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Abstract

Objectives

To determine the antibiotic susceptibility of isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2014–16 from patients with community-acquired respiratory infections in the Czech 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 (n = 200) showed high rates of susceptibility (>95%) to amoxicillin, amoxicillin/clavulanic acid, penicillin [intravenous (iv) non-meningitis], ceftriaxone, cefuroxime and the fluoroquinolones using CLSI breakpoints. Susceptibility to cefaclor and trimethoprim/sulfamethoxazole was 94%–94.5%, to penicillin (oral) 91.5% and to the macrolides 89.5%. Susceptibility of H. influenzae (n = 197) to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime, azithromycin and the fluoroquinolones was ≥98% by CLSI criteria. Rates of susceptibility to the remaining agents were ≥75% except for clarithromycin at 37.1%. Great variability was seen across breakpoints, especially for the macrolides, cefaclor and cefuroxime (oral), 98.0% of H. influenzae showing susceptibility to the latter by CLSI criteria, 69.5% by PK/PD and 1.5% by EUCAST standards. The β-lactamase rate was 13.7% with no β-lactamase-negative-ampicillin-resistant (BLNAR) isolates by CLSI criteria.

Conclusions

Antibiotic resistance among the two major respiratory pathogens remained low in the Czech Republic. These findings support local clinicians in continuing the historically restrictive use of antibiotics in the Czech Republic, with selection of narrower-spectrum agents for the empirical therapy of community-acquired respiratory tract infections. This highlights one of the great benefits of continuous surveillance of antimicrobial resistance: knowledge of current local resistance patterns reduces the need to choose broad-spectrum agents that contribute to increasing resistance worldwide.

Introduction

In Europe in 2015, lower respiratory tract infections were the sixth most common cause of death with a crude mortality rate of 262.5 per 100 000 population.1 Respiratory bacteria make up the major group of pathogens causing community-acquired pneumonia, with Streptococcus pneumoniae the most frequently identified organism in all settings and Haemophilus influenzae frequently detected in outpatients.2 Antimicrobial therapy for lower respiratory infections is typically empirical, as the causative agent and its susceptibility profile are usually unknown when treatment is initiated. Surveillance studies of respiratory pathogens such as the Survey of Antibiotic Resistance (SOAR) have shown that resistance levels can vary substantially across countries and even between institutions in the same country.3–8 It is therefore critical for clinicians to have knowledge of local resistance levels to be able to select the most appropriate antimicrobial agents for empirical therapy, i.e. agents that are effective yet have as narrow a spectrum as possible. SOAR has been running since 2002 in Europe, the Middle East, Africa, Latin America, Asia-Pacific and Commonwealth of Independent States, providing antimicrobial resistance data that can be analysed across regions and over time.9 For this report, recent SOAR data for S. pneumoniae and H. influenzae from the Czech Republic were examined to see whether historically low resistance levels in the country have been maintained.

Materials and methods

Collaborating centres

One centre from the Czech Republic took part in the study (National Institute of Public Health, Centre for Epidemiology and Microbiology, National Reference Laboratory for Antibiotics, Prague, Czech Republic). 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. The following data were obtained from each patient: specimen source (direct respiratory specimen or blood sample from confirmed community-acquired pneumonia infection), age and gender.

Susceptibility testing

Isolates were evaluated for antibiotic susceptibility using broth microdilution methodology recommended by CLSI.10

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.11–13 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≥8NAcNAcNAcNANANANANANA
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≥8NAcNAcNAcNANANANANANA
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,13 which is the same as CLSI for H. influenzae and one dilution higher for S. pneumoniae.

b

Breakpoints used are for cefuroxime axetil (oral).

c

EUCAST do not give iv breakpoints but dose-specific-susceptible breakpoints are noted for pneumonia: 1.2 g × 4 ≤0.5, 2.4 g × 4 (or 1.2 g × 6) ≤1 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≥8NAcNAcNAcNANANANANANA
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≥8NAcNAcNAcNANANANANANA
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,13 which is the same as CLSI for H. influenzae and one dilution higher for S. pneumoniae.

b

Breakpoints used are for cefuroxime axetil (oral).

c

EUCAST do not give iv breakpoints but dose-specific-susceptible breakpoints are noted for pneumonia: 1.2 g × 4 ≤0.5, 2.4 g × 4 (or 1.2 g × 6) ≤1 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 and source of infection 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 200 S. pneumoniae isolates were collected from one centre in the Czech Republic from 2014–16. Most pneumococci came from blood (n = 126; 63.0%), sputum (n = 30; 15.0%) and bronchoalveolar lavage (n = 24; 12.0%). Less frequently, isolates were from endotracheal aspirate (n = 9; 4.5%), middle ear effusion (n = 8; 4.0%) and sinuses (n = 3; 1.5%). Most isolates (n = 95; 47.5%) came from adult patients (13–64 years old), 89 (44.5%) were from elderly patients (aged ≥65 years) and 15 (7.5%) were from children (aged ≤12 years). One isolate (0.5%) was from a patient for whom age was not provided.

