sources.22 New breakpoints
were recommended in 2009 specifically for use with S. pneumoniae
from RTIs. High doses of penicillin and other b-lactam antibiotics,
SOAR: Pakistan 2002 – 15 JAC
Table 1. MIC breakpoints (mg/L) used for S. pneumoniae and H. influenzae isolates

CLSI breakpointsa

PK/PD breakpoints S. pneumoniae H. influenzae

Antimicrobial S R S I R S I R

Penicillinb — — ≤0.06 0.12– 1 ≥2 — — —

Penicillinc (only for 2007– 09/2014 – 15) — — ≤2 4 ≥8 — — —
≤1 ≥4

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Ampicillin — — — — — 2
Amoxicillin ≤2 ≥4 ≤2 4 ≥8 — — —
AMCd ≤2 ≥4 ≤2 4 ≥8 ≤4 — ≥8
Cefaclor ≤0.5 ≥1 ≤1 2 ≥4 ≤8 16 ≥32
Cefixime ≤1 ≥2 — — — ≤1 — —
Cefprozil ≤1 ≥2 ≤2 4 ≥8 ≤8 16 ≥32
Cefuroximee ≤1 ≥2 ≤1 2 ≥4 ≤4 8 ≥16
Azithromycinf ≤0.12 ≥0.25 ≤0.5 1 ≥2 ≤8 — —
Clarithromycinf ≤0.25 ≥0.5 ≤0.25 0.5 ≥1 ≤16 32 ≥64
Ciprofloxacin ≤1 ≥2 — — ≤1 — — —
Levofloxacin ≤2 ≥4 ≤2 4 ≥8 ≤2 — —

AMC, amoxicillin/clavulanic acid; —, no breakpoint available.

a
For breakpoints see CLSI.22
b
CLSI 2008 breakpoints/CLSI 2009 breakpoints for oral penicillin V.
c
CLSI 2009 breakpoints for parenteral penicillin/non-meningeal.
d
Amoxicillin/clavulanic acid was tested in a 2 : 1 ratio of amoxicillin to clavulanic acid; breakpoints are expressed as the amoxicillin component.
e
Breakpoints used are for cefuroxime axetil.
f
Azithromycin and clarithromycin breakpoints are those provided by AB Biodisk for incubation in CO2.

such as amoxicillin, were also recommended for treatment of PISP
or penicillin-resistant S. pneumoniae infections.
These changes are documented in Table 1 and show that
S. pneumoniae with penicillin MICs ≤2.0 mg/L are regarded as sus-
ceptible, whereas previously some of these isolates would have
been regarded as having intermediate susceptibility. Clinical stud-
ies showed that, provided penicillin was used in adequate dosage,
the new susceptibility category could be used as a breakpoint for
non-meningeal isolates.
Antibiotic resistance in S. pneumoniae
Overall, non-susceptibility to penicillin among S. pneumoniae
strains rose steeply, from 10% in 2002 to 34.1% in 2009. The
prevalence of penicillin-non-susceptible S. pneumoniae was 10%
during 2002 – 03, 18.3% during 2004 – 06 and 34.1% during
2007– 09. During 2014 –15, only 10 S. pneumoniae isolates were
collected, of which two were non-susceptible to penicillin. Of the
31 isolates that were penicillin non-susceptible in the 2007 – 09
survey, all had MICs of 4 mg/L, making them intermediate
(Table 2). No isolates of S. pneumoniae obtained during the
study were highly resistant to penicillin (MICs ≥8.0 mg/L),
although 1.1% of strains in the 2004 – 06 survey were penicillin
resistant using the lower CLSI breakpoint in use at that time.
Macrolide resistance rose from 13% to 29.7% (depending on
the macrolide being tested) over the study period (Figure 1 and
Table 2, respectively). By contrast, susceptibility to amoxicillin/
clavulanic acid (or amoxicillin alone) between 2002 and 2015
has remained between 99.4% and 100% among S. pneumoniae
isolates. Ciprofloxacin was tested only during 2007 – 09, when
91.2% of S. pneumoniae isolates were found to be susceptible.
S. pneumoniae strains showing reduced susceptibility to penicil-
lin were more likely to show increased resistance to macrolides
and other antimicrobial agents, particularly older agents such as
first-generation cephalosporins (cefaclor), tetracycline or tri-
methoprim/sulfamethoxazole (Table 3). Almost all PISP strains
were resistant to trimethoprim/sulfamethoxazole, .70% were
resistant to tetracycline and 50% were resistant to macrolides
(erythromycin and clarithromycin). This contrasted with the
macrolide resistance rate in penicillin-susceptible S. pneumoniae
strains, which was only 10% – 15%. In the Lahore 2014 – 15
study, the erythromycin susceptibility of all S. pneumoniae isolates
was 70%.
Clindamycin resistance plus macrolide resistance is a use-
ful proxy for detection of the erm(B) resistance marker. 24
In the 2007 – 09 study period, clindamycin resistance was
22.6% among PISP strains and this was coupled with a concomi-
tant high incidence of macrolide resistance (50%) (Table 3). This
finding suggests that a number of these isolates are more likely
to have macrolide resistance attributable to the erm(B) resist-
ance marker rather than the efflux mechanism of macrolide
resistance. In the 2007 – 09 study period, of the S. pneumoniae
isolates, 93.4% were susceptible to chloramphenicol (Table 2).
Antibiotic resistance in H. influenzae
H. influenzae isolates studied in Pakistan during the 2002 –03 win-
ter season (n ¼ 93) were fully susceptible (100%) to amoxicillin/
clavulanic acid, cefuroxime, cefprozil, cefaclor, cefixime, clarithro-
mycin and azithromycin (Table 4). Furthermore, 3.2% of isolates

