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Abstract

Objectives

To determine antibiotic susceptibility in isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2014–16 from Ukraine and the Slovak Republic.

Methods

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

Results

S. pneumoniae isolates collected in Ukraine (n = 100) showed susceptibility rates ≥97% for amoxicillin, amoxicillin/clavulanic acid, penicillin [intravenous (iv) non-meningitis] and fluoroquinolones, between 83% and 86% for oral penicillin, macrolides and cefaclor, and 75% for trimethoprim/sulfamethoxazole. Susceptibility was substantially lower in the Slovak Republic (n = 95). All isolates were susceptible to the fluoroquinolones, but susceptibility to penicillin, amoxicillin, amoxicillin/clavulanic acid, cefuroxime and trimethoprim/sulfamethoxazole varied between 61% and 64%, with only 44% of isolates susceptible to the macrolides. Susceptibility of H. influenzae was more homogeneous, with susceptibility to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime, azithromycin and the fluoroquinolones seen in >90% of isolates by CLSI criteria in both countries. Much greater variability was seen across breakpoints, especially for azithromycin, cefaclor and cefuroxime. The β-lactamase rate was 5.1% (5/98) in the Slovak Republic and 7.3% (7/96) in Ukraine, but the Slovak Republic also had a relatively high rate of β-lactamase-negative-ampicillin-resistant (BLNAR) isolates (7.1%; 7/98).

Conclusions

The variability found across these two neighbouring countries illustrates the need to monitor and publish national and local resistance patterns. This information is not only critical for effective empirical therapy but can also be used to help shape and support antimicrobial stewardship efforts in order to limit antibiotic resistance.

Introduction

In 2015, lower respiratory infections remained the most deadly communicable disease and the third leading cause of death worldwide with 3.2 million deaths.1 Even in Europe, where mortality due to communicable diseases is much lower than in many other regions of the world, these infections still represent the sixth most common cause of death.1 It is therefore critical that decisions regarding antimicrobial therapy, which is typically empirical for lower respiratory infections, are supported by solid surveillance data of local antimicrobial resistance patterns. This is especially important since surveillance studies have shown that resistance levels can vary substantially across countries and even between institutions in the same country.2–5 Monitoring and reporting of local resistance rates can be undertaken by individual hospitals and laboratories as well as through larger surveillance studies that can facilitate comparative analyses across regions and longitudinal analyses over time. The Survey of Antibiotic Resistance (SOAR) is an international antimicrobial resistance surveillance study that focuses on key respiratory pathogens 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 the Slovak Republic and Ukraine were analysed to provide a picture of the current state of antimicrobial susceptibility of Streptococcus pneumoniae and Haemophilus influenzae, two important bacterial pathogens associated with lower respiratory tract infections.

Materials and methods

Collaborating centres

The following centres took part in the study: one from the Slovak Republic (Hospital Nitra, Nitra) and two from Ukraine (Diagnostic Center of Medical Academy, Dnipropetrovsk, and National Institute of Phthisiology and Pulmonology, Kiev).

Isolates of H. influenzae and S. pneumoniae from community-acquired respiratory tract infections were sent to a central laboratory (International Health Management Associates, Inc., Switzerland) where they were sub-cultured and re-identified. H. influenzae 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 the Clinical and Laboratory Standards Institute (CLSI).6

Both pathogens were assessed for susceptibility to amoxicillin, amoxicillin/clavulanic acid (2:1), azithromycin, cefaclor, ceftriaxone, cefuroxime, clarithromycin, erythromycin, levofloxacin, moxifloxacin and trimethoprim/sulfamethoxazole (1:19). S. pneumoniae was also tested for susceptibility to penicillin whereas H. influenzae was additionally tested for susceptibility to ampicillin.

Susceptibility to the study drugs was calculated based on CLSI breakpoints, EUCAST breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.7–9 These breakpoints are shown in Table 1.

Table 1.
Open in new tab

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

S. pneumoniae
H. influenzae
CLSI
EUCAST
CLSI
EUCAST
AntimicrobialSIRSIRSIRSIRPK/PD (S only)
Amoxicillin≤24≥8NANANANANANA≤2–≥4≤2 (≤4)
AMCa≤24≥8NANANA≤4–≥8≤2–≥4≤2 (≤4)
AmpicillinNANANANANANA≤12≥4≤1–≥2NA
Azithromycin≤0.51≥2≤0.250.5≥1≤4––≤0.120.25–4≥8≤0.12
Cefaclor≤12≥4≤0.030.06–0.5≥1≤816≥32NANANA≤0.5
Ceftriaxone≤12≥4≤0.51–2≥4≤2––≤0.12–≥0.25≤1
Cefuroximeb≤12≥4≤0.250.5≥1≤48≥16≤0.120.25–1≥2≤1
Clarithromycin≤0.250.5≥1≤0.250.5≥1≤816≥32≤12–32≥64≤0.25
Erythromycin≤0.250.5≥1≤0.250.5≥1NANANANANANA≤0.25
Levofloxacin≤24≥8≤2–≥4≤2––≤0.06–≥0.12≤2
Moxifloxacin≤12≥4≤0.5–≥1≤1––≤0.12–≥0.25≤1
Penicillin (iv non-meningitis)≤24≥8NAcNAcNAcNANANANANANANA
Penicillin (oral)≤0.060.12–1≥2≤0.060.12–2≥4NANANANANANANA
SXTd≤0.51–2≥4≤12≥4≤0.51–2≥4≤0.51≥2≤0.5
S. pneumoniae
H. influenzae
CLSI
EUCAST
CLSI
EUCAST
AntimicrobialSIRSIRSIRSIRPK/PD (S only)
Amoxicillin≤24≥8NANANANANANA≤2–≥4≤2 (≤4)
AMCa≤24≥8NANANA≤4–≥8≤2–≥4≤2 (≤4)
AmpicillinNANANANANANA≤12≥4≤1–≥2NA
Azithromycin≤0.51≥2≤0.250.5≥1≤4––≤0.120.25–4≥8≤0.12
Cefaclor≤12≥4≤0.030.06–0.5≥1≤816≥32NANANA≤0.5
Ceftriaxone≤12≥4≤0.51–2≥4≤2––≤0.12–≥0.25≤1
Cefuroximeb≤12≥4≤0.250.5≥1≤48≥16≤0.120.25–1≥2≤1
Clarithromycin≤0.250.5≥1≤0.250.5≥1≤816≥32≤12–32≥64≤0.25
Erythromycin≤0.250.5≥1≤0.250.5≥1NANANANANANA≤0.25
Levofloxacin≤24≥8≤2–≥4≤2––≤0.06–≥0.12≤2
Moxifloxacin≤12≥4≤0.5–≥1≤1––≤0.12–≥0.25≤1
Penicillin (iv non-meningitis)≤24≥8NAcNAcNAcNANANANANANANA
Penicillin (oral)≤0.060.12–1≥2≤0.060.12–2≥4NANANANANANANA
SXTd≤0.51–2≥4≤12≥4≤0.51–2≥4≤0.51≥2≤0.5

