Results from the Survey of Antibiotic Resistance (SOAR) 2016–18 in Vietnam, Cambodia, Singapore and the Philippines: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints

Abstract

Objectives

To determine antibiotic susceptibility of Streptococcus pneumoniae and Haemophilus influenzae isolates collected from community-acquired respiratory tract infections (CA-RTIs) in 2016–18 in four Asian countries.

Methods

MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.

Results

In total, 260 S. pneumoniae and 258 H. influenzae isolates were tested. Pneumococci from Vietnam (n = 161) were the least susceptible, with rates of susceptibility >90% for fluoroquinolones by CLSI breakpoints, ∼60% for amoxicillin, amoxicillin/clavulanic acid and ceftriaxone but <14% for most other agents. Pneumococcal isolates from Cambodia (n = 48) and Singapore (n = 34) showed susceptibilities ranging from ∼30% for trimethoprim/sulfamethoxazole and oral penicillin to 100% for fluoroquinolones. Among isolates of H. influenzae from Cambodia (n = 30), the Philippines (n = 59) and Singapore (n = 80), rates of susceptibility using CLSI breakpoints were >90% for amoxicillin/clavulanic acid, cephalosporins [except cefaclor in Singapore (77.5%)], macrolides and fluoroquinolones; for isolates from Vietnam (n = 89) the rates of susceptibility were >85% only for amoxicillin/clavulanic acid (95.5%), ceftriaxone (100%) and macrolides (87.6%–89.9%). Susceptibility to other antibiotics ranged from 7.9% (trimethoprim/sulfamethoxazole) to 57.3%–59.6% (fluoroquinolones) and 70.8% (cefixime). The application of different EUCAST breakpoints for low and higher doses for some of the antibiotics (amoxicillin, amoxicillin/clavulanic acid, ampicillin, penicillin, ceftriaxone, clarithromycin, erythromycin, levofloxacin and trimethoprim/sulfamethoxazole) allowed, for the first time in a SOAR study, the effect of raising the dosage on susceptibility to be quantified. A limitation of the study was the small sample sizes and only one or two sites participating per country; however, since susceptibility data are scarce in some of the participating countries any information concerning antibiotic susceptibility is of value.

Conclusions

Antibiotic susceptibility varied across countries and species, with isolates from Vietnam demonstrating the lowest susceptibility. Knowledge of resistance patterns can be helpful for clinicians when choosing empirical therapy options for CA-RTIs.

Introduction

Globally, community-acquired respiratory tract infections (CA-RTIs) are a significant cause of morbidity and mortality, but the impact is especially serious in Asia-Pacific countries, where the high incidence of CA-RTIs combined with frequent poor access to healthcare results in a major clinical and economic burden.¹ As in other regions of the world, Streptococcus pneumoniae and Haemophilus influenzae are among the most prevalent aetiological agents of community-acquired pneumonia (CAP) in Asia-Pacific countries.¹ Isolates of these two species have shown higher resistance rates in Asia-Pacific countries than in other global regions.^2,3 Even within a global region, rates of resistance can vary substantially from country to country.³ Because therapy of CAP is typically empirical and a delay in appropriate antibiotic treatment has a negative impact on patient outcomes,^4,5 surveillance data at country level can provide useful information to guide local antibiotic prescribing policies.

The Survey of Antibiotic Resistance (SOAR) is an international antibiotic resistance surveillance study that focuses on key respiratory pathogens from community-acquired infections and has been running since 2002 in the Middle East, Africa, Latin America, Asia-Pacific and Commonwealth of Independent States countries. For this report, recent SOAR data from hospitals in Vietnam, Cambodia, Singapore and the Philippines were analysed to provide a picture of the current state of antibiotic susceptibility of S. pneumoniae and H. influenzae associated with CA-RTIs.

Materials and methods

Collaborating centres

The following five centres took part in the Asia-Pacific study: Nguyen Tri Phuong Hospital and Nhi Dong 1 Hospital, Vietnam (both in the southern part of the country); National Medical Microbiology Laboratory Network, Cambodia; Changi General Hospital, Singapore; St Luke’s Medical Center Quezon City; and Bonifacio Global City, Philippines.

Clinical isolates

Isolates of H. influenzae and S. pneumoniae from CA-RTIs (patients with respiratory tract infections in the community, not hospitalized for more than 48 h) were sent to a central laboratory (LGC, Fordham, UK) in transport swabs, where they were subcultured and re-identified, with the exception of the Vietnamese isolates, which were subcultured and re-identified at IHMA Europe (Monthey, Switzerland). H. influenzae isolates were re-identified by MALDI-TOF MS methodology and S. pneumoniae identity was confirmed by optochin susceptibility and bile solubility. β-Lactamase production was determined for each H. influenzae isolate by a chromogenic cephalosporin (nitrocefin) disc method. Duplicate isolates from the same patient were not accepted.

Susceptibility testing

Isolates were evaluated for antibiotic susceptibility using broth microdilution methodology recommended by CLSI.⁶ Both pathogens were assessed for susceptibility to amoxicillin, amoxicillin/clavulanic acid (2:1), ampicillin, azithromycin, cefaclor, cefdinir, cefditoren, cefixime, cefpodoxime, ceftriaxone, cefuroxime, clarithromycin, levofloxacin, moxifloxacin and trimethoprim/sulfamethoxazole (1:19). S. pneumoniae was also tested for susceptibility to penicillin and erythromycin.

Susceptibility to the study drugs was calculated based on CLSI breakpoints, EUCAST (dose-specific) breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.^7–9 These breakpoints are shown in Tables 1–3. To fully assess antibiotic agents where high-dose therapies are available, susceptibility using EUCAST criteria was calculated by combining percentage susceptible and percentage intermediate (susceptible, increased exposure) into the susceptible category.⁸ The antibiotic agents with high dose availability assessed in this way were as follows: amoxicillin (0.75–1 g oral, 3 × daily), amoxicillin/clavulanic acid (0.875 g amoxicillin/0.125 g clavulanic acid oral, 3 × daily), ampicillin (2 g IV, 4 × daily), penicillin (2.4 g IV, 2 MU 4–6 × daily), ceftriaxone (2 g IV, 2 × daily), clarithromycin (0.5 g oral, 2 × daily), erythromycin (1 g oral or IV, 4 × daily), levofloxacin (0.75 g oral, 2 × daily; or 0.4 g IV, 3 × daily) and trimethoprim/sulfamethoxazole (0.24 g trimethoprim/1.2 g sulfamethoxazole oral or IV, 2 × daily).⁸

Table 1.

CLSI MIC breakpoints (mg/L) used for S. pneumoniae and H. influenzae isolates

	S. pneumoniae			H. influenzae
Antibiotic	S	I	R	S	I	R
Amoxicillin	≤2	4	≥8	–	–	–
Amoxicillin/clavulanic acida	≤2	4	≥8	≤4	–	≥8
Ampicillin	–	–	–	≤1	2	≥4
Penicillin (2.4 g 2 MU × 4–6 IV)	≤2	4	≥8	–	–	–
Penicillin (oral)	≤0.06	0.12–1	≥2	–	–	–
Cefaclor	≤1	2	≥4	≤8	16	≥32
Cefdinir	≤0.5	1	≥2	≤1	–	–
Cefditoren	–	–	–	–	–	–
Cefixime	–	–	–	≤1	–	–
Cefpodoxime	≤0.5	1	≥2	≤2	–	–
Ceftriaxone	≤1	2	≥4	≤2	–	–
Cefuroximeb	≤1	2	≥4	≤4	8	≥16
Azithromycin	≤0.5	1	≥2	≤4	–	–
Clarithromycin	≤0.25	0.5	≥1	≤8	16	≥32
Erythromycin	≤0.25	0.5	≥1	–	–	–
Levofloxacin	≤2	4	≥8	≤2	–	–
Moxifloxacin	≤1	2	≥4	≤1	–	–
Trimethoprim/ sulfamethoxazolec	≤0.5	1–2	≥4	≤0.5	1–2	≥4

S, susceptible; I, intermediate; R, resistant; –, not applicable.

a

Amoxicillin/clavulanic acid was tested at a 2:1 amoxicillin to clavulanic acid ratio; breakpoints are expressed as the amoxicillin component.

b

Breakpoints used are for cefuroxime axetil (oral).

c

Trimethoprim/sulfamethoxazole was tested at a 1:19 trimethoprim to sulfamethoxazole ratio; breakpoints are expressed as the trimethoprim component.

Table 2.

EUCAST MIC breakpoints (mg/L) used for S. pneumoniae and H. influenzae isolates

	S. pneumoniae		H. influenzae
Antibiotic	S	R	S	R
Amoxicillin (0.5 g × 3 oral)	≤0.5	>1	–	–
Amoxicillin (0.75–1 g × 3 oral)	≤1	>1	≤2	>2
Amoxicillin/clavulanic acida (0.5 g/0.125 g × 3 oral)	≤0.5	>1	–	–
Amoxicillin/clavulanic acida (0.875 g/0.125 g × 3 oral)	≤1	>1	≤2	>2
Ampicillin (2 g × 3 IV)	≤0.5	>2	≤1	>1
Ampicillin (2 g × 4 IV)	≤2	>2	≤1	>1
Penicillin (0.6 g 1 MU × 4 IV)	≤0.06	>2	–	–
Penicillin (2.4 g 2 MU × 4–6 IV)	≤2	>2	–	–
Cefaclor	≤0.03	>0.5	–	–
Cefdinir	–	–	–	–
Cefditoren	–	–	–	–
Cefixime	–	–	≤0.12	>0.12
Cefpodoxime	≤0.25	>0.5	≤0.25	>0.25
Ceftriaxone (1 g × 1 IV)	≤0.5	>2	≤0.12	>0.12
Ceftriaxone (2 g × 2 IV)	≤2	>2	≤0.12	>0.12
Cefuroximeb	≤0.25	>0.5	≤0.12	>1
Azithromycin	≤0.25	>0.5	–	–
Clarithromycin (0.25 g × 2 oral)	≤0.25	>0.5	–	–
Clarithromycin (0.5 g × 2 oral)	≤0.5	>0.5	–	–
Erythromycin (0.5 g × 2–4 oral or 0.5 g × 2–4 IV)	≤0.25	>0.5	–	–
Erythromycin (1 g × 4 oral or 1 g × 4 IV)	≤0.5	>0.5	–	–
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	≤2	>2	≤0.06	>0.06
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	≤2	>2	≤0.06	>0.06
Moxifloxacin	≤0.5	>0.5	≤0.12	>0.12
Trimethoprim/sulfamethoxazolec (0.16 g/0.8 g × 2 oral or IV)	≤1	>2	≤0.5	>1
Trimethoprim/sulfamethoxazolec (0.24 g/1.2 g × 2 oral or IV)	≤2	>2	≤1	>1

The I category is not listed but is interpreted as the values between the S and the R breakpoints. If the S and R breakpoints are the same value there is no I category.⁸ S, susceptible; R, resistant; –, not applicable.

a

Amoxicillin/clavulanic acid was tested at a 2:1 amoxicillin to clavulanic acid ratio; breakpoints are expressed as the amoxicillin component.

b

Breakpoints used are for cefuroxime axetil (oral).

c

Trimethoprim/sulfamethoxazole was tested at a 1:19 trimethoprim to sulfamethoxazole ratio; breakpoints are expressed as the trimethoprim component.