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Zafar et al.

Table 2. Susceptibility (%) of S. pneumoniae in Pakistan to antimicrobials using CLSI or PK/PD breakpoints

2002 –03 2004– 06 2007– 09 2014– 15

(n¼100)a (n¼180)b (n¼91)c (n ¼10)c

CLSI PK/PD CLSI PK/PD CLSI PK/PD CLSI

Antimicrobial S I or (R) S S I or (R) S S I or (R) S S I or (R)

Penicillin 90.0 10.0 NA 81.7 18.3 (1.1) NA 65.9 34.1 (0) NA 80.0 20.0

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AMC 100 0 99.4 99.4 0.6 (0) 100 100 0 100 100 0
Cefixime 93.0d 7.0 80.6 — — 92.3 — — — —
Cefuroxime 98.0 2.0 98.3 98.3 1.7 (1.1) 100 100 0 100 100 0
Cefaclor 96.0 4.0 67.2 89.4 10.6 (2.8) 69.2 94.5 5.5 70.0 90.0 10.0
Cefprozil 99.0 1.0 — — — — — — — — —
Clarithromycin 86.0e 14.0 90.8 90.8 9.2 76.9 76.9 23.1 — — —
Azithromycin 87.0e 13.0 73.4 90.2 9.8 — — — — — —
Erythromycin — — NA 87.2 12.8 NA 70.3 29.7 — 70.0 30.0
Clindamycin — — NA 88.9 11.1 NA 90.1 9.9 — — —
SXT — — NA — — NA 13.2 86.8 — — —
Tetracycline — — NA — — NA 42.8 57.2 — — —
Chloramphenicol — — NA — — NA 93.4 6.6 — 80.0 20.0
Ciprofloxacin — — — — — 91.2 — — —

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable; —, no data
available.
a
Data for strains from Pakistan summarized by Shibl et al.13
b
Data from Pakistan summarized by Sievers et al. 15
c
Pakistan current SOAR study data.
d
PK/PD breakpoint used.
e
Revised breakpoints for Etestw used.

35 at 29%. Some 86.8% of H. influenzae isolates were susceptible

Erythromycin resistance to levofloxacin (Table 4).
30
Resistance (%)