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable.

a

Amoxicillin/clavulanic acid was tested at a 2:1 amoxicillin to clavulanic acid ratio; breakpoints are expressed as the amoxicillin component. PK/PD breakpoints based on high dose (4 g of amoxicillin with 250 mg of clavulanate per day for adults) shown in parentheses,9 which is the same as CLSI for H. influenzae and one dilution higher for S. pneumoniae.

b

Breakpoints used are for cefuroxime axetil.

c

EUCAST do not give iv breakpoints but dose-specific-susceptible breakpoints are noted for pneumonia: 1.2 g × 4,  ≤ 0.5 mg/L; 2.4 g × 4 (or 1.2 g × 6), ≤1 mg/L and 2.4 g × 6 , ≤ 2 mg/L.

d

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

Table 1.
Open in new tab

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

S. pneumoniae
H. influenzae
CLSI
EUCAST
CLSI
EUCAST
AntimicrobialSIRSIRSIRSIRPK/PD (S only)
Amoxicillin≤24≥8NANANANANANA≤2–≥4≤2 (≤4)
AMCa≤24≥8NANANA≤4–≥8≤2–≥4≤2 (≤4)
AmpicillinNANANANANANA≤12≥4≤1–≥2NA
Azithromycin≤0.51≥2≤0.250.5≥1≤4––≤0.120.25–4≥8≤0.12
Cefaclor≤12≥4≤0.030.06–0.5≥1≤816≥32NANANA≤0.5
Ceftriaxone≤12≥4≤0.51–2≥4≤2––≤0.12–≥0.25≤1
Cefuroximeb≤12≥4≤0.250.5≥1≤48≥16≤0.120.25–1≥2≤1
Clarithromycin≤0.250.5≥1≤0.250.5≥1≤816≥32≤12–32≥64≤0.25
Erythromycin≤0.250.5≥1≤0.250.5≥1NANANANANANA≤0.25
Levofloxacin≤24≥8≤2–≥4≤2––≤0.06–≥0.12≤2
Moxifloxacin≤12≥4≤0.5–≥1≤1––≤0.12–≥0.25≤1
Penicillin (iv non-meningitis)≤24≥8NAcNAcNAcNANANANANANANA
Penicillin (oral)≤0.060.12–1≥2≤0.060.12–2≥4NANANANANANANA
SXTd≤0.51–2≥4≤12≥4≤0.51–2≥4≤0.51≥2≤0.5
S. pneumoniae
H. influenzae
CLSI
EUCAST
CLSI
EUCAST
AntimicrobialSIRSIRSIRSIRPK/PD (S only)
Amoxicillin≤24≥8NANANANANANA≤2–≥4≤2 (≤4)
AMCa≤24≥8NANANA≤4–≥8≤2–≥4≤2 (≤4)
AmpicillinNANANANANANA≤12≥4≤1–≥2NA
Azithromycin≤0.51≥2≤0.250.5≥1≤4––≤0.120.25–4≥8≤0.12
Cefaclor≤12≥4≤0.030.06–0.5≥1≤816≥32NANANA≤0.5
Ceftriaxone≤12≥4≤0.51–2≥4≤2––≤0.12–≥0.25≤1
Cefuroximeb≤12≥4≤0.250.5≥1≤48≥16≤0.120.25–1≥2≤1
Clarithromycin≤0.250.5≥1≤0.250.5≥1≤816≥32≤12–32≥64≤0.25
Erythromycin≤0.250.5≥1≤0.250.5≥1NANANANANANA≤0.25
Levofloxacin≤24≥8≤2–≥4≤2––≤0.06–≥0.12≤2
Moxifloxacin≤12≥4≤0.5–≥1≤1––≤0.12–≥0.25≤1
Penicillin (iv non-meningitis)≤24≥8NAcNAcNAcNANANANANANANA
Penicillin (oral)≤0.060.12–1≥2≤0.060.12–2≥4NANANANANANANA
SXTd≤0.51–2≥4≤12≥4≤0.51–2≥4≤0.51≥2≤0.5

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable.

a

Amoxicillin/clavulanic acid was tested at a 2:1 amoxicillin to clavulanic acid ratio; breakpoints are expressed as the amoxicillin component. PK/PD breakpoints based on high dose (4 g of amoxicillin with 250 mg of clavulanate per day for adults) shown in parentheses,9 which is the same as CLSI for H. influenzae and one dilution higher for S. pneumoniae.

b

Breakpoints used are for cefuroxime axetil.

c

EUCAST do not give iv breakpoints but dose-specific-susceptible breakpoints are noted for pneumonia: 1.2 g × 4,  ≤ 0.5 mg/L; 2.4 g × 4 (or 1.2 g × 6), ≤1 mg/L and 2.4 g × 6 , ≤ 2 mg/L.

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 32518 were included on each day of testing. Results of susceptibility testing were accepted if the results of the control strains were within published limits. Differences in susceptibility (using CLSI criteria) across age groups, source of infection and penicillin susceptibility (S. pneumoniae only) were assessed for statistical significance (where n ≥ 20) with Fisher’s exact test using XLSTAT version 2011.1.05. A P value <0.05 was considered statistically significant.

Results

S. pneumoniae isolates

A total of 195 S. pneumoniae isolates were collected from three centres in the Slovak Republic and Ukraine from 2014 to 2016. Most pneumococci came from sputum (n = 60; 30.8%) and bronchoalveolar lavage (n = 56; 28.7%). Less frequently, isolates were from sinuses (n = 35; 17.9%), middle ear effusion (n = 20; 10.3%), endotracheal aspirate (n = 5; 2.6%) and blood (n = 3; 1.5%). Sixteen isolates were from an undisclosed respiratory source (8.2%). Most isolates (n = 98; 50.3%) came from adult patients (13–64 years old), 69 (35.4%) were from children (aged ≤12 years) and 28 (14.4%) were from elderly patients (aged ≥65 years).

Summary MIC and susceptibility data for all 195 S. pneumoniae isolates broken down by country of origin are shown in Table 2. MIC distribution data are given in Table 3.