Table 3.

PK/PD MIC breakpoints (mg/L) used for S. pneumoniae and H. influenzae isolates

	S. pneumoniae and H. influenzae
Antibiotic	S only
Amoxicillin (1.5 g/day)	≤2
Amoxicillin (4 g/day)	≤4
Amoxicillin/clavulanic acida (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	≤2
Amoxicillin/clavulanic acidb (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	≤4
Ampicillin	–
Penicillin	–
Cefaclor	≤0.5
Cefdinir	≤0.25
Cefditoren	–
Cefixime	≤1
Cefpodoxime	≤0.5
Ceftriaxone	≤1
Cefuroximec	≤1
Azithromycin	≤0.12
Clarithromycin	≤0.25
Erythromycin	≤0.25
Levofloxacin	≤2
Moxifloxacin	≤1
Trimethoprim/sulfamethoxazoled	≤0.5

S, susceptible; –, not applicable.

a

Amoxicillin/clavulanic acid low dose for adults/children.

b

Amoxicillin/clavulanic acid high dose for adults/children.

c

Breakpoints used are for cefuroxime axetil (oral).

d

Trimethoprim/sulfamethoxazole was tested at a 1:19 trimethoprim to sulfamethoxazole ratio; breakpoints are expressed as the trimethoprim component.

Quality control and data analysis

Quality control strains S. pneumoniae ATCC 49619, Escherichia coli ATCC 25922, H. influenzae ATCC 49247, H. influenzae ATCC 49766 and E. coli ATCC 35218 were included on each day of testing. Results of susceptibility testing were accepted if the results for the control strains were within published limits. Differences in susceptibility (using CLSI criteria only) across countries and penicillin susceptibility (S. pneumoniae only) were assessed for statistical significance with Fisher’s exact test using XLSTAT version 2019.1.3.57796. A P value <0.05 was considered statistically significant.

Ethics

SOAR studies are not human subject studies. During the study, only microorganisms were tested.

Results

S. pneumoniae isolates

A total of 260 S. pneumoniae isolates were collected during 2016–18 from five centres in Vietnam, Cambodia, Singapore and the Philippines. These included 161 from Vietnam, 48 from Cambodia, 34 from Singapore and 17 from the Philippines.

Most pneumococci came from blood (n = 107; 41.2%), sputum (n = 64; 24.6%) and nasotracheal aspirate (n = 42; 16.2%). Less frequently, isolates were from transtracheal aspirate (n = 13; 5%), sinuses (n = 12; 4.6%), middle ear effusion (n = 9; 3.5%), bronchoalveolar lavage (n = 8; 3.1%) and endotracheal aspirate (n = 5; 1.9%). Most isolates (n = 132; 50.8%) came from paediatric patients (≤12 years), 76 (29.2%) were from adults (aged 13–64), 51 (19.6%) were from elderly patients (aged ≥65 years), and for 1 isolate the age of the patient was not specified.

Summary MIC and susceptibility data for all 260 S. pneumoniae isolates are shown in Tables 4–15 and Figures 1–3. MIC distribution data are shown in Tables S1–S4 (available as Supplementary data at JAC Online).

Figure 1.

Percentage susceptibility rates (with 95% CI) based on CLSI breakpoints for antibiotics against all S. pneumoniae isolates collected in the four Asia-Pacific countries in the period 2016–18. ^aSusceptibility was significantly higher among isolates from Cambodia and the Philippines than Vietnam and from the Philippines than Singapore (P < 0.05). ^bSusceptibility was significantly higher among isolates from the Philippines than the other countries and from Cambodia and Singapore than Vietnam (P < 0.05). ^cSusceptibility was significantly higher among isolates from Cambodia, the Philippines and Singapore than Vietnam (P < 0.05). ^dSusceptibility was significantly higher among isolates from Cambodia than Vietnam (P < 0.05).

Figure 2.

Percentage susceptibility rates based on EUCAST (dose-specific) breakpoints for antibiotics against all S. pneumoniae isolates collected in the four Asia-Pacific countries in the period 2016–18.

Figure 3.

Percentage susceptibility rates based on PK/PD breakpoints for antibiotics against all S. pneumoniae isolates collected in the four Asia-Pacific countries in the period 2016–18. Low-dose amoxicillin/clavulanic acid = 1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children. High-dose amoxicillin/clavulanic acid = 4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children.

Table 4.

MIC and susceptibility data for S. pneumoniae isolates (n = 161) from Vietnam using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	2	8	0.03	16	60.3	11.8	28.0
Amoxicillin/ clavulanic acid	2	8	≤0.015	16	59.6	12.4	28.0
Penicillin (2.4 g 2 MU × 4–6 IV)	2	4	≤0.03	8	69.6	25.4	5.0
Penicillin (oral)	2	4	≤0.03	8	1.2	23.6	75.2
Cefaclor	>32	>32	0.25	>32	3.1	3.7	93.2
Cefdinir	8	16	0.06	>16	9.3	5.6	85.1
Cefditoren	1	2	≤0.015	8	–	–	–
Cefixime	16	64	0.25	>64	–	–	–
Cefpodoxime	8	>16	≤0.015	>16	5.6	1.2	93.2
Ceftriaxone	1	4	0.03	8	62.1	27.3	10.6
Cefuroxime	4	16	0.03	>16	13.7	12.4	73.9
Azithromycin	>32	>32	≤0.03	>32	4.4	1.9	93.8
Clarithromycin	>16	>16	≤0.015	>16	2.5	1.2	96.3
Erythromycin	>16	>16	≤0.015	>16	1.9	2.5	95.7
Levofloxacin	1	2	0.5	64	90.1	1.9	8.1
Moxifloxacin	0.12	0.25	0.06	16	93.2	4.4	2.5
Trimethoprim/ sulfamethoxazole	4	16	0.12	>32	13.0	8.7	78.3

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 5.

MIC and susceptibility data for S. pneumoniae isolates (n = 161) from Vietnam using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.5 g × 3 oral)	2	8	0.03	16	13.0	11.2	75.8
Amoxicillin (0.75–1 g × 3 oral)	2	8	0.03	16	24.2	–	75.8
Amoxicillin/clavulanic acid (0.5 g/0.125 g × 3 oral)	2	8	≤0.015	16	12.4	13.7	73.9
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	2	8	≤0.015	16	26.1	–	73.9
Ampicillin (2 g × 3 IV)	4	8	≤0.03	16	9.3	19.3	71.4
Ampicillin (2 g × 4 IV)	4	8	≤0.03	16	28.6	–	71.4
Penicillin (0.6 g 1 MU × 4 IV)	2	4	≤0.03	8	1.2	68.3	30.4
Penicillin (2.4 g 2 MU × 4–6 IV)	2	4	≤0.03	8	69.6	–	30.4
Cefaclor	>32	>32	0.25	>32	0.0	2.5	97.5
Cefdinir	8	16	0.06	>16	–	–	–
Cefditoren	1	2	≤0.015	8	–	–	–
Cefixime	16	64	0.25	>64	–	–	–
Cefpodoxime	8	>16	≤0.015	>16	2.5	3.1	94.4
Ceftriaxone (1 g × 1 IV)	1	4	0.03	8	30.4	59.0	10.6
Ceftriaxone (2 g × 2 IV)	1	4	0.03	8	89.4	–	10.6
Cefuroxime	4	16	0.03	>16	4.4	4.4	91.3
Azithromycin	>32	>32	≤0.03	>32	3.7	0.6	95.7
Clarithromycin (0.25 g × 2 oral)	>16	>16	≤0.015	>16	2.5	1.2	96.3
Clarithromycin (0.5 g × 2 oral)	>16	>16	≤0.015	>16	3.7	–	96.3
Erythromycin (0.5 g × 2–4 oral or × 2–4 IV)	>16	>16	≤0.015	>16	1.9	2.5	95.7
Erythromycin (1 g × 4 oral or × 4 IV)	>16	>16	≤0.015	>16	4.3	–	95.7
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	1	2	0.5	64	90.1	–	9.9
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	1	2	0.5	64	90.1	–	9.9
Moxifloxacin	0.12	0.25	0.06	16	91.9	–	8.1
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	4	16	0.12	>32	16.8	5.0	78.3
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	4	16	0.12	>32	21.7	–	78.3

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 6.

MIC and susceptibility data for S. pneumoniae isolates (n = 161) from Vietnam using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	2	8	0.03	16	60.3
Amoxicillin (4 g/day)	2	8	0.03	16	72.1
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	2	8	≤0.015	16	59.6
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	2	8	≤0.015	16	72.1
Ampicillin	4	8	≤0.03	16	–
Penicillin	2	4	≤0.03	8	–
Cefaclor	>32	>32	0.25	>32	2.5
Cefdinir	8	16	0.06	>16	6.8
Cefditoren	1	2	≤0.015	8	–
Cefixime	16	64	0.25	>64	5.6
Cefpodoxime	8	>16	≤0.015	>16	5.6
Ceftriaxone	1	4	0.03	8	62.1
Cefuroxime	4	16	0.03	>16	13.7
Azithromycin	>32	>32	≤0.03	>32	2.5
Clarithromycin	>16	>16	≤0.015	>16	2.5
Erythromycin	>16	>16	≤0.015	>16	1.9
Levofloxacin	1	2	0.5	64	90.1
Moxifloxacin	0.12	0.25	0.06	16	93.2
Trimethoprim/sulfamethoxazole	4	16	0.12	>32	13.0

min, minimum; max, maximum; S, susceptible; –, not applicable.

Table 7.

MIC and susceptibility data for S. pneumoniae isolates (n = 48) from Cambodia using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	0.5	4	≤0.015	8	89.6	4.2	6.3
Amoxicillin/clavulanic acid	0.25	4	≤0.015	8	89.6	4.2	6.3
Penicillin (2.4 g 2 MU × 4–6 IV)	0.25	2	≤0.06	4	91.7	8.3	0.0
Penicillin (oral)	0.25	2	≤0.06	4	29.2	47.9	22.9
Cefaclor	2	>32	0.06	>32	37.5	12.5	50.0
Cefdinir	0.25	8	≤0.015	16	58.3	2.1	39.6
Cefditoren	0.12	1	≤0.015	2	–	–	–
Cefixime	2	32	≤0.06	64	–	–	–
Cefpodoxime	0.25	4	≤0.015	8	62.5	8.3	29.2
Ceftriaxone	0.12	1	≤0.015	2	95.8	4.2	0.0
Cefuroxime	0.5	16	≤0.015	>16	56.3	2.1	41.7
Azithromycin	0.12	>32	≤0.03	>32	50.0	6.3	43.8
Clarithromycin	0.06	>16	≤0.015	>16	50.0	4.2	45.8
Erythromycin	0.06	>16	≤0.015	>16	50.0	2.1	47.9
Levofloxacin	1	1	0.5	2	100	0.0	0.0
Moxifloxacin	0.12	0.12	≤0.03	0.12	100	0.0	0.0
Trimethoprim/sulfamethoxazole	2	8	0.06	16	29.2	27.1	43.8

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 8.