25 Except for the 2014 –15 study period, all ampicillin-resistant

Clarithromycin resistance H. influenzae isolates were b-lactamase positive.
20
15 Although the prevalence of BLNAR isolates was not reported
10
Reduced penicillin during different study periods, based on CLSI guidelines, rare
susceptibility BLNAR strains of H. influenzae should be considered resistant to
5
amoxicillin/clavulanic acid, ampicillin/sulbactam, cefaclor, cefa-
0
2002–03 2004–07 2007–09 mandole, cefetamet, cefonicid, cefprozil, cefuroxime, loracarbef
Survey timepoint
and piperacillin/tazobactam, despite apparent in vitro susceptibil-
ity of some BLNAR strains to these agents.
Figure 1. Penicillin and macrolide resistance in S. pneumoniae strains from
CA-RTIs from Pakistan during 2002 –09.
Antibiotic resistance in S. pyogenes
S. pyogenes was also studied in the 2007 – 09 survey. All strains
were designated b-lactamase positive on the basis of nitrocefin were susceptible to penicillin. Based on penicillin susceptibility,
disc testing.13 the strains were also susceptible to amoxicillin, amoxicillin/clavu-
For 2007–09 (n ¼99), amoxicillin/clavulanic acid susceptibility lanic acid, cefuroxime, cefotaxime and cefaclor. By contrast,
remained at 100% among H. influenzae isolates in Pakistan and macrolide (erythromycin, azithromycin and clarithromycin) resist-
ampicillin resistance was 4% (4/99 isolates). All isolates were sus- ance in these Pakistani CA-RTI isolates was 22% (data not shown).
ceptible to cefuroxime and cefixime. The prevalence of resistance
to macrolides was between 6.1% and 8.1%. Ciprofloxacin was
Discussion
tested only during 2007–09, when 95.9% of H. influenzae isolates
were found to be susceptible (Table 4). The increase in antimicrobial resistance among CA-RTI pathogens
Of the 2014 –15 (n¼ 38) H. influenzae isolates, 100% were sus- is a serious problem throughout the world and has important
ceptible to amoxicillin/clavulanic acid and 97.4% were susceptible implications for the successful management of these infections.
to ampicillin. Only 1 of the 38 isolates (2.63%) from 2014–15 was Since there may be variation in levels of resistance between differ-
b-lactamase positive. Susceptibility to chloramphenicol was low ent geographical areas, it is essential to be aware of the local

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SOAR: Pakistan 2002 – 15 JAC
Table 3. Susceptibility (%) of penicillin-susceptible S. pneumoniae (PSSP) The SOAR studies have been conducted using the Etestw
and penicillin-intermediate S. pneumoniae (PISP) strains from CA-RTIs in because reliable MIC results can be obtained relatively easily
Pakistan in SOAR during 2007 –09 and subsequently the results can be analysed with reference to
different breakpoint criteria. In these studies, analyses have
PSSP (n¼60), penicillin PISP (n¼31), penicillin been performed using breakpoints defined by CLSI and also
MIC ≤2.0 mg/La MIC ≥4 mg/La newer breakpoints defined by PK/PD criteria, which take account
of both susceptibility and attainable antibiotic concentrations in
Antimicrobial S (PK/PD) S (CLSI) R (CLSI) S (PK/PD) S (CLSI) R (CLSI) the blood. Interpretation of the data has also been made with
the revised breakpoints issued in 2009. Use of these new break-
Penicillin NA 100 0 NA 0 0 points means that direct comparison between time periods is