Table 2.
Open in new tab

MIC and susceptibility data for S. pneumoniae isolates

Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina950.038≤0.015>864.21.134.764.2 (65.3)NANANA
 AMCa95≤0.0158≤0.015864.215.820.064.2 (80.0)NANANA
 azithromycin95>2>20.06>244.20.055.841.144.20.055.8
 cefaclor951>40.5>457.93.239.06.30.06.393.7
 ceftriaxone950.1220.03282.117.90.082.163.236.80.0
 cefuroxime95≤0.12>4≤0.12>463.20.036.863.256.86.336.8
 clarithromycin95>1>1≤0.015>144.20.055.844.244.20.055.8
 erythromycin95>0.5>0.50.03>0.544.20.055.844.244.20.055.8
 levofloxacin95110.521000.00.0100100–0.0
 moxifloxacin950.120.250.060.251000.00.0100100–0.0
 penicillin (oral)95≤0.064≤0.06>461.13.235.8NA61.13.235.8
 penicillin (iv non-meningitis)95≤0.064≤0.06>464.231.64.2NANANANA
 SXT950.12>2≤0.06>264.21.134.764.264.21.134.7
Ukraine
 amoxicillina100≤0.0151≤0.015897.00.03.097.0 (97.0)NANANA
 AMCa100≤0.0150.5≤0.015897.02.01.097.0 (99.0)NANANA
 azithromycin1000.12>2≤0.03>284.00.016.076.084.00.016.0
 cefaclor100140.25>486.01.013.028.00.028.072.0
 ceftriaxone1000.030.5≤0.015298.02.00.098.090.010.00.0
 cefuroxime100≤0.122≤0.12>489.02.09.089.088.00.012.0
 clarithromycin100≤0.015>1≤0.015>184.01.015.084.084.01.015.0
 erythromycin1000.03>0.50.03>0.583.00.017.083.083.00.017.0
 levofloxacin10011121000.00.0100100–0.0
 moxifloxacin1000.120.250.060.51000.00.0100100–0.0
 penicillin (oral)100≤0.061≤0.06483.09.08.0NA83.014.03.0
 penicillin (iv non-meningitis)100≤0.061≤0.06497.03.00.0NANANANA
 SXT1000.25>20.12>275.013.012.075.075.013.012.0
Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina950.038≤0.015>864.21.134.764.2 (65.3)NANANA
 AMCa95≤0.0158≤0.015864.215.820.064.2 (80.0)NANANA
 azithromycin95>2>20.06>244.20.055.841.144.20.055.8
 cefaclor951>40.5>457.93.239.06.30.06.393.7
 ceftriaxone950.1220.03282.117.90.082.163.236.80.0
 cefuroxime95≤0.12>4≤0.12>463.20.036.863.256.86.336.8
 clarithromycin95>1>1≤0.015>144.20.055.844.244.20.055.8
 erythromycin95>0.5>0.50.03>0.544.20.055.844.244.20.055.8
 levofloxacin95110.521000.00.0100100–0.0
 moxifloxacin950.120.250.060.251000.00.0100100–0.0
 penicillin (oral)95≤0.064≤0.06>461.13.235.8NA61.13.235.8
 penicillin (iv non-meningitis)95≤0.064≤0.06>464.231.64.2NANANANA
 SXT950.12>2≤0.06>264.21.134.764.264.21.134.7
Ukraine
 amoxicillina100≤0.0151≤0.015897.00.03.097.0 (97.0)NANANA
 AMCa100≤0.0150.5≤0.015897.02.01.097.0 (99.0)NANANA
 azithromycin1000.12>2≤0.03>284.00.016.076.084.00.016.0
 cefaclor100140.25>486.01.013.028.00.028.072.0
 ceftriaxone1000.030.5≤0.015298.02.00.098.090.010.00.0
 cefuroxime100≤0.122≤0.12>489.02.09.089.088.00.012.0
 clarithromycin100≤0.015>1≤0.015>184.01.015.084.084.01.015.0
 erythromycin1000.03>0.50.03>0.583.00.017.083.083.00.017.0
 levofloxacin10011121000.00.0100100–0.0
 moxifloxacin1000.120.250.060.51000.00.0100100–0.0
 penicillin (oral)100≤0.061≤0.06483.09.08.0NA83.014.03.0
 penicillin (iv non-meningitis)100≤0.061≤0.06497.03.00.0NANANANA
 SXT1000.25>20.12>275.013.012.075.075.013.012.0

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable.

a

Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.

Table 2.
Open in new tab

MIC and susceptibility data for S. pneumoniae isolates

Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina950.038≤0.015>864.21.134.764.2 (65.3)NANANA
 AMCa95≤0.0158≤0.015864.215.820.064.2 (80.0)NANANA
 azithromycin95>2>20.06>244.20.055.841.144.20.055.8
 cefaclor951>40.5>457.93.239.06.30.06.393.7
 ceftriaxone950.1220.03282.117.90.082.163.236.80.0
 cefuroxime95≤0.12>4≤0.12>463.20.036.863.256.86.336.8
 clarithromycin95>1>1≤0.015>144.20.055.844.244.20.055.8
 erythromycin95>0.5>0.50.03>0.544.20.055.844.244.20.055.8
 levofloxacin95110.521000.00.0100100–0.0
 moxifloxacin950.120.250.060.251000.00.0100100–0.0
 penicillin (oral)95≤0.064≤0.06>461.13.235.8NA61.13.235.8
 penicillin (iv non-meningitis)95≤0.064≤0.06>464.231.64.2NANANANA
 SXT950.12>2≤0.06>264.21.134.764.264.21.134.7
Ukraine
 amoxicillina100≤0.0151≤0.015897.00.03.097.0 (97.0)NANANA
 AMCa100≤0.0150.5≤0.015897.02.01.097.0 (99.0)NANANA
 azithromycin1000.12>2≤0.03>284.00.016.076.084.00.016.0
 cefaclor100140.25>486.01.013.028.00.028.072.0
 ceftriaxone1000.030.5≤0.015298.02.00.098.090.010.00.0
 cefuroxime100≤0.122≤0.12>489.02.09.089.088.00.012.0
 clarithromycin100≤0.015>1≤0.015>184.01.015.084.084.01.015.0
 erythromycin1000.03>0.50.03>0.583.00.017.083.083.00.017.0
 levofloxacin10011121000.00.0100100–0.0
 moxifloxacin1000.120.250.060.51000.00.0100100–0.0
 penicillin (oral)100≤0.061≤0.06483.09.08.0NA83.014.03.0
 penicillin (iv non-meningitis)100≤0.061≤0.06497.03.00.0NANANANA
 SXT1000.25>20.12>275.013.012.075.075.013.012.0
Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina950.038≤0.015>864.21.134.764.2 (65.3)NANANA
 AMCa95≤0.0158≤0.015864.215.820.064.2 (80.0)NANANA
 azithromycin95>2>20.06>244.20.055.841.144.20.055.8
 cefaclor951>40.5>457.93.239.06.30.06.393.7
 ceftriaxone950.1220.03282.117.90.082.163.236.80.0
 cefuroxime95≤0.12>4≤0.12>463.20.036.863.256.86.336.8
 clarithromycin95>1>1≤0.015>144.20.055.844.244.20.055.8
 erythromycin95>0.5>0.50.03>0.544.20.055.844.244.20.055.8
 levofloxacin95110.521000.00.0100100–0.0
 moxifloxacin950.120.250.060.251000.00.0100100–0.0
 penicillin (oral)95≤0.064≤0.06>461.13.235.8NA61.13.235.8
 penicillin (iv non-meningitis)95≤0.064≤0.06>464.231.64.2NANANANA
 SXT950.12>2≤0.06>264.21.134.764.264.21.134.7
Ukraine
 amoxicillina100≤0.0151≤0.015897.00.03.097.0 (97.0)NANANA
 AMCa100≤0.0150.5≤0.015897.02.01.097.0 (99.0)NANANA
 azithromycin1000.12>2≤0.03>284.00.016.076.084.00.016.0
 cefaclor100140.25>486.01.013.028.00.028.072.0
 ceftriaxone1000.030.5≤0.015298.02.00.098.090.010.00.0
 cefuroxime100≤0.122≤0.12>489.02.09.089.088.00.012.0
 clarithromycin100≤0.015>1≤0.015>184.01.015.084.084.01.015.0
 erythromycin1000.03>0.50.03>0.583.00.017.083.083.00.017.0
 levofloxacin10011121000.00.0100100–0.0
 moxifloxacin1000.120.250.060.51000.00.0100100–0.0
 penicillin (oral)100≤0.061≤0.06483.09.08.0NA83.014.03.0
 penicillin (iv non-meningitis)100≤0.061≤0.06497.03.00.0NANANANA
 SXT1000.25>20.12>275.013.012.075.075.013.012.0