MIC and susceptibility data for S. pneumoniae isolates (n = 48) from Cambodia using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.5 g × 3 oral)	0.5	4	≤0.015	8	62.5	10.4	27.1
Amoxicillin (0.75–1 g × 3 oral)	0.5	4	≤0.015	8	72.9	–	27.1
Amoxicillin/clavulanic acid (0. 5 g/0.125 g × 3 oral)	0.25	4	≤0.015	8	62.5	14.6	22.9
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	0.25	4	≤0.015	8	77.1	–	22.9
Ampicillin (2 g × 3 IV)	0.5	4	≤0.03	8	52.1	25.0	22.9
Ampicillin (2 g × 4 IV)	0.5	4	≤0.03	8	77.1	–	22.9
Penicillin (0.6 g 1 MU × 4 IV)	0.25	2	≤0.06	4	29.2	62.5	8.3
Penicillin (2.4 g 2 MU × 4–6 IV)	0.25	2	≤0.06	4	91.7	–	8.3
Cefaclor	2	>32	0.06	>32	0.0	22.9	77.1
Cefdinir	0.25	8	≤0.015	16	–	–	–
Cefditoren	0.12	1	≤0.015	2	–	–	–
Cefixime	2	32	≤0.06	64	–	–	–
Cefpodoxime	0.25	4	≤0.015	8	52.1	10.4	37.5
Ceftriaxone (1 g × 1 IV)	0.12	1	≤0.015	2	77.1	22.9	0.0
Ceftriaxone (2 g × 2 IV)	0.12	1	≤0.015	2	100	–	0.0
Cefuroxime	0.5	16	≤0.015	>16	41.7	12.5	45.8
Azithromycin	0.12	>32	≤0.03	>32	50.0	0.0	50.0
Clarithromycin (0.25 g × 2 oral)	0.06	>16	≤0.015	>16	50.0	4.2	45.8
Clarithromycin (0.5 g × 2 oral)	0.06	>16	≤0.015	>16	54.2	–	45.8
Erythromycin (0.5 g × 2–4 oral or × 2–4 IV)	0.06	>16	≤0.015	>16	50.0	2.1	47.9
Erythromycin (1 g × 4 oral or × 4 IV)	0.06	>16	≤0.015	>16	52.1	–	47.9
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	1	1	0.5	2	100	–	0.0
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	1	1	0.5	2	100	–	0.0
Moxifloxacin	0.12	0.12	≤0.03	0.12	100	–	0.0
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	2	8	0.06	16	47.9	8.3	43.8
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	2	8	0.06	16	56.2	–	43.8

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 9.

MIC and susceptibility data for S. pneumoniae isolates (n = 48) from Cambodia using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	0.5	4	≤0.015	8	89.6
Amoxicillin (4 g/day)	0.5	4	≤0.015	8	93.8
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	0.25	4	≤0.015	8	89.6
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	0.25	4	≤0.015	8	93.8
Ampicillin	0.5	4	≤0.03	8	–
Penicillin	0.25	2	≤0.06	4	–
Cefaclor	2	>32	0.06	>32	22.9
Cefdinir	0.25	8	≤0.015	16	50.0
Cefditoren	0.12	1	≤0.015	2	–
Cefixime	2	32	≤0.06	64	45.8
Cefpodoxime	0.25	4	≤0.015	8	62.5
Ceftriaxone	0.12	1	≤0.015	2	95.8
Cefuroxime	0.5	16	≤0.015	>16	56.3
Azithromycin	0.12	>32	≤0.03	>32	50.0
Clarithromycin	0.06	>16	≤0.015	>16	50.0
Erythromycin	0.06	>16	≤0.015	>16	50.0
Levofloxacin	1	1	0.5	2	100
Moxifloxacin	0.12	0.12	≤0.03	0.12	100
Trimethoprim/sulfamethoxazole	2	8	0.06	16	29.2

min, minimum; max, maximum; S, susceptible; –, not applicable.

Table 10.

MIC and susceptibility data for S. pneumoniae isolates (n = 34) from Singapore using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	0.25	8	≤0.015	16	76.5	5.9	17.7
Amoxicillin/clavulanic acid	0.25	8	≤0.015	16	76.5	5.9	17.7
Penicillin (2.4 g 2 MU × 4–6 IV)	0.25	4	≤0.06	>4	82.4	11.8	5.9
Penicillin (oral)	0.25	4	≤0.06	>4	29.4	35.3	35.3
Cefaclor	8	>32	0.25	>32	32.4	8.8	58.8
Cefdinir	0.5	16	0.03	>16	50.0	2.9	47.1
Cefditoren	0.12	2	≤0.015	2	–	–	–
Cefixime	4	>64	≤0.06	>64	–	–	–
Cefpodoxime	0.5	16	≤0.015	>16	55.9	2.9	41.2
Ceftriaxone	0.25	4	≤0.015	4	82.4	5.9	11.8
Cefuroxime	0.5	>16	≤0.015	>16	55.9	2.9	41.2
Azithromycin	8	>32	≤0.03	>32	29.4	2.9	67.7
Clarithromycin	2	>16	≤0.015	>16	29.4	2.9	67.7
Erythromycin	4	>16	≤0.015	>16	29.4	0.0	70.6
Levofloxacin	1	1	0.5	1	100	0.0	0.0
Moxifloxacin	0.12	0.25	≤0.03	0.25	100	0.0	0.0
Trimethoprim/sulfamethoxazole	2	16	0.06	>32	38.2	14.7	47.1

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 11.

MIC and susceptibility data for S. pneumoniae isolates (n = 34) from Singapore using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.5 g × 3 oral)	0.25	8	≤0.015	16	55.9	5.9	38.2
Amoxicillin (0.75–1 g × 3 oral)	0.25	8	≤0.015	16	61.8	–	38.2
Amoxicillin/clavulanic acid (0. 5 g/0.125 g × 3 oral)	0.25	8	≤0.015	16	55.9	11.8	32.4
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	0.25	8	≤0.015	16	67.6	–	32.4
Ampicillin (2 g × 3 IV)	0.5	8	≤0.03	16	52.9	14.7	32.4
Ampicillin (2 g × 4 IV)	0.5	8	≤0.03	16	67.6	–	32.4
Penicillin (0.6 g 1 MU × 4 IV)	0.25	4	≤0.06	>4	29.4	52.9	17.6
Penicillin (2.4 g 2 MU × 4–6 IV)	0.25	4	≤0.06	>4	82.4	–	17.6
Cefaclor	8	>32	0.25	>32	0.0	17.7	82.4
Cefdinir	0.5	16	0.03	>16	–	–	–
Cefditoren	0.12	2	≤0.015	2	–	–	–
Cefixime	4	>64	≤0.06	>64	–	–	–
Cefpodoxime	0.5	16	≤0.015	>16	44.1	11.8	44.1
Ceftriaxone (1 g × 1 IV)	0.25	4	≤0.015	4	61.8	26.5	11.8
Ceftriaxone (2 g × 2 IV)	0.25	4	≤0.015	4	88.2	–	11.8
Cefuroxime	0.5	>16	≤0.015	>16	41.2	11.8	47.1
Azithromycin	8	>32	≤0.03	>32	29.4	0.0	70.6
Clarithromycin (0.25 g × 2 oral)	2	>16	≤0.015	>16	29.4	2.9	67.7
Clarithromycin (0.5 g × 2 oral)	2	>16	≤0.015	>16	32.3	–	67.7
Erythromycin (0.5 g × 2–4 oral or × 2–4 IV)	4	>16	≤0.015	>16	29.4	0.0	70.6
Erythromycin (1 g × 4 oral or × 4 IV)	4	>16	≤0.015	>16	29.4	–	70.6
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	1	1	0.5	1	100	–	0.0
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	1	1	0.5	1	100	–	0.0
Moxifloxacin	0.12	0.25	≤0.03	0.25	100	–	0.0
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	2	16	0.06	>32	47.1	5.9	47.1
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	2	16	0.06	>32	52.9	–	47.1

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 12.

MIC and susceptibility data for S. pneumoniae isolates (n = 34) from Singapore using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	0.25	8	≤0.015	16	76.5
Amoxicillin (4 g/day)	0.25	8	≤0.015	16	82.4
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	0.25	8	≤0.015	16	76.5
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	0.25	8	≤0.015	16	82.4
Ampicillin	0.5	8	≤0.03	16	–
Penicillin	0.25	4	≤0.06	>4	–
Cefaclor	8	>32	0.25	>32	17.7
Cefdinir	0.5	16	0.03	>16	41.2
Cefditoren	0.12	2	≤0.015	2	–
Cefixime	4	>64	≤0.06	>64	32.4
Cefpodoxime	0.5	16	≤0.015	>16	55.9
Ceftriaxone	0.25	4	≤0.015	4	82.4
Cefuroxime	0.5	>16	≤0.015	>16	55.9
Azithromycin	8	>32	≤0.03	>32	29.4
Clarithromycin	2	>16	≤0.015	>16	29.4
Erythromycin	4	>16	≤0.015	>16	29.4
Levofloxacin	1	1	0.5	1	100
Moxifloxacin	0.12	0.25	≤0.03	0.25	100
Trimethoprim/sulfamethoxazole	2	16	0.06	>32	38.2

min, minimum; max, maximum; S, susceptible; –, not applicable.

Table 13.

MIC and susceptibility data for S. pneumoniae isolates (n = 17) from the Philippines using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	≤0.015	0.03	≤0.015	0.25	100	0.0	0.0
Amoxicillin/clavulanic acid	≤0.015	0.03	≤0.015	0.25	100	0.0	0.0
Penicillin (2.4 g 2 MU × 4–6 IV)	≤0.06	≤0.06	≤0.06	0.12	100	0.0	0.0
Penicillin (oral)	≤0.06	≤0.06	≤0.06	0.12	94.1	5.9	0.0
Cefaclor	0.5	1	0.5	2	94.1	5.9	0.0
Cefdinir	0.06	0.12	0.06	0.25	100	0.0	0.0
Cefditoren	≤0.015	≤0.015	≤0.015	0.03	–	–	–
Cefixime	0.25	0.25	0.12	0.5	–	–	–
Cefpodoxime	0.03	0.03	≤0.015	0.06	100	0.0	0.0
Ceftriaxone	≤0.015	0.03	≤0.015	0.06	100	0.0	0.0
Cefuroxime	0.03	0.25	≤0.015	0.25	100	0.0	0.0
Azithromycin	0.06	0.06	≤0.03	0.25	100	0.0	0.0
Clarithromycin	≤0.015	0.03	≤0.015	0.03	100	0.0	0.0
Erythromycin	0.03	0.03	≤0.015	0.06	100	0.0	0.0
Levofloxacin	1	1	1	2	100	0.0	0.0
Moxifloxacin	0.25	0.25	0.12	0.25	100	0.0	0.0
Trimethoprim/sulfamethoxazole	0.25	1	0.06	1	88.2	11.8	0.0

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 14.