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AMC 100 100 0 100 100 0 less straightforward, but is still useful.
Cefixime 98.3 — — 80.6 — — Data from other studies in Pakistan have highlighted that
Cefuroxime 100 100 0 100 100 0 although the prevalence of S. pneumoniae strains with reduced
Cefaclor 86.7 98.3 0 34.5 87.1 0 susceptibility to penicillin and macrolides may be lower than
Clarithromycin 90 90 10 51.6 51.6 48.4 reported in some regions of Asia,6,25 it remains an important con-
Ciprofloxacin 91.7 — — 90.3 — — sideration for effective empirical treatment of CA-RTIs. The
Erythromycin NA 83.3 15 NA 45.2 54.8 reduced susceptibility of S. pneumoniae isolates to commonly
Clindamycinb NA 96.7 3.3 NA 77.4 22.6 used macrolides, such as erythromycin, is of concern. The
SXT NA 18.3 78.4 NA 3.2 96.8 2007 – 09 data showed that 29.7% of isolates had reduced sus-
Tetracycline NA 50 40 NA 29.1 70.9 ceptibility to erythromycin (Table 2), which concurs with the
Chloramphenicol NA 93.3 6.7 NA 93.5 6.5 28% resistance reported in 2006 isolates by Zafar et al.8 Of par-
ticular concern, in the SOAR data analysis, erythromycin resist-
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; ance rose to 54.8% in PISP isolates (Table 3).
S, susceptible; I, intermediate; R, resistant; NA, not applicable; —, no The clinical treatment of pneumonia or meningitis caused by
data available. S. pneumoniae may need to take into account the increase in
a
New CLSI breakpoints for penicillin applied. PISP strains when selecting appropriate antimicrobial therapy.
b
Included to differentiate erm(B)-mediated macrolide resistance. Specifically, clinical studies have shown that doses of penicillin
and other agents may need to be adjusted if it is suspected that
penicillin susceptibility is reduced.26
Table 4. Susceptibility (%) of H. influenzae in Pakistan to antimicrobials Guidelines in several countries propose use of higher doses of
using CLSI breakpoints some b-lactam antibiotics because of concerns that PISP strains
may not be adequately treated with those doses that were origin-
2002 –03 2007 –09 2014 –15 ally recommended some 30 years ago. The data from the SOAR
(n ¼93)a (n¼99)b (n¼38)b studies for Pakistan have, however, confirmed full susceptibility
to amoxicillin/clavulanic acid (amoxicillin) and cefuroxime, enab-
Antimicrobial S I or (R) S I or (R) S I or (R) ling these agents to continue to be used with confidence for
appropriate S. pneumoniae-associated infections.
Ampicillin 96.8 3.2 96 4 97.4 2.6
For H. influenzae, data from the SOAR studies has shown that
AMC 100 0 100 0 100 0
ampicillin resistance among H. influenzae strains isolated from
Cefaclor 100 0 98 2 89.5 10.5
documented CA-RTIs in Pakistan appears to be relatively rare
Cefixime 100 0 100 0 — —
(4%) and almost unchanged from 2002 to 2009. Furthermore,
Cefprozil 100 0 — — — —
no BLNAR isolates were reported in this survey. This type of resist-
Cefuroxime 100 0 100 0 97.4 2.6
ance is most frequently attributable to carriage of plasmids medi-
Clarithromycin 100 0 91.9 8.1 — —
ating b-lactamase with consequent opportunity for rapid spread.
Azithromycin 100 0 93.9 6.1 100 0 The low level of resistance in Pakistan contrasts markedly with
Chloramphenicol — — 88.8 11.2 29 71 the situation in some countries in Asia where b-lactamase pro-
Levofloxacin — — — — 86.8 13.2 duction is approaching 50%.25 Knowledge of this very fortunate
Ciprofloxacin — — 95.9 4.1 — — position in Pakistan may provide the opportunity for this low
SXT — — 15.2 84.8 — — level of resistance to be maintained for as long as possible.
Tetracycline — — 67.7 32.3 — Group A streptococci (GAS) isolates have remained highly sus-
ceptible to b-lactam antibiotics, but the level of macrolide resist-
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; ance is high: 21% in Pakistan compared with ,5% in Algeria and
S, susceptible; I, intermediate; R, resistant; —, no data available.
a
Egypt.16 As well as being a cause of tonsillopharyngitis, GAS, if
Data for strains from Pakistan summarized by Shibl et al.13 untreated, can lead to more severe complications including
b
Pakistan current SOAR study data. rheumatic fever with cardiac sequelae. In Pakistan, cardiac
heart murmur due to rheumatic heart disease is common (preva-
resistance pattern before considering empirical antimicrobial lence 5.7/1000 patients screened in one survey).7
therapy. SOAR was therefore established to provide information Effective primary treatment of proven S. pyogenes is therefore
on local resistance patterns, as well as overall levels of resistance crucial and, whilst penicillin susceptibility remains at 100%, com-
and susceptibility trends, for key CA-RTI pathogens. pliance may be an issue for the recommended full treatment of