Summary MIC and susceptibility data for S. pneumoniae isolates are shown in Table 2. MIC distribution data are given in Table 3. By CLSI penicillin intravenous (iv) (non-meningitis) breakpoints 97.5% of 200 S. pneumoniae from the Czech Republic were penicillin susceptible, but using CLSI penicillin oral breakpoints and EUCAST breakpoints 91.5% were penicillin susceptible (Table 2). Susceptibility to levofloxacin and moxifloxacin was 99.5% by all breakpoints, to ceftriaxone 98.0% by CLSI and PK/PD breakpoints and 95.5% with the lower EUCAST breakpoints, and to amoxicillin and amoxicillin/clavulanic acid 97.5% by CLSI and low-dose PK/PD criteria. Susceptibility to cefuroxime (oral) was 95.5% by CLSI or PK/PD breakpoints and 94.0% by EUCAST breakpoints. Susceptibility to trimethoprim/sulfamethoxazole was around 95% by all three breakpoints. On the other hand, susceptibility using CLSI standards showed that cefaclor had good activity (94.0%) but was poorly active or inactive by PK/PD (25.0%) and EUCAST breakpoints (0%).

Table 2.
Open in new tab

MIC and susceptibility data for S. pneumoniae isolates (n = 200) from the Czech Republic

Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina0.030.03≤0.015897.51.01.597.5 (98.5)NANANA
AMCa≤0.015≤0.015≤0.015897.51.51.097.5 (99.0)NANANA
Azithromycin0.121≤0.03>289.50.510.082.589.50.010.5
Cefaclor110.25>494.00.55.525.00.025.075.0
Ceftriaxone0.030.06≤0.015298.02.00.098.095.54.50.0
Cefuroxime (oral)≤0.12≤0.12≤0.12>495.51.03.595.594.01.05.0
Clarithromycin≤0.0150.5≤0.015>189.50.510.089.589.50.510.0
Erythromycin0.03>0.50.03>0.589.50.010.589.589.50.010.5
Levofloxacin110.5>499.50.00.599.599.5–0.5
Moxifloxacin0.120.250.06299.50.50.099.599.5–0.5
Penicillin (oral)≤0.06≤0.06≤0.06>491.55.03.5NA91.56.02.5
Penicillin (iv non-meningitis)≤0.06≤0.06≤0.06>497.52.00.5NANANANA
SXT0.120.25≤0.06>294.52.03.594.595.01.53.5
Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina0.030.03≤0.015897.51.01.597.5 (98.5)NANANA
AMCa≤0.015≤0.015≤0.015897.51.51.097.5 (99.0)NANANA
Azithromycin0.121≤0.03>289.50.510.082.589.50.010.5
Cefaclor110.25>494.00.55.525.00.025.075.0
Ceftriaxone0.030.06≤0.015298.02.00.098.095.54.50.0
Cefuroxime (oral)≤0.12≤0.12≤0.12>495.51.03.595.594.01.05.0
Clarithromycin≤0.0150.5≤0.015>189.50.510.089.589.50.510.0
Erythromycin0.03>0.50.03>0.589.50.010.589.589.50.010.5
Levofloxacin110.5>499.50.00.599.599.5–0.5
Moxifloxacin0.120.250.06299.50.50.099.599.5–0.5
Penicillin (oral)≤0.06≤0.06≤0.06>491.55.03.5NA91.56.02.5
Penicillin (iv non-meningitis)≤0.06≤0.06≤0.06>497.52.00.5NANANANA
SXT0.120.25≤0.06>294.52.03.594.595.01.53.5

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.