MIC and susceptibility data for S. pneumoniae isolates (n = 17) from the Philippines using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.5 g × 3 oral)	≤0.015	0.03	≤0.015	0.25	100	0.0	0.0
Amoxicillin (0.75–1 g × 3 oral)	≤0.015	0.03	≤0.015	0.25	100	–	0.0
Amoxicillin/clavulanic acid (0.5 g/0.125 g × 3 oral)	≤0.015	0.03	≤0.015	0.25	100	0.0	0.0
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	≤0.015	0.03	≤0.015	0.25	100	–	0.0
Ampicillin (2 g × 3 IV)	≤0.03	≤0.03	≤0.03	0.25	100	0.0	0.0
Ampicillin (2 g × 4 IV)	≤0.03	≤0.03	≤0.03	0.25	100	–	0.0
Penicillin (0.6 g 1 MU × 4 IV)	≤0.06	≤0.06	≤0.06	0.12	94.1	5.9	0.0
Penicillin (2.4 g 2 MU × 4–6 IV)	≤0.06	≤0.06	≤0.06	0.12	100	–	0.0
Cefaclor	0.5	1	0.5	2	0.0	64.7	35.3
Cefdinir	0.06	0.12	0.06	0.25	–	–	–
Cefditoren	≤0.015	≤0.015	≤0.015	0.03	–	–	–
Cefixime	0.25	0.25	0.12	0.5	–	–	–
Cefpodoxime	0.03	0.03	≤0.015	0.06	100	0.0	0.0
Ceftriaxone (1 g × 1 IV)	≤0.015	0.03	≤0.015	0.06	100	0.0	0.0
Ceftriaxone (2 g × 2 IV)	≤0.015	0.03	≤0.015	0.06	100	0.0	0.0
Cefuroxime	0.03	0.25	≤0.015	0.25	100	0.0	0.0
Azithromycin	0.06	0.06	≤0.03	0.25	100	0.0	0.0
Clarithromycin (0.25 g × 2 oral)	≤0.015	0.03	≤0.015	0.03	100	0.0	0.0
Clarithromycin (0.5 g × 2 oral)	≤0.015	0.03	≤0.015	0.03	100	–	0.0
Erythromycin (0.5 g × 2–4 oral or × 2–4 IV)	0.03	0.03	≤0.015	0.06	100	0.0	0.0
Erythromycin (1 g × 4 oral or × 4 IV)	0.03	0.03	≤0.015	0.06	100	–	0.0
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	1	1	1	2	100	–	0.0
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	1	1	1	2	100	–	0.0
Moxifloxacin	0.25	0.25	0.12	0.25	100	–	0.0
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	0.25	1	0.06	1	100	0.0	0.0
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	0.25	1	0.06	1	100	–	0.0

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 15.

MIC and susceptibility data for S. pneumoniae isolates (n = 17) from the Philippines using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	≤0.015	0.03	≤0.015	0.25	100
Amoxicillin (4 g/day)	≤0.015	0.03	≤0.015	0.25	100
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	≤0.015	0.03	≤0.015	0.25	100
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	≤0.015	0.03	≤0.015	0.25	100
Ampicillin	≤0.03	≤0.03	≤0.03	0.25	–
Penicillin	≤0.06	≤0.06	≤0.06	0.12	–
Cefaclor	0.5	1	0.5	2	64.7
Cefdinir	0.06	0.12	0.06	0.25	100
Cefditoren	≤0.015	≤0.015	≤0.015	0.03	–
Cefixime	0.25	0.25	0.12	0.5	100
Cefpodoxime	0.03	0.03	≤0.015	0.06	100
Ceftriaxone	≤0.015	0.03	≤0.015	0.06	100
Cefuroxime	0.03	0.25	≤0.015	0.25	100
Azithromycin	0.06	0.06	≤0.03	0.25	94.1
Clarithromycin	≤0.015	0.03	≤0.015	0.03	100
Erythromycin	0.03	0.03	≤0.015	0.06	100
Levofloxacin	1	1	1	2	100
Moxifloxacin	0.25	0.25	0.12	0.25	100
Trimethoprim/sulfamethoxazole	0.25	1	0.06	1	88.2

min, minimum; max, maximum; S, susceptible; –, not applicable.

S. pneumoniae susceptibility in Vietnam

A total of 161 pneumococcal isolates were collected from Vietnam. Most isolates were from paediatric patients (≤12 years). Levofloxacin and moxifloxacin were the only agents for which the rate of susceptibility exceeded 90% (90.1%–93.2% susceptible by all breakpoints). Susceptibility to ceftriaxone was 89.4% by the EUCAST high-dose breakpoint but reduced to 62.1% by CLSI and PK/PD criteria and 30.4% by the EUCAST low-dose breakpoint. Susceptibility to penicillin IV was 69.6% by CLSI and high-dose EUCAST criteria (but only 1.2% for penicillin using CLSI oral and EUCAST low-dose IV breakpoints). Amoxicillin and amoxicillin/clavulanic acid showed activity against 59.6%–60.3% of isolates by CLSI and PK/PD (low-dose) criteria and 12.4% (low-dose), and 26.1% (high-dose) using EUCAST breakpoints. By PK/PD (high-dose) criteria, 72.1% of S. pneumoniae isolates were susceptible to amoxicillin and amoxicillin/clavulanic acid. All other agents were active against ≤28.6% of isolates by all breakpoints (Tables 4–6, Figures 1–3).

S. pneumoniae susceptibility in Cambodia

Of the 48 pneumococci collected in Cambodia, all isolates were susceptible to levofloxacin and moxifloxacin by all breakpoints; 95.8%–100% were susceptible to ceftriaxone by CLSI, PK/PD and EUCAST high-dose breakpoints, with 77.1% showing reduced susceptibility when EUCAST low-dose criteria were applied. Other agents with activity of ∼90% were: penicillin IV using CLSI breakpoints or EUCAST high-dose criteria (91.7%, but with reduced susceptibility for oral penicillin of 29.2% using CLSI and EUCAST low-dose IV criteria); and amoxicillin and amoxicillin/clavulanic acid using CLSI or low-dose PK/PD breakpoints (89.6%) and using high-dose PK/PD breakpoints (93.8%), again with lower susceptibility using EUCAST breakpoints (62.5% low dose and 77.1% high dose). Susceptibility to all other agents was seen in <63% of isolates, including the macrolides (∼50% using all breakpoints), cefpodoxime (62.5% by CLSI and PK/PD criteria and 52.1% by EUCAST breakpoints) and oral cefuroxime (56.3% by CLSI and PK/PD criteria and 41.7% by EUCAST breakpoints). Low susceptibility was observed for trimethoprim/sulfamethoxazole (29.2% by CLSI and PK/PD criteria, 47.9% by EUCAST low-dose breakpoints and 56.2% by EUCAST high-dose breakpoints). The largest difference between rates of susceptibility found using different breakpoints was observed for cefaclor, with 37.5% and 0% of isolates categorized as susceptible using CLSI and EUCAST breakpoints, respectively (Tables 7–9, Figures 1–3).

S. pneumoniae susceptibility in Singapore

A total of 34 pneumococci were collected from Singapore, all of which were susceptible to levofloxacin and moxifloxacin by all breakpoints. Of the remaining antibiotics tested, only amoxicillin, amoxicillin/clavulanic acid, ceftriaxone and penicillin IV exceeded 75% susceptibility based on CLSI breakpoints, but this was not universal for all breakpoint criteria. Susceptibility of isolates to amoxicillin and amoxicillin/clavulanic acid was 82.4% by high-dose PK/PD criteria (which reduced to 76.5% by low-dose PK/PD and CLSI breakpoints, and 55.9%–67.6% by EUCAST low-dose and high-dose criteria). Susceptibility to ceftriaxone was 82.4%–88.2% by CLSI, PK/PD and EUCAST high-dose breakpoints, but reduced to 61.8% when EUCAST low-dose criteria were applied. For penicillin, around 82% of isolates were susceptible using CLSI IV and EUCAST high-dose breakpoints, but only 29.4% by CLSI oral and EUCAST low-dose IV breakpoints. Low susceptibility (29.4%–32.3%) was also observed for the macrolides using all available breakpoints. Susceptibility to cefaclor was 17.7% by PK/PD and 0% by EUCAST criteria. By PK/PD criteria, only 32.4% of S. pneumoniae isolates were susceptible to cefixime (Tables 10–12, Figures 1–3).

S. pneumoniae susceptibility in the Philippines

All 17 pneumococcal isolates from the Philippines were susceptible to amoxicillin, amoxicillin/clavulanic acid, all tested cephalosporins (except cefaclor), clarithromycin, erythromycin and fluoroquinolones by all available breakpoints. Susceptibility to penicillin IV was also 100% by CLSI and EUCAST high-dose breakpoints but slightly reduced to 94.1% for oral penicillin by CLSI and by EUCAST low-dose IV breakpoints. Similarly, susceptibility to azithromycin was 100% by CLSI and EUCAST criteria but reduced to 94.1% by PK/PD breakpoints, while susceptibility to trimethoprim/sulfamethoxazole was 100% using EUCAST criteria and reduced to 88.2% with CLSI and PK/PD breakpoints. Again, the largest differences in susceptibility across breakpoints were observed for cefaclor, with 94.1%, 64.7% and 0% susceptible using CLSI, PK/PD and EUCAST criteria, respectively (Tables 13–15, Figures 1–3).

Comparative susceptibility of S. pneumoniae by country

Using CLSI breakpoints, only the fluoroquinolones showed consistent activity across all four countries, with 100% activity in Cambodia, the Philippines and Singapore, and 90%–93% susceptibility in Vietnam (Figure 1). Larger differences were seen for the other antibiotics, with highest susceptibility among isolates from the Philippines, although the differences were only significant (P < 0.01) compared with all other countries for the macrolides, cephalosporins (except ceftriaxone), oral penicillin and trimethoprim/sulfamethoxazole. Antibiotic activity against isolates from Vietnam was significantly lower (P < 0.05) than against isolates from all other countries, except for moxifloxacin, amoxicillin and amoxicillin/clavulanic acid, for which the rates were not significantly different from isolates collected in Singapore, and levofloxacin, for which susceptibility was not significantly different for isolates from the Philippines or Singapore. Histograms indicating susceptibility by EUCAST and PK/PD breakpoints are shown in Figures 2 and 3, respectively.