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Zafar et al.
10 days of oral penicillin V. The high level of macrolide resistance
means that this class of antibiotic may not be an appropriate
treatment for GAS in Pakistan. Shorter treatments (4 – 5 days)
with amoxicillin/clavulanic acid (or amoxicillin) or cefuroxime axe-
til have been shown to be as effective, or superior to, standard
penicillin treatment and may aid compliance.27
In conclusion, when choosing antibiotic therapy for CA-RTIs, local
antibiotic susceptibility/resistance data are essential to support
informed therapy choices. The SOAR studies over the period from
2002 to 2009, along with the further study in 2014–15, have con-
firmed that the highly effective antibiotics, amoxicillin/clavulanic
acid (amoxicillin in the case of S. pneumoniae) and cefuroxime,
have retained almost 100% susceptibility against common CA-RTI
isolates of S. pneumoniae, H. influenzae and S. pyogenes. In addition,
organizations such as the WHO have emphasized the importance of
choosing the best possible drug and treating for the optimal dur-
ation to prevent the further emergence of resistant bacterial strains.
Acknowledgements
SOAR 2002– 03 results were presented at the 14th European Congress of
Clinical Microbiology and Infectious Diseases, Prague, Czech Republic,
2004 (abstract number: P-507). SOAR 2004 – 06 results were presented
at the 8th European Congress of Chemotherapy and Infection, Budapest,
Hungary, 2006 (abstract number: 279) and at the 46th Interscience
Conference on Antimicrobial Agents and Chemotherapy, San Francisco,
CA, USA, 2006 (abstract number: C2-0425). SOAR 2007 – 09 results were
presented at the 49th Interscience Conference on Antimicrobial Agents
and Chemotherapy, San Francisco, CA, USA, 2009 (abstract number:
C2-1402).
Funding
This study was funded by GlaxoSmithKline.
Transparency declarations
This article is part of a Supplement sponsored by GlaxoSmithKline. D.
Torumkuney, F. Ali and K. Barker are employees of GlaxoSmithKline. D.
Torumkuney and K. Barker also hold shares in GlaxoSmithKline. I. Morrissey
is an employee of IHMA, a medical communication and consultancy com-
pany, who participated in the exploration, interpretation of the results on
behalf of GSK. All other authors declare that they have no conflict of interest.
Livewire Editorial Communications (Stella Deane and Tracey Morris)
provided medical writing support in the form of writing assistance, collat-
ing author’s comments, grammatical editing and referencing that was
paid for by GSK.
References
1 Sahm DF, Brown NP, Thornsberry C et al. Antimicrobial susceptibility pro-
files among common respiratory tract pathogens: a GLOBAL perspective.
Postgrad Med 2008; 120 Suppl 1: 16– 24.
2 File TM. Community-acquired pneumonia. Lancet 2003; 362: 1991–2001.
3 Guthrie R. Community-acquired lower respiratory tract infections: eti-
ology and treatment. Chest 2001; 120: 2021 –34.
4 Nicolau D. Clinical and economic implications of antimicrobial resistance
for the management of community-acquired respiratory tract infections.
J Antimicrob Chemother 2002; 50 Suppl 1: 61– 70.
5 Bhutta ZA. Burden of H. influenzae and S. pneumoniae infections in
Pakistan. J College Phys Surg Pakistan 2001; 10: 346–54.
i108
6 Bravo LC, Asian Strategic Alliance for Pneumococcal Disease Prevention
(ASAP) Working Group. Overview of the disease burden of invasive
pneumococcal disease in Asia. Vaccine 2009; 27: 7282– 9.
7 Rizvi SF, Khan MA, Kundi A et al. Status of rheumatic heart disease in
rural Pakistan. Heart 2004; 90: 394–9.
8 Zafar A, Hussain Z, Lomama E et al. Antibiotic susceptibility of pathogens
isolated from patients with community-acquired respiratory tract in-
fections in Pakistan—the active study. J Ayub Med Coll Abbottabad
2008; 20: 7 –9.
9 Pallares R, Fenoll A, Linares J et al. The epidemiology of antibiotic resist-
Downloaded from https://academic.oup.com/jac/article-abstract/71/suppl_1/i103/2488638 by guest on 16 June 2019
ance in Streptococcus pneumoniae and the clinical relevance of resistance
to cephalosporins, macrolides and quinolones. Int J Antimicrob Agents
2003; 22 Suppl 1: S15–24.
10 Beekmann SE, Heilmann KP, Richter SS et al. Antimicrobial resistance in