Table 2.
Open in new tab

MIC and susceptibility data for S. pneumoniae isolates (n = 200) from the Czech Republic

Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina0.030.03≤0.015897.51.01.597.5 (98.5)NANANA
AMCa≤0.015≤0.015≤0.015897.51.51.097.5 (99.0)NANANA
Azithromycin0.121≤0.03>289.50.510.082.589.50.010.5
Cefaclor110.25>494.00.55.525.00.025.075.0
Ceftriaxone0.030.06≤0.015298.02.00.098.095.54.50.0
Cefuroxime (oral)≤0.12≤0.12≤0.12>495.51.03.595.594.01.05.0
Clarithromycin≤0.0150.5≤0.015>189.50.510.089.589.50.510.0
Erythromycin0.03>0.50.03>0.589.50.010.589.589.50.010.5
Levofloxacin110.5>499.50.00.599.599.5–0.5
Moxifloxacin0.120.250.06299.50.50.099.599.5–0.5
Penicillin (oral)≤0.06≤0.06≤0.06>491.55.03.5NA91.56.02.5
Penicillin (iv non-meningitis)≤0.06≤0.06≤0.06>497.52.00.5NANANANA
SXT0.120.25≤0.06>294.52.03.594.595.01.53.5
Susceptibility using indicated breakpoints
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina0.030.03≤0.015897.51.01.597.5 (98.5)NANANA
AMCa≤0.015≤0.015≤0.015897.51.51.097.5 (99.0)NANANA
Azithromycin0.121≤0.03>289.50.510.082.589.50.010.5
Cefaclor110.25>494.00.55.525.00.025.075.0
Ceftriaxone0.030.06≤0.015298.02.00.098.095.54.50.0
Cefuroxime (oral)≤0.12≤0.12≤0.12>495.51.03.595.594.01.05.0
Clarithromycin≤0.0150.5≤0.015>189.50.510.089.589.50.510.0
Erythromycin0.03>0.50.03>0.589.50.010.589.589.50.010.5
Levofloxacin110.5>499.50.00.599.599.5–0.5
Moxifloxacin0.120.250.06299.50.50.099.599.5–0.5
Penicillin (oral)≤0.06≤0.06≤0.06>491.55.03.5NA91.56.02.5
Penicillin (iv non-meningitis)≤0.06≤0.06≤0.06>497.52.00.5NANANANA
SXT0.120.25≤0.06>294.52.03.594.595.01.53.5

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.

Table 3.
Open in new tab

MIC distribution data for S. pneumoniae isolates (n = 200) from the Czech Republic

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
Amoxicillin821005311323
AMC18332312132
Azithromycin1515914120
Cefaclor11391381110
Ceftriaxone3176542154
Cefuroxime (oral)185321234
Clarithromycin141381119
Erythromycin1691021
Levofloxacin219161
Moxifloxacin8138531
Penicillin1835221241
SXT3143376137
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
Amoxicillin821005311323
AMC18332312132
Azithromycin1515914120
Cefaclor11391381110
Ceftriaxone3176542154
Cefuroxime (oral)185321234
Clarithromycin141381119
Erythromycin1691021
Levofloxacin219161
Moxifloxacin8138531
Penicillin1835221241
SXT3143376137

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

Table 3.
Open in new tab

MIC distribution data for S. pneumoniae isolates (n = 200) from the Czech Republic

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
Amoxicillin821005311323
AMC18332312132
Azithromycin1515914120
Cefaclor11391381110
Ceftriaxone3176542154
Cefuroxime (oral)185321234
Clarithromycin141381119
Erythromycin1691021
Levofloxacin219161
Moxifloxacin8138531
Penicillin1835221241
SXT3143376137
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
Amoxicillin821005311323
AMC18332312132
Azithromycin1515914120
Cefaclor11391381110
Ceftriaxone3176542154
Cefuroxime (oral)185321234
Clarithromycin141381119
Erythromycin1691021
Levofloxacin219161
Moxifloxacin8138531
Penicillin1835221241
SXT3143376137

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

Susceptibility to clarithromycin and erythromycin was 89.5% by all breakpoints. Susceptibility to azithromycin was also 89.5% by CLSI and EUCAST breakpoints but was slightly lower (82.5%) using PK/PD breakpoints.

Antimicrobial susceptibility using CLSI criteria was compared across specimen sources and age groups. The only statistically significant difference (P = 0.04) observed was for the macrolides between isolates from blood (n = 126, 92.9% susceptible to all three macrolides) and sputum (n = 30, 80.0% susceptible).