Comparative susceptibility of S. pneumoniae by penicillin susceptibility

Among the 260 S. pneumoniae isolates from the four Asia-Pacific countries combined, 42 (16.2%) were penicillin susceptible (PSSP), 74 (28.5%) were penicillin intermediate (PISP) and 144 (55.4%) were penicillin resistant (PRSP) according to CLSI oral breakpoints. PSSP isolates were fully susceptible to amoxicillin, amoxicillin/clavulanic acid, all tested cephalosporins with CLSI breakpoints (except cefaclor) and the fluoroquinolones using CLSI breakpoints (Figure 4). Susceptibility was slightly reduced for cefaclor (95.2%) and the macrolides (88.1%), but trimethoprim/sulfamethoxazole showed the lowest activity (81%). PSSP isolates demonstrated significantly higher (P < 0.0001) susceptibility rates than PISP isolates for all agents except amoxicillin and amoxicillin/clavulanic acid (97.3% susceptible), ceftriaxone (98.7%), levofloxacin (93.2%) and moxifloxacin (97.3%), and PSSP isolates were significantly more susceptible (P < 0.0001) than PRSP isolates to all agents except the fluoroquinolones. In fact, among PRSP isolates, only levofloxacin and moxifloxacin exceeded 90% activity (92.4% and 93.8%, respectively), and amoxicillin, amoxicillin/clavulanic acid and ceftriaxone were the only other agents to exceed 12% susceptibility (47.9%, 47.2% and 52.8%, respectively).

Figure 4.

Percentage susceptibility rates (with 95% CI) based on CLSI breakpoints for antibiotics against PSSP, PISP and PRSP, combining results from the four Asia-Pacific countries. Penicillin susceptibility categories are based on oral penicillin CLSI breakpoints. ^aSusceptibility was significantly higher among PSSP and PISP isolates than PRSP isolates (P < 0.0001). ^bSusceptibility was significantly higher among PSSP than PISP isolates and among PISP than PRSP isolates (P <  0.0001). ^cSusceptibility was significantly higher among PSSP isolates than PISP and PRSP isolates (P < 0.0001).

H. influenzae isolates

A total of 258 H. influenzae isolates were collected from five centres in Vietnam, Cambodia, Singapore and the Philippines in 2016–18. They included 89 isolates from Vietnam, 30 isolates from Cambodia, 80 from Singapore and 59 from the Philippines. Most isolates originated from sputum (n = 118; 45.7%), nasotracheal aspirate (n = 52; 20.2%) and transtracheal aspirate (n = 38; 14.7%). Less frequently, isolates were from sinuses (n = 17; 6.6%), blood (n = 16; 6.2%), bronchoalveolar lavage (n = 8; 3.1%), middle ear effusion (n = 5; 1.9%) and endotracheal aspirate (n = 4; 1.6%). Most isolates (n = 106; 41.1%) came from adults (aged 13–64 years) or from paediatric patients (≤12 years; 31.4%, n = 81), with the remaining 27.5% (n = 71) from elderly patients (aged ≥65 years).

Summary MIC and susceptibility data for all 258 H. influenzae isolates are shown in Tables 16–27 and Figures 5–7. MIC distribution data are shown in Tables S5–S8.

Figure 5.

Percentage susceptibility rates based on CLSI breakpoints (with 95% CI) for antibiotics against all H. influenzae isolates collected in the four Asia-Pacific countries in the period 2016–18. ^aSusceptibility was significantly higher among isolates from the Philippines than Singapore and from Cambodia and Singapore than Vietnam (P < 0.05). ^bSusceptibility was significantly higher among isolates from the Philippines and Singapore than Vietnam (P < 0.05). ^cSusceptibility was significantly higher among isolates from Cambodia, the Philippines and Singapore than Vietnam (P < 0.001). ^dSusceptibility was significantly higher among isolates from Philippines than Vietnam (P < 0.05). ^eSusceptibility was significantly higher among isolates from Singapore than the Philippines and from Cambodia and the Philippines than Vietnam (P < 0.05).

Figure 6.

Percentage susceptibility rates based on EUCAST (dose-specific) breakpoints for antibiotics against all H. influenzae isolates collected in the four Asia-Pacific countries in the period 2016–18.

Figure 7.

Percentage susceptibility rates based on PK/PD breakpoints for antibiotics against all H. influenzae isolates collected in the four Asia-Pacific countries in the period 2016–18. Low-dose amoxicillin/clavulanic acid = 1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children. High-dose amoxicillin/clavulanic acid = 4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children.

Table 16.

MIC and susceptibility data for H. influenzae isolates (n = 89) from Vietnam using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	32	>128	≤0.12	>128	–	–	–
Amoxicillin/clavulanic acid	1	4	≤0.06	8	95.5	0.0	4.5
Ampicillin	64	>128	≤0.06	>128	11.2	6.7	82.0
Cefaclor	32	>32	0.5	>32	40.5	7.9	51.7
Cefdinir	1	8	0.06	32	56.2	–	–
Cefditoren	0.12	0.25	≤0.03	1	–	–	–
Cefixime	1	4	≤0.015	16	70.8	–	–
Cefpodoxime	2	8	≤0.015	>16	64.0	–	–
Ceftriaxone	0.12	0.25	≤0.015	1	100	–	–
Cefuroxime	4	>32	0.06	>32	51.7	22.5	25.8
Azithromycin	0.5	16	0.06	>32	87.6	–	–
Clarithromycin	4	16	≤0.03	>32	89.9	2.3	7.9
Levofloxacin	1	>8	≤0.004	>8	59.6	–	–
Moxifloxacin	0.5	8	≤0.004	>8	57.3	–	–
Trimethoprim/sulfamethoxazole	16	>16	0.06	>16	7.9	1.1	91.0

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 17.

MIC and susceptibility data for H. influenzae isolates (n = 89) from Vietnam using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.75–1 g × 3 oral)	32	>128	≤0.12	>128	18.0	–	82.0
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	1	4	≤0.06	8	75.3	–	24.7
Ampicillin (2 g × 3 IV)	64	>128	≤0.06	>128	11.2	–	88.8
Ampicillin (2 g × 4 IV)	64	>128	≤0.06	>128	11.2	–	88.8
Cefaclor	32	>32	0.5	>32	–	–	–
Cefdinir	1	8	0.06	32	–	–	–
Cefditoren	0.12	0.25	≤0.03	1	–	–	–
Cefixime	1	4	≤0.015	16	9.0	–	91.0
Cefpodoxime	2	8	≤0.015	>16	42.7	–	57.3
Ceftriaxone (1 g × 1 IV)	0.12	0.25	≤0.015	1	62.9	–	37.1
Ceftriaxone (2 g × 2 IV)	0.12	0.25	≤0.015	1	62.9	–	37.1
Cefuroxime	4	>32	0.06	>32	1.1	18.0	80.9
Azithromycin	0.5	16	0.06	>32	–	–	–
Clarithromycin	4	16	≤0.03	>32	–	–	–
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	1	>8	≤0.004	>8	37.1	–	62.9
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	1	>8	≤0.004	>8	37.1	–	62.9
Moxifloxacin	0.5	8	≤0.004	>8	38.2	–	61.8
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	16	>16	0.06	>16	7.9	0.0	92.1
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	16	>16	0.06	>16	7.9	0.0	92.1

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 18.

MIC and susceptibility data for H. influenzae isolates (n = 89) from Vietnam using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	32	>128	≤0.12	>128	18.0
Amoxicillin (4 g/day)	32	>128	≤0.12	>128	31.5
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	1	4	≤0.06	8	75.3
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	1	4	≤0.06	8	95.5
Ampicillin	64	>128	≤0.06	>128	–
Cefaclor	32	>32	0.5	>32	1.1
Cefdinir	1	8	0.06	32	11.2
Cefditoren	0.12	0.25	≤0.03	1	–
Cefixime	1	4	≤0.015	16	70.8
Cefpodoxime	2	8	≤0.015	>16	42.7
Ceftriaxone	0.12	0.25	≤0.015	1	100
Cefuroxime	4	>32	0.06	>32	19.1
Azithromycin	0.5	16	0.06	>32	9.0
Clarithromycin	4	16	≤0.03	>32	25.8
Levofloxacin	1	>8	≤0.004	>8	59.6
Moxifloxacin	0.5	8	≤0.004	>8	57.3
Trimethoprim/sulfamethoxazole	16	>16	0.06	>16	7.9

min, minimum; max, maximum; S, susceptible; –, not applicable.

Table 19.

MIC and susceptibility data for H. influenzae isolates (n = 30) from Cambodia using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	0.5	4	0.5	128	–	–	–
Amoxicillin/clavulanic acid	0.5	1	0.25	4	100	–	0.0
Ampicillin	0.12	4	≤0.06	32	73.3	10.0	16.7
Cefaclor	2	8	0.5	32	93.3	3.3	3.3
Cefdinir	0.25	1	0.12	1	100	–	–
Cefditoren	≤0.03	0.06	≤0.03	0.5	–	–	–
Cefixime	0.03	0.12	≤0.015	1	100	–	–
Cefpodoxime	0.06	0.25	≤0.015	1	100	–	–
Ceftriaxone	≤0.015	≤0.015	≤0.015	0.12	100	–	–
Cefuroxime	0.5	2	0.12	8	96.7	3.3	0.0
Azithromycin	1	1	0.25	1	100	–	–
Clarithromycin	4	8	2	8	100	0.0	0.0
Levofloxacin	0.015	0.06	≤0.004	>8	96.7	–	–
Moxifloxacin	0.015	0.03	0.008	>8	96.7	–	–
Trimethoprim/sulfamethoxazole	2	16	0.03	>16	43.3	6.7	50.0

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 20.

MIC and susceptibility data for H. influenzae isolates (n = 30) from Cambodia using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.75–1 g × 3 oral)	0.5	4	0.5	128	70.0	–	30.0
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	0.5	1	0.25	4	93.3	–	6.7
Ampicillin (2 g × 3 IV)	0.12	4	≤0.06	32	73.3	–	26.7
Ampicillin (2 g × 4 IV)	0.12	4	≤0.06	32	73.3	–	26.7
Cefaclor	2	8	0.5	32	–	–	–
Cefdinir	0.25	1	0.12	1	–	–	–
Cefditoren	≤0.03	0.06	≤0.03	0.5	–	–	–
Cefixime	0.03	0.12	≤0.015	1	90.0	–	10.0
Cefpodoxime	0.06	0.25	≤0.015	1	90.0	–	10.0
Ceftriaxone (1 g × 1 IV)	≤0.015	≤0.015	≤0.015	0.12	100	–	0.0
Ceftriaxone (2 g × 2 IV)	≤0.015	≤0.015	≤0.015	0.12	100	–	0.0
Cefuroxime	0.5	2	0.12	8	3.3	83.3	13.3
Azithromycin	1	1	0.25	1	–	–	–
Clarithromycin	4	8	2	8	–	–	–
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	0.015	0.06	≤0.004	>8	96.7	–	3.3
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	0.015	0.06	≤0.004	>8	96.7	–	3.3
Moxifloxacin	0.015	0.03	0.008	>8	96.7	–	3.3
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	2	16	0.03	>16	43.3	3.3	53.3
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	2	16	0.03	>16	46.7	–	53.3

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 21.