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis
and group A b-haemolytic streptococci in 2002 – 2003. Results of the
multinational GRASP Surveillance Program. Int J Antimicrob Agents
2005; 25: 148–56.
11 Jacobs MR, Felmingham D, Applebaum PC et al. The Alexander Project
1998 – 2000: susceptibility of pathogens isolated from community-
acquired respiratory tract infection to commonly used antimicrobial
agents. J Antimicrob Chemother 2003; 52: 229–46.
12 Felmingham D, Feldman C, Hryniewicz W et al. Surveillance of resist-
ance in bacteria causing community-acquired respiratory tract infections.
Clin Microbiol Infect 2002; 8 Suppl 2: 12–42.
13 Shibl AM, Daniels J, Sievers J, SOAR in AME Study Group. Antimicrobial
resistance among Streptococcus pneumoniae and Haemophilus influenzae
from Africa and the Middle East: 2002/2003. In: Abstracts of the Fourteenth
European Congress of Clinical Microbiology and Infectious Diseases, Prague,
2004. Clin Micro Infect 2004; 10 Suppl 3: 111. Poster data on file GSK-
2014N216848_00.2014.
14 Sievers J, SOAR Study Group. Antibacterial resistance among
Haemophilus influenzae from 8 countries in Africa and the Middle East:
results from the Survey of Antibiotic Resistance (SOAR) 2004 – 2006.
In: Abstracts of the Eightieth European Congress of Chemotherapy and
Infection, Budapest, 2006. Abstract 279.
15 Sievers J, SOAR Study Group. Antibacterial resistance among
Streptococcus pneumoniae from ten countries in Africa and the
Middle East: results from the Survey of Antibiotic Resistance (SOAR)
2004 – 2006. In: Abstracts of the Forty-sixth Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2006.
Abstract C2-0425.
16 Torumkuney-O’Brien D, SOAR Study Group. Antibacterial resistance
among Streptococcus pneumoniae, Haemophilus influenzae and
Streptococcus pyogenes from 9 countries in the Middle East and
Africa: results from the Survey of Antibiotic Resistance (SOAR) 2007–2009.
In: Abstracts of the Forty-ninth Interscience Conference on Antimicrobial
Agents and Chemotherapy, San Francisco, CA, 2009. Abstract C2-1402.
17 O’Callaghan CH, Morris A, Kirby SM et al. Novel method for detection
of b-lactamases by using a chromogenic cephalosporin substrate.
Antimicrob Agents Chemother 1972; 1: 283–8.
18 Clinical and Laboratory Standards Institute. Performance Standards for
Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement
M100-S15. CLSI, Wayne, PA, USA, 2005.
19 Clinical and Laboratory Standards Institute. Performance Standards for
Antimicrobial Susceptibility Testing: Fourteenth Informational Supplement
M100-S14. CLSI, Wayne, PA, USA, 2004.
20 Clinical and Laboratory Standards Institute. Performance Standards for
Antimicrobial Susceptibility Testing: Nineteenth Informational Supplement
M100-S19. PA, USA, 2009.
SOAR: Pakistan 2002 – 15
21 Clinical and Laboratory Standards Institute. Performance Standards
for Antimicrobial Susceptibility Testing: Twenty Fourth Informational
Supplement M100-S24. Wayne, PA, USA, 2014.
22 Clinical and Laboratory Standards Institute. Performance Standards for
Antimicrobial Disk Susceptibility Tests—Tenth Edition: Approved Standard
M2-A10. CLSI, Wayne, PA, USA, 2009.
23 Jacobs MR. Optimisation of antimicrobial therapy using pharmacoki-
netic and pharmacodynamic parameters. Clin Microbiol Infect 2001; 7:
589–96.
24 Shibl AM. Patterns of macrolide resistance determinants among
S. pyogenes and S. pneumoniae isolates in Saudi Arabia. J Int Med Res
2005; 33: 349–55.
JAC
25 Wang H, Chen M, Xu Y et al. Antimicrobial susceptibility of bacterial
pathogens associated with community-acquired respiratory tract infec-
tions in Asia: report from the Community-Acquired Respiratory Tract
Infection Pathogen Surveillance (CARTIPS) study, 2009 – 2010. Int J
Antimicrob Agents 2011; 38: 376–83.
26 Heffelfinger JD, Dowell SF, Jorgensen JH et al. Management of
community-acquired pneumonia in the era of pneumococcal resistance.
Arch Int Med 2000; 160: 1399–408.
27 Adam D, Scholz H, Helmerking M. Comparison of short-course (5 day)
cefuroxime axetil with a standard 10 day oral penicillin V regimen in the
Downloaded from https://academic.oup.com/jac/article-abstract/71/suppl_1/i103/2488638 by guest on 16 June 2019
treatment of tonsillopharyngitis. J Antimicrob Chemother 2000; 45
Suppl: 23–30.
i109