Antimicrobial susceptibility of S. pneumoniae by penicillin susceptibility

Of the 200 S. pneumoniae isolates, 183 (91.5%) were penicillin susceptible (PSSP), 10 (5.0%) were penicillin intermediate (PISP), and only 7 (3.5%) were penicillin resistant (PRSP) according to CLSI oral breakpoints. Among PSSP isolates (using penicillin oral CLSI criteria), susceptibility to the fluoroquinolones, amoxicillin, amoxicillin/clavulanic acid and the cephalosporins was 100%, to trimethoprim/sulfamethoxazole it was 98.9% and to the macrolides it was 95.1%. Among PISP isolates, 100% susceptibility was maintained for the fluoroquinolones, amoxicillin, amoxicillin/clavulanic acid and ceftriaxone; susceptibility was reduced for cefuroxime (oral) and trimethoprim/sulfamethoxazole (80.0%), cefaclor (50.0%) and the macrolides (40.0%). However, the sample size was small (n = 10). Of the seven PRSP isolates, six were susceptible to the fluoroquinolones, three to ceftriaxone, two to amoxicillin and amoxicillin/clavulanic acid, one to the macrolides and none to the oral cephalosporins and trimethoprim/sulfamethoxazole. Sample sizes were too small to allow the detection of significant differences between PSSP, PISP and PRSP isolates.

H. influenzae

A total of 197 H. influenzae isolates were collected from the one centre in the Czech Republic from 2014–16. Infection origins of the isolates included sputum (n = 85; 43.1%), blood (n = 33, 16.8%), middle ear effusion (n = 24; 12.2%), endotracheal aspirate (n = 23; 11.7%), sinuses (n = 19; 9.6%) and bronchoalveolar lavage (n = 13; 6.6%). Ninety-five isolates (48.2%) came from adult patients, 58 (29.4%) were from elderly patients and 41 (20.8%) were from children. Three isolates (1.5%) were from patients for whom age was not provided. The β-lactamase rate was 13.7% (27/197). No isolates were β-lactamase-negative-ampicillin-resistant (BLNAR) by CLSI breakpoints (ampicillin MIC ≥4 mg/L), but 5 (2.5%) were BLNAR by EUCAST breakpoints (ampicillin MIC ≥2 mg/L).

Summary MIC and susceptibility data for H. influenzae isolates are shown in Table 4. MIC distribution data are given in Table 5. Among 197 H. influenzae isolates, susceptibility was >99% for levofloxacin and moxifloxacin by all three breakpoint guidelines (except for one isolate that was resistant to levofloxacin using current EUCAST criteria). All isolates were also susceptible to ceftriaxone by CLSI and PK/PD breakpoints (and 99.5% by EUCAST criteria), and to amoxicillin/clavulanic acid by CLSI and high-dose PK/PD breakpoints (and 98.0% by low-dose PK/PD and EUCAST criteria). Susceptibility of isolates was high for azithromycin (99.0%) and oral cefuroxime (98.0%) using CLSI criteria, but was much reduced by PK/PD (0.5% and 69.5%, respectively) and EUCAST standards (0.5 and 1.5%, respectively). Cefaclor showed similarly large variability between breakpoints (84.8% susceptible by CLSI and 1.5% by PK/PD breakpoints). Susceptibility to amoxicillin was 82.7% by low-dose PK/PD and EUCAST criteria and susceptibility to ampicillin was 83.8% by CLSI and EUCAST criteria, while to the remaining agents the isolates were <80% susceptible (trimethoprim/sulfamethoxazole 75.1% by all breakpoints and clarithromycin 37.1% by CLSI, 0% by PK/PD and 1.0% by EUCAST criteria).

Table 4.
Open in new tab

MIC and susceptibility data for H. influenzae isolates (n = 197) from the Czech Republic

Susceptibility
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina≤264≤2>128NANANA82.7 (85.8)82.7–17.3
AMCa0.520.124100–0.098.0 (100)98.0–2.0
Ampicillin164≤0.06>12883.82.513.7–83.8–16.2
Azithromycin240.12>1699.0––0.50.598.51.0
Cefaclor416≤0.5>3284.813.71.51.5NANANA
Ceftriaxone≤0.03≤0.03≤0.030.25100––10099.5–0.5
Cefuroxime (oral)140.12898.02.00.069.51.568.030.5
Clarithromycin1616≤1>1637.158.94.10.01.099.00.0
Levofloxacin0.0150.030.0080.25100––10099.5–0.5
Moxifloxacin0.0150.03≤0.0040.06100––100100–0.0
SXT0.12>2≤0.015>275.11.523.475.175.10.524.4
Susceptibility
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina≤264≤2>128NANANA82.7 (85.8)82.7–17.3
AMCa0.520.124100–0.098.0 (100)98.0–2.0
Ampicillin164≤0.06>12883.82.513.7–83.8–16.2
Azithromycin240.12>1699.0––0.50.598.51.0
Cefaclor416≤0.5>3284.813.71.51.5NANANA
Ceftriaxone≤0.03≤0.03≤0.030.25100––10099.5–0.5
Cefuroxime (oral)140.12898.02.00.069.51.568.030.5
Clarithromycin1616≤1>1637.158.94.10.01.099.00.0
Levofloxacin0.0150.030.0080.25100––10099.5–0.5
Moxifloxacin0.0150.03≤0.0040.06100––100100–0.0
SXT0.12>2≤0.015>275.11.523.475.175.10.524.4