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable.

a

Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.

Table 3.
Open in new tab

MIC distribution data for S. pneumoniae isolates

AntimicrobialNumber of isolates at MIC (mg/L)
≤0.015≤0.030.03≤0.060.06≤0.120.120.250.5>0.51>12>24>48>8
Slovak Republic (n = 95)
 amoxicillin15367211321
 AMC52511111519
 azithromycin138353
 cefaclor6493136
 ceftriaxone34122211817
 cefuroxime5226233
 clarithromycin35753
 erythromycin41153
 levofloxacin1904
 moxifloxacin15935
 penicillin58111304
 SXT25351133
Ukraine (n = 100)
 amoxicillin5132231623
 AMC8421111721
 azithromycin41359816
 cefaclor22658158
 ceftriaxone378331282
 cefuroxime881263
 clarithromycin731011213
 erythromycin79417
 levofloxacin919
 moxifloxacin2158201
 penicillin83231353
 SXT4911151312
AntimicrobialNumber of isolates at MIC (mg/L)
≤0.015≤0.030.03≤0.060.06≤0.120.120.250.5>0.51>12>24>48>8
Slovak Republic (n = 95)
 amoxicillin15367211321
 AMC52511111519
 azithromycin138353
 cefaclor6493136
 ceftriaxone34122211817
 cefuroxime5226233
 clarithromycin35753
 erythromycin41153
 levofloxacin1904
 moxifloxacin15935
 penicillin58111304
 SXT25351133
Ukraine (n = 100)
 amoxicillin5132231623
 AMC8421111721
 azithromycin41359816
 cefaclor22658158
 ceftriaxone378331282
 cefuroxime881263
 clarithromycin731011213
 erythromycin79417
 levofloxacin919
 moxifloxacin2158201
 penicillin83231353
 SXT4911151312

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole.

Table 3.
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MIC distribution data for S. pneumoniae isolates

AntimicrobialNumber of isolates at MIC (mg/L)
≤0.015≤0.030.03≤0.060.06≤0.120.120.250.5>0.51>12>24>48>8
Slovak Republic (n = 95)
 amoxicillin15367211321
 AMC52511111519
 azithromycin138353
 cefaclor6493136
 ceftriaxone34122211817
 cefuroxime5226233
 clarithromycin35753
 erythromycin41153
 levofloxacin1904
 moxifloxacin15935
 penicillin58111304
 SXT25351133
Ukraine (n = 100)
 amoxicillin5132231623
 AMC8421111721
 azithromycin41359816
 cefaclor22658158
 ceftriaxone378331282
 cefuroxime881263
 clarithromycin731011213
 erythromycin79417
 levofloxacin919
 moxifloxacin2158201
 penicillin83231353
 SXT4911151312
AntimicrobialNumber of isolates at MIC (mg/L)
≤0.015≤0.030.03≤0.060.06≤0.120.120.250.5>0.51>12>24>48>8
Slovak Republic (n = 95)
 amoxicillin15367211321
 AMC52511111519
 azithromycin138353
 cefaclor6493136
 ceftriaxone34122211817
 cefuroxime5226233
 clarithromycin35753
 erythromycin41153
 levofloxacin1904
 moxifloxacin15935
 penicillin58111304
 SXT25351133
Ukraine (n = 100)
 amoxicillin5132231623
 AMC8421111721
 azithromycin41359816
 cefaclor22658158
 ceftriaxone378331282
 cefuroxime881263
 clarithromycin731011213
 erythromycin79417
 levofloxacin919
 moxifloxacin2158201
 penicillin83231353
 SXT4911151312

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole.

S. pneumoniae susceptibility in the Slovak Republic

Of the 95 pneumococci collected in the Slovak Republic, 64.2% were penicillin susceptible by CLSI penicillin intravenous (iv) (non-meningitis) breakpoints and 61.1% by CLSI penicillin oral breakpoints or EUCAST breakpoints. All the S. pneumoniae were susceptible to levofloxacin and moxifloxacin by all breakpoints. Susceptibility to ceftriaxone was 82.1% by CLSI and PK/PD breakpoints, but only 63.2% by EUCAST breakpoints. Susceptibility to amoxicillin and amoxicillin/clavulanic acid was 65.3% and 80.0%, respectively, at high-dose PK/PD breakpoints, but reduced to 64.2% by CLSI and low-dose PK/PD breakpoints. Susceptibility to trimethoprim/sulfamethoxazole was 64.2% by all breakpoints, and to cefuroxime it was 63.2% by CLSI and PK/PD criteria and 56.8% by EUCAST standards. The other antimicrobials showed susceptibility rates of <60% (Table 2).