MIC and susceptibility data for H. influenzae isolates (n = 30) from Cambodia using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	0.5	4	0.5	128	70.0
Amoxicillin (4 g/day)	0.5	4	0.5	128	90.0
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	0.5	1	0.25	4	93.3
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	0.5	1	0.25	4	100
Ampicillin	0.12	4	≤0.06	32	–
Cefaclor	2	8	0.5	32	3.3
Cefdinir	0.25	1	0.12	1	73.3
Cefditoren	≤0.03	0.06	≤0.03	0.5	–
Cefixime	0.03	0.12	≤0.015	1	100
Cefpodoxime	0.06	0.25	≤0.015	1	93.3
Ceftriaxone	≤0.015	≤0.015	≤0.015	0.12	100
Cefuroxime	0.5	2	0.12	8	86.7
Azithromycin	1	1	0.25	1	0.0
Clarithromycin	4	8	2	8	0.0
Levofloxacin	0.015	0.06	≤0.004	>8	96.7
Moxifloxacin	0.015	0.03	0.008	>8	96.7
Trimethoprim/sulfamethoxazole	2	16	0.03	>16	43.3

min, minimum; max, maximum; S, susceptible; –, not applicable.

Table 22.

MIC and susceptibility data for H. influenzae isolates (n = 80) from Singapore using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	2	128	≤0.12	>128	–	–	–
Amoxicillin/clavulanic acid	1	4	≤0.06	8	93.8	–	6.3
Ampicillin	1	64	≤0.06	>128	61.3	6.3	32.5
Cefaclor	8	16	0.06	32	77.5	16.3	6.3
Cefdinir	0.5	1	0.12	8	92.5	–	–
Cefditoren	≤0.03	0.06	≤0.03	0.5	–	–	–
Cefixime	0.06	0.5	≤0.015	2	97.5	–	–
Cefpodoxime	0.12	0.5	≤0.015	2	100	–	–
Ceftriaxone	≤0.015	0.03	≤0.015	0.25	100	–	–
Cefuroxime	2	4	0.25	32	95.0	1.3	3.8
Azithromycin	0.5	1	≤0.03	32	97.5	–	–
Clarithromycin	4	8	≤0.03	>32	96.3	1.3	2.5
Levofloxacin	0.015	0.03	≤0.004	>8	98.8	–	–
Moxifloxacin	0.015	0.03	≤0.004	8	97.5	–	–
Trimethoprim/sulfamethoxazole	0.12	16	≤0.015	>16	61.3	3.8	35.0

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 23.

MIC and susceptibility data for H. influenzae isolates (n = 80) from Singapore using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.75–1 g × 3 oral)	2	128	≤0.12	>128	56.3	–	43.8
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	1	4	≤0.06	8	77.5	–	22.5
Ampicillin (2 g × 3 IV)	1	64	≤0.06	>128	61.3	–	38.8
Ampicillin (2 g × 4 IV)	1	64	≤0.06	>128	61.3	–	38.8
Cefaclor	8	16	0.06	32	–	–	–
Cefdinir	0.5	1	0.12	8	–	–	–
Cefditoren	≤0.03	0.06	≤0.03	0.5	–	–	–
Cefixime	0.06	0.5	≤0.015	2	78.8	–	21.3
Cefpodoxime	0.12	0.5	≤0.015	2	85.0	–	15.0
Ceftriaxone (1 g × 1 IV)	≤0.015	0.03	≤0.015	0.25	98.8	–	1.3
Ceftriaxone (2 g × 2 IV)	≤0.015	0.03	≤0.015	0.25	98.8	–	1.3
Cefuroxime	2	4	0.25	32	0.0	47.5	52.5
Azithromycin	0.5	1	≤0.03	32	–	–	–
Clarithromycin	4	8	≤0.03	>32	–	–	–
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	0.015	0.03	≤0.004	>8	95.0	–	5.0
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	0.015	0.03	≤0.004	>8	95.0	–	5.0
Moxifloxacin	0.015	0.03	≤0.004	8	95.0	–	5.0
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	0.12	16	≤0.015	>16	61.3	1.3	37.5
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	0.12	16	≤0.015	>16	62.5	–	37.5

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 24.

MIC and susceptibility data for H. influenzae isolates (n = 80) from Singapore using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	2	128	≤0.12	>128	56.3
Amoxicillin (4 g/day)	2	128	≤0.12	>128	67.5
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	1	4	≤0.06	8	77.5
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	1	4	≤0.06	8	93.8
Ampicillin	1	64	≤0.06	>128	–
Cefaclor	8	16	0.06	32	2.5
Cefdinir	0.5	1	0.12	8	40.0
Cefditoren	≤0.03	0.06	≤0.03	0.5	–
Cefixime	0.06	0.5	≤0.015	2	97.5
Cefpodoxime	0.12	0.5	≤0.015	2	90.0
Ceftriaxone	≤0.015	0.03	≤0.015	0.25	100
Cefuroxime	2	4	0.25	32	47.5
Azithromycin	0.5	1	≤0.03	32	6.3
Clarithromycin	4	8	≤0.03	>32	1.3
Levofloxacin	0.015	0.03	≤0.004	>8	98.8
Moxifloxacin	0.015	0.03	≤0.004	8	97.5
Trimethoprim/sulfamethoxazole	0.12	16	≤0.015	>16	61.3

min, minimum; max, maximum; S, susceptible; –, not applicable.

Table 25.

MIC and susceptibility data for H. influenzae isolates (n = 59) from the Philippines using CLSI breakpoints

	MIC (mg/L)				CLSI susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin	0.5	4	≤0.12	32	–	–	–
Amoxicillin/clavulanic acid	0.25	1	≤0.06	4	100	–	0.0
Ampicillin	0.12	4	≤0.06	16	84.7	1.7	13.6
Cefaclor	2	8	0.25	16	98.3	1.7	0.0
Cefdinir	0.12	0.25	≤0.03	1	100	–	–
Cefditoren	≤0.03	≤0.03	≤0.03	0.12	–	–	–
Cefixime	≤0.015	0.03	≤0.015	0.25	100	–	–
Cefpodoxime	0.06	0.12	≤0.015	0.25	100	–	–
Ceftriaxone	≤0.015	≤0.015	≤0.015	0.03	100	–	–
Cefuroxime	0.5	1	≤0.03	4	100	0.0	0.0
Azithromycin	0.5	0.5	0.12	1	100	–	–
Clarithromycin	2	4	1	8	100	0.0	0.0
Levofloxacin	0.03	0.03	0.008	0.06	100	–	–
Moxifloxacin	0.015	0.03	≤0.004	0.06	100	–	–
Trimethoprim/sulfamethoxazole	4	16	≤0.015	16	42.4	3.4	54.2

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 26.

MIC and susceptibility data for H. influenzae isolates (n = 59) from the Philippines using EUCAST (dose-specific) breakpoints

	MIC (mg/L)				EUCAST susceptibility
Antibiotic	50%	90%	min	max	%S	%I	%R
Amoxicillin (0.75–1 g × 3 oral)	0.5	4	≤0.12	32	84.8	–	15.3
Amoxicillin/clavulanic acid (0.875 g/0.125 g × 3 oral)	0.25	1	≤0.06	4	98.3	–	1.7
Ampicillin (2 g × 3 IV)	0.12	4	≤0.06	16	84.8	–	15.3
Ampicillin (2 g × 4 IV)	0.12	4	≤0.06	16	84.8	–	15.3
Cefaclor	2	8	0.25	16	–	–	–
Cefdinir	0.12	0.25	≤0.03	1	–	–	–
Cefditoren	≤0.03	≤0.03	≤0.03	0.12	–	–	–
Cefixime	≤0.015	0.03	≤0.015	0.25	98.3	–	1.7
Cefpodoxime	0.06	0.12	≤0.015	0.25	100	–	0.0
Ceftriaxone (1 g × 1 IV)	≤0.015	≤0.015	≤0.015	0.03	100	–	0.0
Ceftriaxone (2 g × 2 IV)	≤0.015	≤0.015	≤0.015	0.03	100	–	0.0
Cefuroxime	0.5	1	≤0.03	4	17.0	74.6	8.5
Azithromycin	0.5	0.5	0.12	1	–	–	–
Clarithromycin	2	4	1	8	–	–	–
Levofloxacin (0.5 g × 2 oral or 0.4 g × 2 IV)	0.03	0.03	0.008	0.06	100	–	0.0
Levofloxacin (0.75 g × 2 oral or 0.4 g × 3 IV)	0.03	0.03	0.008	0.06	100	–	0.0
Moxifloxacin	0.015	0.03	≤0.004	0.06	100	–	0.0
Trimethoprim/sulfamethoxazole (0.16 g/0.8 g × 2 oral or IV)	4	16	≤0.015	16	42.4	0.0	57.6
Trimethoprim/sulfamethoxazole (0.24 g/1.2 g × 2 oral or IV)	4	16	≤0.015	16	42.4	0.0	57.6

min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; –, not applicable.

Table 27.

MIC and susceptibility data for H. influenzae isolates (n = 59) from the Philippines using PK/PD breakpoints

	MIC (mg/L)				PK/PD susceptibility
Antibiotic	50%	90%	min	max	%S only
Amoxicillin (1.5 g/day)	0.5	4	≤0.12	32	84.8
Amoxicillin (4 g/day)	0.5	4	≤0.12	32	91.5
Amoxicillin/clavulanic acid (1.75 g/0.25 g/day adults; 45 mg/6.4 mg/kg/day children)	0.25	1	≤0.06	4	98.3
Amoxicillin/clavulanic acid (4 g/0.25 g/day adults; 90 mg/6.4 mg/kg/day children)	0.25	1	≤0.06	4	100
Ampicillin	0.12	4	≤0.06	16	–
Cefaclor	2	8	0.25	16	17.0
Cefdinir	0.12	0.25	≤0.03	1	93.2
Cefditoren	≤0.03	≤0.03	≤0.03	0.12	–
Cefixime	≤0.015	0.03	≤0.015	0.25	100
Cefpodoxime	0.06	0.12	≤0.015	0.25	100
Ceftriaxone	≤0.015	≤0.015	≤0.015	0.03	100
Cefuroxime	0.5	1	≤0.03	4	91.5
Azithromycin	0.5	0.5	0.12	1	8.5
Clarithromycin	2	4	1	8	0.0
Levofloxacin	0.03	0.03	0.008	0.06	100
Moxifloxacin	0.015	0.03	≤0.004	0.06	100
Trimethoprim/sulfamethoxazole	4	16	≤0.015	16	42.4

min, minimum; max, maximum; S, susceptible; –, not applicable.