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

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.

a

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

Table 4.
Open in new tab

MIC and susceptibility data for H. influenzae isolates (n = 197) from the Czech Republic

Susceptibility
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina≤264≤2>128NANANA82.7 (85.8)82.7–17.3
AMCa0.520.124100–0.098.0 (100)98.0–2.0
Ampicillin164≤0.06>12883.82.513.7–83.8–16.2
Azithromycin240.12>1699.0––0.50.598.51.0
Cefaclor416≤0.5>3284.813.71.51.5NANANA
Ceftriaxone≤0.03≤0.03≤0.030.25100––10099.5–0.5
Cefuroxime (oral)140.12898.02.00.069.51.568.030.5
Clarithromycin1616≤1>1637.158.94.10.01.099.00.0
Levofloxacin0.0150.030.0080.25100––10099.5–0.5
Moxifloxacin0.0150.03≤0.0040.06100––100100–0.0
SXT0.12>2≤0.015>275.11.523.475.175.10.524.4
Susceptibility
MIC (mg/L)
CLSI
PK/PD
EUCAST
Antimicrobial50%90%minmax%S%I%R%S%S%I%R
Amoxicillina≤264≤2>128NANANA82.7 (85.8)82.7–17.3
AMCa0.520.124100–0.098.0 (100)98.0–2.0
Ampicillin164≤0.06>12883.82.513.7–83.8–16.2
Azithromycin240.12>1699.0––0.50.598.51.0
Cefaclor416≤0.5>3284.813.71.51.5NANANA
Ceftriaxone≤0.03≤0.03≤0.030.25100––10099.5–0.5
Cefuroxime (oral)140.12898.02.00.069.51.568.030.5
Clarithromycin1616≤1>1637.158.94.10.01.099.00.0
Levofloxacin0.0150.030.0080.25100––10099.5–0.5
Moxifloxacin0.0150.03≤0.0040.06100––100100–0.0
SXT0.12>2≤0.015>275.11.523.475.175.10.524.4

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

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.

a

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

Table 5.
Open in new tab

MIC distribution data for all H. influenzae isolates (n = 197)

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
Amoxicillin1636111214
AMC2356442504
Ampicillin328592735134316
Azithromycin1668863411
Cefaclor3134264452721
Ceftriaxone19511
Cefuroxime (oral)34696132244
Clarithromycin216641168
Levofloxacin729314171
Moxifloxacin2201263514
SXT30539343911246
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
Amoxicillin1636111214
AMC2356442504
Ampicillin328592735134316
Azithromycin1668863411
Cefaclor3134264452721
Ceftriaxone19511
Cefuroxime (oral)34696132244
Clarithromycin216641168
Levofloxacin729314171
Moxifloxacin2201263514
SXT30539343911246

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

Table 5.
Open in new tab

MIC distribution data for all H. influenzae isolates (n = 197)

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
Amoxicillin1636111214
AMC2356442504
Ampicillin328592735134316
Azithromycin1668863411
Cefaclor3134264452721
Ceftriaxone19511
Cefuroxime (oral)34696132244
Clarithromycin216641168
Levofloxacin729314171
Moxifloxacin2201263514
SXT30539343911246
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
Amoxicillin1636111214
AMC2356442504
Ampicillin328592735134316
Azithromycin1668863411
Cefaclor3134264452721
Ceftriaxone19511
Cefuroxime (oral)34696132244
Clarithromycin216641168
Levofloxacin729314171
Moxifloxacin2201263514
SXT30539343911246

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

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

Discussion

Antimicrobial resistance in S. pneumoniae isolates collected in the Czech Republic was low, with susceptibility rates around 90% or higher for all studied agents using CLSI breakpoints. This finding is in stark contrast to high resistance levels in Slovakia,8 which is interesting because the two countries are immediate neighbours and were part of the same country until 1993.