Insufficient isolates were obtained to analyse antimicrobial susceptibility by specimen source. There was no significant difference in antimicrobial susceptibility based on patient age (data not shown).

S. pneumoniae susceptibility in Ukraine

Of the pneumococcal isolates from Ukraine, 97.0% were susceptible to penicillin by CLSI penicillin iv (non-meningitis) breakpoints and 83.0% were susceptible by CLSI penicillin oral breakpoints or EUCAST breakpoints. All were susceptible to levofloxacin and moxifloxacin by all breakpoints. Ninety-eight percent were also susceptible to ceftriaxone by CLSI and PK/PD breakpoints, with a reduction to 90.0% by EUCAST breakpoints. Susceptibility to amoxicillin and amoxicillin/clavulanic acid was 97.0% by CLSI and PK/PD low-dose breakpoints; using high-dose PK/PD criteria susceptibility to amoxicillin remained at 97.0%, whereas susceptibility to amoxicillin/clavulanic acid increased to 99.0%. Susceptibility by CLSI breakpoints to the oral cephalosporins and the macrolides ranged from 83.0% for erythromycin to 89.0% for cefuroxime. Susceptibility was the same or similar by PK/PD and EUCAST breakpoints except for susceptibility of isolates to cefaclor, which showed values of 28.0% using PK/PD criteria and 0% using EUCAST standards. Trimethoprim/sulfamethoxazole was the only agent to which <80% of isolates were susceptible (75.0% by all three breakpoints) (Table 2).

Antimicrobial susceptibility using CLSI criteria was compared across specimen sources and age groups. The only statistically significant difference observed was for the macrolides between isolates from paediatric patients (n = 27; 70.4% susceptible to all three macrolides) and adults (n = 65; 89.2% susceptible, P = 0.03) and for cefaclor between isolates from paediatric patients (70.4% susceptible) and adults (90.8% susceptible, P = 0.02).

Antimicrobial susceptibility of S. pneumoniae by penicillin susceptibility

Among the 195 S. pneumoniae isolates from both countries, 141 (72.3%) were penicillin susceptible (PSSP), 12 (6.2%) were penicillin intermediate (PISP) and 42 (21.5%) were penicillin resistant (PRSP) according to CLSI oral breakpoints. PSSP and PRSP sub-groups had a sample size >20 and were compared for susceptibility to other antimicrobial agents (Figure 1). Among PSSP isolates, susceptibility to the fluoroquinolones, amoxicillin, amoxicillin/clavulanic acid, cefuroxime and ceftriaxone was 100%, to cefaclor it was 97.9%, to trimethoprim/sulfamethoxazole 90.8% and to the macrolides 80.9% (using CLSI criteria). The fluoroquinolones also maintained 100% activity against PRSP isolates, but susceptibility to the other agents was significantly lower than in PSSP isolates (P < 0.0001), with rates ranging from 0% to 12% to all remaining agents except ceftriaxone (54.8%).

Percentage susceptibility rates (with 95% CI) using CLSI criteria for antimicrobials against all S. pneumoniae according to susceptibility to penicillin (oral). *PSSP significantly more susceptible than PRSP isolates (P < 0.0001). PSSP, penicillin-susceptible S. pneumoniae; PRSP, penicillin-resistant S. pneumoniae.
Figure 1.

Percentage susceptibility rates (with 95% CI) using CLSI criteria for antimicrobials against all S. pneumoniae according to susceptibility to penicillin (oral). *PSSP significantly more susceptible than PRSP isolates (P < 0.0001). PSSP, penicillin-susceptible S. pneumoniae; PRSP, penicillin-resistant S. pneumoniae.

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H. influenzae isolates

A total of 194 H. influenzae isolates were collected from the three centres in the Slovak Republic and Ukraine from 2014 to 2016. Specimen origins of the isolates included sputum (n = 91; 46.9%), sinuses (n = 43; 22.2%), bronchoalveolar lavage (n = 30; 15.5%), endotracheal aspirate (n = 14, 7.2%) and middle ear effusion (n = 10, 5.2%). Six isolates (3.1%) were from an undisclosed respiratory source. Most isolates (n = 116; 59.8%) came from adult patients, 52 (26.8%) were from children and 26 (13.4%) were from elderly patients. The rate of β-lactamase-positive isolates was 5.1% in the Slovak Republic (5/98) and 7.3% in Ukraine (7/96). Seven isolates from the Slovak Republic (7.1%) and one from Ukraine (1.0%) were β-lactamase-negative-ampicillin-resistant (BLNAR) by CLSI breakpoints (ampicillin MIC ≥4 mg/L), and eight from the Slovak Republic (8.2%) and one from Ukraine (1.0%) were BLNAR by EUCAST breakpoints (ampicillin MIC ≥2 mg/L).

Summary MIC and susceptibility data for all 194 H. influenzae isolates broken down by country of origin are shown in Table 4. MIC distribution data are given in Table 5.

Table 4.
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MIC and susceptibility data for H. influenzae isolates

Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina98≤28≤2>128NANANA86.7 (89.8)86.7–13.3
 AMCa,b980.520.254100 (92.9)–0.0 (7.1)92.9 (100)92.9–7.1
 ampicillin980.254≤0.06>12886.71.012.2–86.7–13.3
 azithromycin982214100––0.00.01000.0
 cefaclorb9841611689.8 (86.7)10.2 (6.1)0.0 (7.1)0.0NANANA
 ceftriaxone98≤0.030.06≤0.030.25100––10096.9–3.1
 cefuroximeb980.520.064100 (92.9)0.00.0 (7.1)82.71.081.617.4
 clarithromycin9816168>1634.759.26.10.00.01000.0
 levofloxacin980.0150.030.0080.06100––100100–0.0
 moxifloxacin980.0150.0150.0080.06100––100100–0.0
 SXT980.25>20.03>277.63.119.477.677.60.022.5
Ukraine
 amoxicillina96≤24≤2>128NANANA87.5 (91.7)87.5–12.5
 AMCa,b960.520.254100 (99.0)–0.0 (1.0)95.8 (100)95.8–4.2
 ampicillin960.2510.12>12891.70.08.3–91.7–8.3
 azithromycin96220.12897.9––2.12.195.82.1
 cefaclorb9641613287.56.36.30.0NANANA
 ceftriaxone96≤0.03≤0.03≤0.030.12100––100100–0.0
 cefuroximeb96140.25897.9 (96.9)2.10.0 (1.0)70.80.070.829.2
 clarithromycin96816≤1>1661.537.51.00.02.197.90.0
 levofloxacin960.0150.030.0080.06100––100100–0.0
 moxifloxacin960.0150.030.0080.12100––100100–0.0
 SXT960.25>2≤0.015>260.42.137.560.460.40.039.6
Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina98≤28≤2>128NANANA86.7 (89.8)86.7–13.3
 AMCa,b980.520.254100 (92.9)–0.0 (7.1)92.9 (100)92.9–7.1
 ampicillin980.254≤0.06>12886.71.012.2–86.7–13.3
 azithromycin982214100––0.00.01000.0
 cefaclorb9841611689.8 (86.7)10.2 (6.1)0.0 (7.1)0.0NANANA
 ceftriaxone98≤0.030.06≤0.030.25100––10096.9–3.1
 cefuroximeb980.520.064100 (92.9)0.00.0 (7.1)82.71.081.617.4
 clarithromycin9816168>1634.759.26.10.00.01000.0
 levofloxacin980.0150.030.0080.06100––100100–0.0
 moxifloxacin980.0150.0150.0080.06100––100100–0.0
 SXT980.25>20.03>277.63.119.477.677.60.022.5
Ukraine
 amoxicillina96≤24≤2>128NANANA87.5 (91.7)87.5–12.5
 AMCa,b960.520.254100 (99.0)–0.0 (1.0)95.8 (100)95.8–4.2
 ampicillin960.2510.12>12891.70.08.3–91.7–8.3
 azithromycin96220.12897.9––2.12.195.82.1
 cefaclorb9641613287.56.36.30.0NANANA
 ceftriaxone96≤0.03≤0.03≤0.030.12100––100100–0.0
 cefuroximeb96140.25897.9 (96.9)2.10.0 (1.0)70.80.070.829.2
 clarithromycin96816≤1>1661.537.51.00.02.197.90.0
 levofloxacin960.0150.030.0080.06100––100100–0.0
 moxifloxacin960.0150.030.0080.12100––100100–0.0
 SXT960.25>2≤0.015>260.42.137.560.460.40.039.6

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable; min, minimum; max, maximum.

a

Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.

b

In clinical settings, isolates of BLNAR are considered resistant to amoxicillin/clavulanic acid, cefaclor and cefuroxime. If clinical susceptibility to these agents was reduced due to BLNAR, data are shown in parentheses.

Table 4.
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MIC and susceptibility data for H. influenzae isolates

Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina98≤28≤2>128NANANA86.7 (89.8)86.7–13.3
 AMCa,b980.520.254100 (92.9)–0.0 (7.1)92.9 (100)92.9–7.1
 ampicillin980.254≤0.06>12886.71.012.2–86.7–13.3
 azithromycin982214100––0.00.01000.0
 cefaclorb9841611689.8 (86.7)10.2 (6.1)0.0 (7.1)0.0NANANA
 ceftriaxone98≤0.030.06≤0.030.25100––10096.9–3.1
 cefuroximeb980.520.064100 (92.9)0.00.0 (7.1)82.71.081.617.4
 clarithromycin9816168>1634.759.26.10.00.01000.0
 levofloxacin980.0150.030.0080.06100––100100–0.0
 moxifloxacin980.0150.0150.0080.06100––100100–0.0
 SXT980.25>20.03>277.63.119.477.677.60.022.5
Ukraine
 amoxicillina96≤24≤2>128NANANA87.5 (91.7)87.5–12.5
 AMCa,b960.520.254100 (99.0)–0.0 (1.0)95.8 (100)95.8–4.2
 ampicillin960.2510.12>12891.70.08.3–91.7–8.3
 azithromycin96220.12897.9––2.12.195.82.1
 cefaclorb9641613287.56.36.30.0NANANA
 ceftriaxone96≤0.03≤0.03≤0.030.12100––100100–0.0
 cefuroximeb96140.25897.9 (96.9)2.10.0 (1.0)70.80.070.829.2
 clarithromycin96816≤1>1661.537.51.00.02.197.90.0
 levofloxacin960.0150.030.0080.06100––100100–0.0
 moxifloxacin960.0150.030.0080.12100––100100–0.0
 SXT960.25>2≤0.015>260.42.137.560.460.40.039.6
Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobialn50%90%minmax%S%I%R%S%S%I%R
Slovak Republic
 amoxicillina98≤28≤2>128NANANA86.7 (89.8)86.7–13.3
 AMCa,b980.520.254100 (92.9)–0.0 (7.1)92.9 (100)92.9–7.1
 ampicillin980.254≤0.06>12886.71.012.2–86.7–13.3
 azithromycin982214100––0.00.01000.0
 cefaclorb9841611689.8 (86.7)10.2 (6.1)0.0 (7.1)0.0NANANA
 ceftriaxone98≤0.030.06≤0.030.25100––10096.9–3.1
 cefuroximeb980.520.064100 (92.9)0.00.0 (7.1)82.71.081.617.4
 clarithromycin9816168>1634.759.26.10.00.01000.0
 levofloxacin980.0150.030.0080.06100––100100–0.0
 moxifloxacin980.0150.0150.0080.06100––100100–0.0
 SXT980.25>20.03>277.63.119.477.677.60.022.5
Ukraine
 amoxicillina96≤24≤2>128NANANA87.5 (91.7)87.5–12.5
 AMCa,b960.520.254100 (99.0)–0.0 (1.0)95.8 (100)95.8–4.2
 ampicillin960.2510.12>12891.70.08.3–91.7–8.3
 azithromycin96220.12897.9––2.12.195.82.1
 cefaclorb9641613287.56.36.30.0NANANA
 ceftriaxone96≤0.03≤0.03≤0.030.12100––100100–0.0
 cefuroximeb96140.25897.9 (96.9)2.10.0 (1.0)70.80.070.829.2
 clarithromycin96816≤1>1661.537.51.00.02.197.90.0
 levofloxacin960.0150.030.0080.06100––100100–0.0
 moxifloxacin960.0150.030.0080.12100––100100–0.0
 SXT960.25>2≤0.015>260.42.137.560.460.40.039.6

AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable; min, minimum; max, maximum.

a

Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.

b

In clinical settings, isolates of BLNAR are considered resistant to amoxicillin/clavulanic acid, cefaclor and cefuroxime. If clinical susceptibility to these agents was reduced due to BLNAR, data are shown in parentheses.