H. influenzae susceptibility in Vietnam

Among the 89 H. influenzae isolates collected in Vietnam, 60 (67.4%) were β-lactamase positive. Of the 29 β-lactamase-negative isolates, 20 were β-lactamase negative and ampicillin resistant (BLNAR) by EUCAST breakpoints and 14 were BLNAR according to CLSI breakpoints. Susceptibility of the 89 H. influenzae isolates was generally reduced compared with the other countries in the study. Only ceftriaxone was active against all isolates using CLSI and PK/PD breakpoints (reduced to 62.9% by EUCAST criteria). Susceptibility to amoxicillin/clavulanic acid was 95.5% by CLSI and high-dose PK/PD breakpoints (with susceptibility reduced to 75.3% using low-dose PK/PD and EUCAST breakpoints). Isolate susceptibility to the macrolides was 87.6%–89.9% using CLSI criteria, but this was substantially reduced to <26% using PK/PD breakpoints. Isolates had susceptibility rates to all other antibiotics tested of ≤70.8% by CLSI and PK/PD criteria and ≤42.7% by EUCAST breakpoints. Notably, susceptibility to the fluoroquinolones was only 57.3%–59.6% by CLSI and PK/PD criteria, and 37.1%–38.2% using EUCAST breakpoints. Susceptibility was lowest to ampicillin and trimethoprim/sulfamethoxazole (≤11.2% by all available breakpoints) (Tables 16–18, Figures 5–7).

H. influenzae susceptibility in Cambodia

Among the 30 H. influenzae isolates collected in Cambodia, 13 (43.3%) were β-lactamase positive. Of the 17 β-lactamase-negative isolates, 1 was BLNAR by CLSI breakpoints (ampicillin MIC ≥4 mg/L) and EUCAST criteria (ampicillin MIC ≥2 mg/L). All H. influenzae isolates were susceptible to ceftriaxone by all breakpoints and to amoxicillin/clavulanic acid by CLSI and high-dose PK/PD breakpoints (with susceptibility reduced to 93.3% using low-dose PK/PD and EUCAST breakpoints). All isolates were also susceptible to azithromycin and clarithromycin using CLSI breakpoints (reduced to 0% by PK/PD criteria), to cefdinir by CLSI breakpoints (reduced to 73.3% by PK/PD criteria), to cefixime by CLSI and PK/PD breakpoints (reduced to 90% by EUCAST breakpoints) and to cefpodoxime by CLSI criteria (reduced to 93.3% by PK/PD and to 90% by EUCAST criteria). Susceptibility to the fluoroquinolones was 96.7% by all breakpoints, while large differences between breakpoints were seen for cefaclor (93.3% susceptible by CLSI and 3.3% by PK/PD breakpoints) and oral cefuroxime (ranging from 96.7% by CLSI criteria to 3.3% by EUCAST breakpoints). Susceptibility to trimethoprim/sulfamethoxazole was low (≤46.7% by all breakpoints) (Tables 19–21, Figures 5–7).

H. influenzae susceptibility in Singapore

Among the 80 H. influenzae isolates collected in Singapore, 26 (32.5%) were β-lactamase positive. Six of the 54 β-lactamase-negative isolates were BLNAR by EUCAST breakpoints and 1 was BLNAR according to CLSI breakpoints. H. influenzae isolates were all susceptible only to ceftriaxone by CLSI and PK/PD breakpoints (slightly reduced to 98.8% by EUCAST criteria) and to cefpodoxime using CLSI breakpoints (reduced to 90% by PK/PD and to 85% by EUCAST criteria). Isolates had susceptibility rates of >90% to the fluoroquinolones by all breakpoints and to amoxicillin/clavulanic acid, the macrolides, cefixime, cefuroxime (oral) and cefdinir by CLSI breakpoints. Among these antibiotics, large reductions in isolate susceptibility using PK/PD breakpoints were seen to the macrolides (1.3%–6.3%), cefdinir (40%) and oral cefuroxime (47.5%) and using EUCAST breakpoints to oral cefuroxime (0%). Susceptibility to ampicillin and trimethoprim/sulfamethoxazole was ≤62.5% by all available breakpoints (Tables 22–24, Figures 5–7).

H. influenzae susceptibility in the Philippines

Among the 59 H. influenzae isolates collected in the Philippines, 8 (13.6%) were β-lactamase positive. No BLNAR isolates were found among the 51 β-lactamase-negative isolates using CLSI breakpoints, and 1 BLNAR isolate was found using EUCAST criteria. All H. influenzae isolates were susceptible to cefpodoxime, ceftriaxone and the fluoroquinolones by all breakpoints. In addition, all isolates were susceptible to amoxicillin/clavulanic acid and cefixime by CLSI and PK/PD breakpoints (high dose for amoxicillin/clavulanic acid) with susceptibility reduced to 98.3% using EUCAST breakpoints. Using CLSI breakpoints, all isolates were susceptible to azithromycin and clarithromycin (reduced to 8.5% and 0%, respectively, by PK/PD criteria), cefdinir (reduced to 93.2% using PK/PD breakpoints) and oral cefuroxime (reduced to 91.5% using PK/PD and to 17% using EUCAST breakpoints). Large differences between breakpoints in susceptibility to cefaclor were also seen (98.3% by CLSI and 17% by PK/PD criteria). Susceptibility to trimethoprim/sulfamethoxazole was low (42.4% by all breakpoints) (Tables 25–27, Figures 5–7).

Comparative susceptibility of H. influenzae by country

By CLSI breakpoints, only amoxicillin/clavulanic acid (ranging from 93.8% susceptibility for isolates from Singapore to 100% for Cambodia and the Philippines) and ceftriaxone (all isolates susceptible for all countries) showed no significant difference in susceptibility rates across the four countries (Figure 5). Azithromycin and clarithromycin also showed consistent activity across all four countries, ranging from 87.6% and 89.9%, respectively, in Vietnam to 100% in Cambodia and the Philippines. The differences between Vietnam and the other countries were significant (P < 0.05) when comparing azithromycin susceptibility with that in the Philippines and Singapore and comparing clarithromycin susceptibility with that in the Philippines. Isolates from Vietnam showed significantly lower susceptibility than isolates from the other three countries for ampicillin (P < 0.05), the cephalosporins (except ceftriaxone) (P < 0.001), the fluoroquinolones (P < 0.001) and trimethoprim/sulfamethoxazole (P < 0.05) (Figure 5).

Histograms indicating antibiotic susceptibility using EUCAST and PK/PD breakpoints are shown in Figures 6 and 7, respectively.

Discussion

SOAR is an ongoing global surveillance study that originated in 2002, focusing on the two major CA-RTI pathogens S. pneumoniae and H. influenzae. The data presented here are an analysis of the antibiotic susceptibility of S. pneumoniae and H. influenzae isolates collected from Vietnam, Cambodia, Singapore and the Philippines between 2016 and 2018.

Pneumococci from the Philippines were generally more susceptible than isolates from the other three countries, being fully susceptible by CLSI breakpoints to all tested agents except oral penicillin and cefaclor (94.1%) and trimethoprim/sulfamethoxazole (88.2%). Although the sample size was small with only 17 isolates tested, these high susceptibility rates were corroborated by two other published studies. Using CLSI breakpoints, Kim et al.¹⁰ reported susceptibility rates of 99% to ceftriaxone and 95% to erythromycin for isolates collected in the Philippines in 2008–09 as part of the ANSORP study, and Sader et al.³ found 92% of isolates collected in 2015–16 to be susceptible to oral penicillin.

S. pneumoniae isolates from Vietnam (n = 161) showed the lowest susceptibility among the four countries (90%–93% for fluoroquinolones by CLSI breakpoints, 69.6% for penicillin IV, ∼60% for amoxicillin/clavulanic acid and ceftriaxone and <14% for most other antibiotics tested). The high resistance rates reported here are consistent with those seen in other studies. The ANSORP study reported low erythromycin and trimethoprim/sulfamethoxazole susceptibility rates of 17% and 8%, respectively, in 2008–09.¹⁰ Similarly, a recent community-based study from 2008–09 of nasopharyngeal swabs of Vietnamese children, both healthy and with acute respiratory infections, reported susceptibility rates for pneumococcal isolates of 3% for oral penicillin, 9% for trimethoprim/sulfamethoxazole and 13% for erythromycin; the rates for oral cefuroxime (31%) and amoxicillin/clavulanic acid (88%) were ∼20% higher in the isolates from 2008–09 than in the current study, so resistance appears to have increased further.¹¹ A previous SOAR report also found low rates of susceptibility to oral penicillin (5%), azithromycin (4%) and trimethoprim/sulfamethoxazole (5%) among pneumococci collected in 2009–11.¹² Compared with isolate susceptibility rates of 76% to amoxicillin/clavulanic acid reported in the 2009–11 study,¹² susceptibility has decreased further to 59.6%.

Susceptibility rates in the current study for pneumococci collected in Cambodia (n = 48) were similar to those described in earlier studies. The current susceptibility rate (using CLSI breakpoints) of 89.6% for amoxicillin and amoxicillin/clavulanic acid was only slightly lower than the susceptibility among isolates collected in 1995–2011 (94% and 97%, respectively)¹³ and among isolates collected in 2005–14 (93% susceptible to amoxicillin/clavulanic acid).¹⁴ The susceptibility rate for erythromycin of 50% using CLSI criteria in the current study appears almost unchanged from rates reported for isolates collected in Cambodia in 1995–2011 (48%),¹³ 2005–14 (49%)¹⁴ and 2013–14 (51% and 52% for inpatients and outpatients, respectively).¹⁵ Similarly, susceptibility to trimethoprim/sulfamethoxazole appears to be low, as demonstrated by different studies since 1995, with rates of 22% for isolates from 1995–2011,¹³ 9% for isolates collected in 2005–14,¹⁴ 15%–32% for isolates from 2013–14¹⁵ and 29.2% for the current study.

Pneumococcal isolates from Singapore (n = 34) appear to have become more resistant in relation to earlier studies. Compared with a SOAR report on isolates from 2012–14,¹⁶ susceptibility using CLSI criteria to amoxicillin/clavulanic acid decreased from 94.8% to 76.5% in the current study, to erythromycin from 55.2% to 29.4%, and to oral penicillin from 63.8% to 29.4%. A study by Vasoo et al.¹⁷ showed similar reductions in susceptibility over earlier time periods for isolates collected from children attending daycare centres in Singapore, with erythromycin and oral penicillin susceptibility decreasing from 67% and 73%, respectively, in 1997 to 22% and 30% in 2007–08.