For example, non-susceptibility to penicillin was 8.5% in the Czech Republic compared with 38.9% in Slovakia, and macrolide resistance was around 10.0% and 55.8%, respectively.

Low resistance levels of invasive (blood and CSF) S. pneumoniae isolates from the Czech Republic were also reported by the European Antimicrobial Resistance Surveillance Network (EARS-Net),14 with a non-susceptibility rate for penicillin of only 3.2% using EUCAST criteria (compared with 22.2% in Slovakia). A similar difference between the two countries was seen in 1997 data from the Alexander Project showing penicillin resistance of 5.4% in the Czech Republic compared with 26.7% in Slovakia, and macrolide resistance of 2.2% and 13.3%, respectively.15 Low resistance rates in the Czech Republic were also reported by Žemličková et al.16 in a study of isolates from the nasopharynx of healthy children collected in 2004–05, with 3.0% of S. pneumoniae non-susceptible to penicillin and 1.2% to erythromycin. Žemličková et al.16 noted that the low level of resistance in the Czech Republic is historically attributed to a more restrictive use of antibiotics together with the preference by general practitioners for narrow-spectrum penicillins for treatment. Indeed, in a study of antibiotic consumption in 2011 in the broader European region, the Czech Republic ranked only 27th among 42 countries in total antibiotic use (while Slovakia ranked 15th).17 Studies have linked high use of antibiotics to increased antimicrobial resistance,18,19 providing support for the view that the difference in antibiotic susceptibility of S. pneumoniae between the Czech Republic and Slovakia is explained, at least in part, by the difference in antibiotic consumption, especially as other factors that may affect pneumococcal susceptibility rates are similar. Both countries established a national pneumococcal surveillance system with regular serotyping (in the Czech Republic in 2008 and in Slovakia in 2011), and both include pneumococcal vaccine in their national immunization programmes (since 2010 in the Czech Republic and since 2009 in Slovakia).20

Antimicrobial activity against H. influenzae isolates from the Czech Republic was also high. Susceptibility to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime (oral), azithromycin, and the fluoroquinolones was ≥98% by CLSI criteria, and the remaining agents showed susceptibility ≥75% except for clarithromycin at 37.1%. Interestingly, in contrast to S. pneumoniae these rates for H. influenzae were similar to those found in Slovakia.8 Data on H. influenzae in the Czech Republic is sparse in the literature. In a study of healthy children in the Czech Republic, Žemličková et al.16 found all isolates to be susceptible to amoxicillin/clavulanic acid and cefuroxime (compared with slightly reduced susceptibility of 98.0% to cefuroxime and unchanged full susceptibility to amoxicillin/clavulanic acid in the current study). Žemličková et al. reported a low β-lactamase rate of 4.6% in healthy children, whereas it was 13.7% in the current study. Interestingly, β-lactamase rates found through the Alexander Project 20 years ago were also already high (13% in 1996 and 8% in 1997 in the Czech Republic).15

As has been documented in other SOAR reports, susceptibility rates in the current study varied widely for some antibiotics when using different breakpoints. For example, 94.0% of S. pneumoniae isolates were susceptible to cefaclor by CLSI criteria, 25.0% by PK/PD and 0% using EUCAST standards. Such differences were found for more antimicrobials for H. influenzae, where susceptibility to the macrolides, cefaclor and cefuroxime differed by as much as 98.5 percentage points. These differences present problems both for clinical practice and for research, and should be resolved.

Only one hospital site participated in the SOAR study in the Czech Republic, making it difficult to generalize the results to the entire country. However, it is reassuring that the findings correlate well with historical reports of high antimicrobial activity in the Czech Republic and further support the concept that low antibiotic use has helped to keep resistance in the country to a minimum. The findings also support local clinicians in continuing to select narrower-spectrum antimicrobials for empirical therapy of community-acquired respiratory tract infections, thus highlighting one of the great benefits of continuous surveillance of antimicrobial resistance: knowledge of current local resistance patterns reduces the need to choose broad-spectrum agents that contribute to increasing resistance worldwide.

Acknowledgements

We thank Gudrun Maechler for reviewing the manuscript and Vladimir Pacholik 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. M. Maruscak is an employee of GlaxoSmithKline and does not hold 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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