Table 5.
Open in new tab

MIC distribution data for all H. influenzae isolates

AntimicrobialNumber of isolates at MIC (mg/L)
≤0.0040.008≤0.0150.015≤0.030.03≤0.060.060.120.25≤0.50.5≤11≤22>24816>1632>3264128>128
Slovak Republic (n = 98)
 amoxicillin85355
 AMC115020107
 ampicillin112541817113
 azithromycin16784
 cefaclor541301210
 ceftriaxone88163
 cefuroxime11542589
 clarithromycin34586
 levofloxacin4712354
 moxifloxacin187361
 SXT8291029319
Ukraine (n = 96)
 amoxicillin8441142
 AMC103920234
 ampicillin7552611123
 azithromycin228364332
 cefaclor522362166
 ceftriaxone9321
 cefuroxime332331882
 clarithromycin2651361
 levofloxacin959217
 moxifloxacin20551641
 SXT17151421236
AntimicrobialNumber of isolates at MIC (mg/L)
≤0.0040.008≤0.0150.015≤0.030.03≤0.060.060.120.25≤0.50.5≤11≤22>24816>1632>3264128>128
Slovak Republic (n = 98)
 amoxicillin85355
 AMC115020107
 ampicillin112541817113
 azithromycin16784
 cefaclor541301210
 ceftriaxone88163
 cefuroxime11542589
 clarithromycin34586
 levofloxacin4712354
 moxifloxacin187361
 SXT8291029319
Ukraine (n = 96)
 amoxicillin8441142
 AMC103920234
 ampicillin7552611123
 azithromycin228364332
 cefaclor522362166
 ceftriaxone9321
 cefuroxime332331882
 clarithromycin2651361
 levofloxacin959217
 moxifloxacin20551641
 SXT17151421236
Table 5.
Open in new tab

MIC distribution data for all H. influenzae isolates

AntimicrobialNumber of isolates at MIC (mg/L)
≤0.0040.008≤0.0150.015≤0.030.03≤0.060.060.120.25≤0.50.5≤11≤22>24816>1632>3264128>128
Slovak Republic (n = 98)
 amoxicillin85355
 AMC115020107
 ampicillin112541817113
 azithromycin16784
 cefaclor541301210
 ceftriaxone88163
 cefuroxime11542589
 clarithromycin34586
 levofloxacin4712354
 moxifloxacin187361
 SXT8291029319
Ukraine (n = 96)
 amoxicillin8441142
 AMC103920234
 ampicillin7552611123
 azithromycin228364332
 cefaclor522362166
 ceftriaxone9321
 cefuroxime332331882
 clarithromycin2651361
 levofloxacin959217
 moxifloxacin20551641
 SXT17151421236
AntimicrobialNumber of isolates at MIC (mg/L)
≤0.0040.008≤0.0150.015≤0.030.03≤0.060.060.120.25≤0.50.5≤11≤22>24816>1632>3264128>128
Slovak Republic (n = 98)
 amoxicillin85355
 AMC115020107
 ampicillin112541817113
 azithromycin16784
 cefaclor541301210
 ceftriaxone88163
 cefuroxime11542589
 clarithromycin34586
 levofloxacin4712354
 moxifloxacin187361
 SXT8291029319
Ukraine (n = 96)
 amoxicillin8441142
 AMC103920234
 ampicillin7552611123
 azithromycin228364332
 cefaclor522362166
 ceftriaxone9321
 cefuroxime332331882
 clarithromycin2651361
 levofloxacin959217
 moxifloxacin20551641
 SXT17151421236

H. influenzae susceptibility in the Slovak Republic

All isolates of H. influenzae from the Slovak Republic were susceptible to levofloxacin and moxifloxacin by all three breakpoint guidelines as well as to ceftriaxone by CLSI and PK/PD breakpoints (but susceptibility was reduced to 96.9% by EUCAST criteria). Susceptibility testing also resulted in 100% susceptibility to amoxicillin/clavulanic acid using CLSI and PK/PD high-dose breakpoints. However, CLSI guidelines state that BLNAR strains should be considered resistant to amoxicillin/clavulanic acid, cefuroxime and cefaclor, even if they appear susceptible in vitro.7 This reduces the percentage susceptible to amoxicillin/clavulanic acid to 92.9%, the same rate as obtained using PK/PD low-dose and EUCAST breakpoints. Similarly, susceptibility to cefuroxime was reduced from 100% to 92.9% by CLSI criteria after adjusting for BLNAR, and susceptibility to cefaclor was reduced from 89.8% to 86.7%. Susceptibility to both agents was dramatically lower using the other breakpoints (82.7% and 1.0% by PK/PD and EUCAST criteria, respectively, for cefuroxime, and 0% by PK/PD breakpoints for cefaclor). Susceptibility to ampicillin and amoxicillin was 86.7%, to trimethoprim/sulfamethoxazole it was 77.6% by all available breakpoints; and to clarithromycin 34.7% by CLSI standards and 0% by PK/PD and EUCAST criteria.

Antimicrobial susceptibility was compared by specimen source and age group with no significant difference observed (data not shown).

H. influenzae susceptibility in Ukraine

In Ukraine, susceptibility of H. influenzae (n = 96) was 100% to ceftriaxone, levofloxacin and moxifloxacin by all three breakpoint guidelines. Susceptibility to amoxicillin/clavulanic acid in vitro was also 100% by CLSI breakpoints and high-dose PK/PD breakpoints, but because one isolate was a BLNAR strain, susceptibility according to CLSI standards was slightly reduced to 99.0%. Susceptibility was 95.8% using low-dose PK/PD or EUCAST breakpoints. Similarly, susceptibility to cefuroxime was slightly reduced from 97.9% to 96.9% after adjusting for BLNAR using CLSI criteria; susceptibility was reduced much further using the other breakpoint criteria (70.8% by PK/PD and 0% by EUCAST standards). Susceptibility to cefaclor by CLSI criteria did not change as one BLNAR isolate had already tested resistant to cefaclor (87.5%), but susceptibility was 0% using the PK/PD breakpoint. A similarly dramatic difference between breakpoints was again seen for clarithromycin (61.5% by CLSI criteria, 0% by PK/PD and 2.1% by EUCAST). Susceptibility to trimethoprim/sulfamethoxazole was seen in 60.4% of isolates by all breakpoints.

Insufficient isolates were obtained to analyse antimicrobial susceptibility by specimen source or age.

Discussion

The countries in eastern Europe studied for this report showed substantial variability in the susceptibility of S. pneumoniae, similar to findings in other regions of the world that have been studied with the SOAR programme.2–5S. pneumoniae isolates collected in Ukraine (n = 100) showed higher susceptibility than those in the Slovak Republic, with rates ≥97% for all studied agents except oral penicillin, macrolides and cefaclor (between 83% and 86% susceptible) as well as cefuroxime (89%) and trimethoprim/sulfamethoxazole (75%). In the Slovak Republic, the fluoroquinolones remained 100% active, but of the other tested agents only ceftriaxone exceeded 80% susceptibility by CLSI criteria. Penicillin (oral and iv), amoxicillin, amoxicillin/clavulanic acid, cefaclor, cefuroxime and trimethoprim/sulfamethoxazole showed susceptibility between 58% and 64%, and the macrolides only 44%. There was significantly lower antimicrobial susceptibility (CLSI breakpoints) seen with isolates from the Slovak Republic compared with isolates from Ukraine to penicillin (iv), amoxicillin, amoxicillin/clavulanic acid, cefuroxime, cefaclor or macrolides (P < 0.0001), ceftriaxone (P = 0.002) and oral penicillin (P = 0.001).