Among H. influenzae isolates, less antibiotic resistance was found in the four countries than that observed with S. pneumoniae. Using CLSI breakpoints, susceptibility in Cambodia, the Philippines and Singapore was >90% to amoxicillin/clavulanic acid, cephalosporins [except cefaclor in Singapore (77.5%, see below)], macrolides and fluoroquinolones; in Vietnam susceptibility was >85% only for amoxicillin/clavulanic acid (95.5%), ceftriaxone (100%) and macrolides (87.6%–89.9%). Susceptibility to other agents ranged from 7.9% (trimethoprim/sulfamethoxazole) to 70.8% (cefixime). The susceptibility rates in the four countries were mostly stable compared with earlier studies. In Cambodia, the activity of amoxicillin/clavulanic acid and azithromycin was 97% and 93%, respectively, in a study by Goyet et al.¹³ evaluating isolates from 1995–2012, compared with 100% in the current study; levofloxacin activity was 100% compared with 96.7% in the current study. The exceptions were ampicillin and trimethoprim/sulfamethoxazole, for which susceptibility increased from 56% and 23%,¹³ respectively, to 73.3% and 43.3%. However, it should be noted that only 30 H. influenzae isolates from Cambodia were included in the current study. All isolates from the Philippines were susceptible to amoxicillin/clavulanic acid, azithromycin, cefixime, cefpodoxime, cefuroxime (oral) and levofloxacin, both in the current study and in a study evaluating isolates from 2012–13.¹⁸ Susceptibility to trimethoprim/sulfamethoxazole was low in both studies (42.4% and 31.6%, respectively).¹⁸ For isolates from Singapore, susceptibility rates for amoxicillin/clavulanic acid (93.8%), ampicillin (61.3%), azithromycin (97.5%), cefaclor (77.5%), levofloxacin (98.8%) and trimethoprim/sulfamethoxazole (61.3%) were within 3% of the values observed in a previous SOAR report of isolates collected in 2012–14, while susceptibility to cefuroxime (oral) increased from 85% to 95%.¹⁶

For isolates from Vietnam susceptibility decreased, compared with the earlier SOAR report on isolates collected in 2009–11, to ampicillin (11.2% versus 35.9%), cefaclor (40.5% versus 61.5%) and oral cefuroxime (51.7% versus 70.3%), but remained stable to amoxicillin/clavulanic acid (95.5% versus 97.4%) and increased for the macrolides (87.6%–89.9% versus 75.9%–79.5%).¹² Data were not available for fluoroquinolones from the previous SOAR Vietnam report, and to our knowledge the low activity of this drug class against H. influenzae isolates from Vietnam (57.3%–59.6% susceptible) has not been reported elsewhere. The emergence of levofloxacin-resistant H. influenzae has been described in Taiwan,^19,20 but in a recent global surveillance study of CAP pathogens collected in 2015–17, susceptibility of H. influenzae to levofloxacin was 100% in Western Europe and Latin America, 99.4% in Eastern Europe, and only slightly reduced to 98.4% in Asia overall.² Isolates from Vietnam were not included in the study.² It is also noteworthy that amongst isolates of H. influenzae from all countries in the current study, levels of β-lactamase-positive organisms were high, in particular in Vietnam, where 67.4% were β-lactamase positive.

These results confirm the findings of other studies that have reported resistance rates of respiratory pathogens to vary across countries and over time.^{3,10,12,16,18} Such regional and temporal differences are probably due to a combination of factors, including clonal epidemiology, antibiotic drug availability, cost and prescribing practice (for example, reduced activity of erythromycin against pneumococci worldwide could be related to increased use of macrolides in the late 1990s and early 2000s), as well as pneumococcal conjugate vaccine (PCV) immunization practice (for example, the introduction of PCV13 appears to have contributed to decreases in penicillin-resistant and MDR pneumococci).^3,18 Therefore, knowledge of the current epidemiology of respiratory pathogens, especially at the local level, is important when choosing antibiotics for empirical therapy of lower respiratory tract infections.

The antibiotics with the highest activity in all four countries against both S. pneumoniae and H. influenzae were the fluoroquinolones, with susceptibility rates >90% except for H. influenzae from Vietnam. However, as Goyet et al.¹³ pointed out in 2014, these agents are expensive, have side effects, are not recommended for children, may be an important therapeutic option against TB in highly endemic settings such as Cambodia, and should be preserved for severe bacterial infection. In the current study, among the oral antibiotics other than fluoroquinolones, only amoxicillin/clavulanic acid was highly active against H. influenzae in all countries and active against ∼90% or more of S. pneumoniae isolates in Cambodia and the Philippines by CLSI breakpoints. In Singapore and Vietnam, susceptibility of S. pneumoniae to amoxicillin/clavulanic acid (76.5% and 59.6%, respectively) and to amoxicillin (76.5% and 60.3%, respectively) was at least 20% higher than to any other oral antibiotic except fluoroquinolones. By CLSI breakpoints, the oral cephalosporins and the macrolides showed strong activity (≥93.3% susceptible) against H. influenzae isolates from Cambodia, the Philippines and Singapore (except cefaclor in Singapore, where susceptibility was 77.5%). In Vietnam, susceptibility to oral cephalosporins was lower (40.5%–70.8%) but susceptibility to the macrolides was ≥87.6%. Using CLSI breakpoints, trimethoprim/sulfamethoxazole showed low activity against S. pneumoniae (13%) and H. influenzae (7.9%) and the activity of oral penicillin against pneumococci was also mostly low, with <30% of isolates susceptible in all countries except the Philippines (94.1%).

Susceptibility rates can change considerably when using different breakpoint guidelines. The greatest difference observed was for cefaclor against S. pneumoniae, no isolates of which were susceptible by EUCAST breakpoints in the Philippines, but susceptibility was 94.1% by CLSI criteria and 64.7% by PK/PD breakpoints. The difference was less for isolates from Cambodia and Singapore, where only 17.7%–37.5% of isolates were susceptible to cefaclor by CLSI criteria. In Vietnam, where antibiotic susceptibility was the lowest overall, only 3.1% of S. pneumoniae isolates were susceptible to cefaclor by CLSI breakpoints. EUCAST does not publish breakpoints for cefdinir against S. pneumoniae whereas CLSI does. In Cambodia, Singapore and Vietnam this is not an issue because susceptibility by CLSI guidelines was low anyway (9.3%–50%), but in the Philippines all isolates were cefdinir susceptible by CLSI criteria. Cefuroxime (oral) susceptibility in S. pneumoniae was generally similar for EUCAST and CLSI breakpoints, but for H. influenzae there was a larger difference (0%–17% susceptible by EUCAST compared with 51.7%–100% by CLSI). Assessment of cefaclor and cefdinir susceptibility also differed for H. influenzae, for which EUCAST does not publish breakpoints, but susceptibility was >90% in Cambodia and the Philippines by CLSI criteria. Similarly, EUCAST does not publish macrolide breakpoints for H. influenzae whereas by CLSI criteria at least 87.6% of isolates were macrolide susceptible in each Asian country surveyed. Assessment of amoxicillin or amoxicillin/clavulanic acid susceptibility against H. influenzae was very similar using all three breakpoint criteria and was also no different for S. pneumoniae from the Philippines (where 100% susceptibility was observed). However, susceptibility to amoxicillin or amoxicillin/clavulanic acid using EUCAST breakpoints, even with the high dose, was lower than by CLSI or PK/PD breakpoints in Cambodia (62.5%–77.1% versus 89.6%–93.8%), Singapore (55.9%–67.6% versus 76.5%–82.4%) and Vietnam (12.4%–26.1% versus 59.6%–72.1%).

These issues give rise to major challenges for clinicians trying to interpret published studies using different breakpoints and are a limitation of the current study when trying to compare these results with previously reported findings. Harmonization of breakpoints and dosing considerations is critical, especially in the light of dramatic differences such as those indicated above for cefaclor. Other limitations of this study pertain to small sample sizes and only one or two sites participating per country. Results may therefore not be representative of the whole country. However, it is reassuring that the results from other studies (some of which also only included one or two hospital sites) often confirmed these findings.

Following discussion and collaboration with EUCAST, this study also employed, for the first time in the SOAR investigations, different EUCAST breakpoints for low and high doses of several antibiotics tested so that the effect of different dosages on the susceptibility of the CA-RTIs pathogens could be observed. Correct antibiotic dosing remains a challenge for the clinician, particularly since PK/PD parameters may alter during serious illness.²¹ Personalized antibiotic treatment may be an option, although it is currently only considered for patients in intensive care.²² The ability to now assess pathogen susceptibility at different antibiotic doses along with advances in diagnostics and monitoring could allow possible progress in this area and the subsequent benefit for a wider range of patient groups.

In conclusion, antibiotic susceptibility varied from country to country and between species, with S. pneumoniae isolates more resistant than H. influenzae, and isolates of both species generally demonstrating the lowest susceptibility rates in Vietnam and high susceptibility rates in the Philippines. Continued monitoring of antibiotic susceptibility is needed both at the local level and through large surveillance studies, such as SOAR, that use consistent methods over time and geography. Such surveillance makes possible the discovery, tracking, and confirmation of emerging resistance patterns, such as our finding of high resistance levels to fluoroquinolones of H. influenzae from Vietnam. Furthermore, it helps clinicians make empirical treatment choices, and allows the assessment of infection control and antibiotic stewardship efforts.

Most antimicrobial surveillance studies, particularly those which involve multiple centres in a country, have limitations that could affect the results. This may include variation in number of isolates between centres or countries, low isolate numbers, collection of different specimen types for the same indication from each centre/country, different patient age groups, and use of different breakpoints.

Acknowledgements

We would like to thank the participating laboratories for supplying the isolates; Dr Federica Monti (IHMA) and Livewire Editorial Communications for editorial support; Dr Sibylle Lob (IHMA) for the statistical analysis; Manuel Hector Silas (GSK-Philippines), Sophea Ang (GSK-Cambodia), Radhika Mehta (GSK-Singapore), Le Thi Thu Huyen (GSK-Vietnam), Hoang Thi Bach Tuyet (GSK-Vietnam), Nguyen Duy Nguyen (GSK-Vietnam) and Truong Ha Lan Ngoc (GSK-Vietnam) for their help with all SOAR-related approvals; Karen Langfeld (GSK) for reviewing the manuscript; and the SOAR Team (Subhashri Kundu, Cristiana Beltrame, Rendani Manenzhe and Nergis Keles) for their continuous support of SOAR.

Funding

This study was funded by GlaxoSmithKline.

Transparency declarations

This article forms part of a Supplement sponsored by GlaxoSmithKline. D. Torumkuney is an employee of GlaxoSmithKline and holds shares in GlaxoSmithKline. I. Morrissey is an employee of IHMA, a medical communication and consultancy company, who participated in the exploration, interpretation of the results and preparation of this manuscript on behalf of GlaxoSmithKline. All other authors: none to declare. Editorial assistance was provided by Livewire Editorial Communications.