Few data on antimicrobial susceptibility have been published for these countries. The most recent data available were generated through the European Antimicrobial Resistance Surveillance Network (EARS-Net);10 however, only the Slovak Republic participated and only invasive (blood and CSF) isolates are included in EARS-Net surveillance. Nevertheless the EARS-Net data of 22.2% penicillin non-susceptibility in 201510 confirmed our findings of low susceptibility to penicillin in the Slovak Republic even though the non-susceptibility rate was higher in the current study of respiratory isolates (38.9%). Interestingly, Marchese and Schito described high resistance rates among respiratory S. pneumoniae isolates from the Slovak Republic over 15 years ago: data from the Alexander Project from 1997 showed penicillin resistance of 26.7% and macrolide resistance of 13.3%.11 Riedel et al.12 also reported high non-susceptibility rates to penicillin (52.3%) and erythromycin (36.4%) in isolates from community-acquired respiratory tract infections collected in 2004–05 in the Slovak Republic. The same study showed that antimicrobial use in the Slovak Republic between 1998 and 2004 was third highest among 15 European countries, thus providing evidence for the association between antimicrobial resistance and increased use of antibiotics.12,13 In a more recent study of antibiotic consumption in 2011 in the broader European region, the Slovak Republic also ranked high (15th among 42 countries) in total antibiotic use.14

Ukraine was not included in any of these studies, but data from an earlier SOAR report are available for comparison.15 Susceptibility among the S. pneumoniae isolates from 2014 to 2016 included in the current study was similar to the S. pneumoniae isolates collected in 2011–13, with only a small decrease of between 2 and 5 percentage points for most antimicrobial agents. For example, amoxicillin/clavulanic acid showed susceptibility by CLSI criteria of 100% in 2011–13 compared with 97.0% in the current study, and the respective values for oral penicillin were 87.3% and 83.0%. The exception is trimethoprim/sulfamethoxazole, where susceptibility was very low in 2011–13 (9.7%),11 but 75% in the current study for 2014–16. It would be interesting to monitor these fluctuations in future studies.

In contrast to S. pneumoniae, antimicrobial activity against H. influenzae was fairly homogeneous between the two countries. Susceptibility to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime, azithromycin and the fluoroquinolones was >90% by CLSI criteria. Susceptibility to clarithromycin was lower and more variable (35% in the Slovak Republic compared with 61.5% in Ukraine), as was trimethoprim/sulfamethoxazole (77.6% in the Slovak Republic compared with 60.4% in Ukraine). The ampicillin resistance rate was 12.2% in the Slovak Republic, where the β-lactamase rate was 5.1% and an additional 7.1% of isolates were BLNAR. Ampicillin resistance was lower in Ukraine (8.3%) due to a lower β-lactamase rate (7.3%) and a low rate of BLNAR isolates (1.0%). These rates were also low in Ukraine in 2011–13, with a β-lactamase rate of 4.5% and no BLNAR isolates.15 Furthermore, susceptibility rates of H. influenzae in Ukraine were similar in the current study compared with the results in 2011–13, with the activity of most antimicrobial agents either still at 100% or only about 2 percentage points lower than in the earlier study. The exception is clarithromycin, where susceptibility was 61.5% using CSLI criteria in 2014–16 but 98.5% in 2011–13.15 Information on H. influenzae is sparse in the literature for the Slovak Republic. Interestingly, β-lactamase rates found through the Alexander Project 20 years ago were similar to those in our current study (5% in 1996 and 1997 in the Slovak Republic).11 Furthermore, the Slovak Republic, which had the highest BLNAR rate in the current study, was one of only four European countries where such isolates were found in 1997 (albeit at a very low rate).11

Although antimicrobial activity against H. influenzae was fairly homogeneous in the two countries, this was not the case when comparing susceptibility rates obtained using different breakpoints. For example, whereas >97% of isolates were susceptible to azithromycin using CLSI breakpoints, only ≤2.1% were susceptible using PK/PD and EUCAST criteria. Similarly, large differences were found for cefaclor between CLSI and PK/PD breakpoints and for cefuroxime between CLSI/PK/PD and EUCAST standards. Furthermore, although differences between breakpoints were small for most antimicrobial agents for S. pneumoniae, they were substantial for cefaclor. For example, in Ukraine 86.0% of S. pneumoniae isolates were susceptible by CLSI criteria, 28.0% by PK/PD and 0% using EUCAST standards. These differences are confusing for clinicians, but also hamper the use of surveillance data for research and public health efforts like antimicrobial stewardship.

This study’s main limitation stems from having to draw conclusions about a country’s antimicrobial susceptibility levels using data from just one or two hospital sites. It is reassuring that the results for Ukraine were very similar in the current study, which used two sites, to the earlier SOAR report, with eight sites. Nevertheless, more solid susceptibility rates can no doubt be achieved if surveillance is undertaken at more hospitals in each country, whether independently or as part of a national, regional or even international surveillance programme. Larger surveillance studies, such as SOAR, have the advantage of being able to employ a consistent methodology, which facilitates comparison between regions as well as trend analyses over time, but even surveillance at a single hospital can help local clinicians in selecting antibiotics for empirical therapy. In this study, data from just one or two hospitals per country were able to confirm a pattern of resistance already seen many years ago: high resistance of S. pneumoniae in the Slovak Republic compared with its neighbour Ukraine to the east. Regular monitoring and publication of such resistance data are not only critical for effective empirical therapy but can also be used to help shape antimicrobial stewardship strategies in an effort to lower historically high resistance rates.

Acknowledgements

We thank Gudrun Maechler and Olena Sopko for reviewing the manuscript and Jana Galisinova and Zuzana Benova for recruiting the centres.

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. O. Sopko is an employee of GlaxoSmithKline and does not hold any shares. 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. IHMA also provided medical writing support in the form of writing assistance, collating authors' comments, grammatical editing and referencing that was paid for by GlaxoSmithKline. All other authors declare that they have no conflict of interest. Editorial assistance was provided by Tracey Morris, Livewire Editorial Communications.

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