Abstract
To determine antibiotic susceptibility in isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2014–16 from Russia.
MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.
A total of 279 S. pneumoniae and 279 H. influenzae were collected. Overall, 67.0% of S. pneumoniae were penicillin susceptible by CLSI oral/EUCAST and 93.2% by CLSI intravenous (iv) breakpoints. All were fluoroquinolone susceptible, with amoxicillin, amoxicillin/clavulanic acid and ceftriaxone susceptibility ≥92.8% by CLSI and PK/PD breakpoints. Isolates showed lower susceptibility to cefuroxime, cefaclor, macrolides and trimethoprim/sulfamethoxazole by CLSI criteria: 85.0%, 76.7%, 68.8% and 67.7%, respectively. Generally, susceptibility was slightly lower by EUCAST criteria, except for cefaclor, for which the difference in susceptibility was much greater. Penicillin-resistant isolates had low susceptibility (≤60%) to all agents except fluoroquinolones. All 279 H. influenzae were ceftriaxone susceptible, 15.4% were β-lactamase positive and ≥97.5% were amoxicillin/clavulanic acid susceptible (CLSI, EUCAST and PK/PD breakpoints). Four isolates were fluoroquinolone non-susceptible by current EUCAST criteria. A major discrepancy was found with azithromycin susceptibility between CLSI (99.3%) and EUCAST and PK/PD (2.2%) breakpoints. Trimethoprim/sulfamethoxazole was poorly active (62.7% susceptible).
Susceptibility to penicillin (oral), macrolides and trimethoprim/sulfamethoxazole was low in S. pneumoniae from Russia. However, isolates were fully susceptible to fluoroquinolones and ≥92.8% were susceptible to amoxicillin, amoxicillin/clavulanic acid and ceftriaxone. Isolates of H. influenzae only showed reduced susceptibility to ampicillin, cefaclor, clarithromycin and trimethoprim/sulfamethoxazole. Some differences were detected between CLSI, EUCAST and PK/PD breakpoints, especially with cefaclor, cefuroxime and macrolides. These data suggest further efforts are required to harmonize international breakpoints.
Introduction
Community-acquired pneumonia (CAP) is a challenge in primary care medicine, with Streptococcus pneumoniae and Haemophilus influenzae important bacterial pathogens associated with this disease.1,2 Prescription decisions are made empirically, so antibiotic resistance surveillance plays a major role in the reporting and management of CAP.3 One such study is the ongoing Survey of Antibiotic Resistance (SOAR), which is an antimicrobial resistance surveillance study of key respiratory pathogens, conducted in the Middle East, Africa, Latin America, Asia-Pacific and Commonwealth of Independent States countries since 2002. Data recently published from this study have shown large differences in antibiotic resistance in these pathogens between countries, with low resistance reported in Ukraine and high resistance in China, for example.4,5 High variability in resistance can often occur between countries within the same region of the world, such as Asia,6 Africa7 and the Gulf states.8 Thus regular dissemination of geographically focused surveillance data is vital to guide optimum therapies for CAP. In this paper we report SOAR data for major respiratory tract pathogens collected from hospitals in Russia.
Materials and methods
Collaborating centres
The following three centres took part in the study: Federal State Autonomous Institution ‘National Scientific and Practical Center of Children's Health’ of the Ministry of Health of the Russian Federation, Moscow, Russia; Institute of Antimicrobial Chemotherapy, Smolensk State Medical University, Smolensk, Russia; and Scientific Research Institute of Children’s Infections, St Petersburg, Russia.
Isolates of H. influenzae and S. pneumoniae 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 patients were excluded from the analysis.
Susceptibility testing
Isolates were evaluated for antibiotic susceptibility using broth microdilution methodology recommended by CLSI.9
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 while 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.10–12 These breakpoints are shown in Table 1.
MIC breakpoints (mg/L) used for S. pneumoniae and H. influenzae isolates
| S. pneumoniae | H. influenzae | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CLSI (mg/L) | EUCAST (mg/L) | CLSI (mg/L) | EUCAST (mg/L) | ||||||||||
| Antimicrobial | S | I | R | S | I | R | S | I | R | S | I | R | PK/PD (S only) |
| Amoxicillin | ≤2 | 4 | ≥8 | NA | NA | NA | NA | NA | NA | ≤2 | – | ≥4 | ≤2 (≤4) |
| AMCa | ≤2 | 4 | ≥8 | NA | NA | NA | ≤4 | – | ≥8 | ≤2 | – | ≥4 | ≤2 (≤4) |
| Ampicillin | NA | NA | NA | NA | NA | NA | ≤1 | 2 | ≥4 | ≤1 | – | ≥2 | NA |
| Azithromycin | ≤0.5 | 1 | ≥2 | ≤0.25 | 0.5 | ≥1 | ≤4 | – | – | ≤0.12 | 0.25–4 | ≥8 | ≤0.12 |
| Cefaclor | ≤1 | 2 | ≥4 | ≤0.03 | 0.06–0.5 | ≥1 | ≤8 | 16 | ≥32 | NA | NA | NA | ≤0.5 |
| Ceftriaxone | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤2 | – | – | ≤0.12 | – | ≥0.25 | ≤1 |
| Cefuroximeb | ≤1 | 2 | ≥4 | ≤0.25 | 0.5 | ≥1 | ≤4 | 8 | ≥16 | ≤0.12 | 0.25–1 | ≥2 | ≤1 |
| Clarithromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | ≤8 | 16 | ≥32 | ≤1 | 2–32 | ≥64 | ≤0.25 |
| Erythromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | NA | NA | NA | NA | NA | NA | ≤0.25 |
| Levofloxacin | ≤2 | 4 | ≥8 | ≤2 | – | ≥4 | ≤2 | – | – | 0.06 | – | 0.12 | ≤2 |
| Moxifloxacin | ≤1 | 2 | ≥4 | ≤0.5 | – | ≥1 | ≤1 | – | – | 0.12 | – | 0.25 | ≤1 |
| Penicillin (iv non-meningitis) | ≤2 | 4 | ≥8 | NAc | NAc | NAc | NA | NA | NA | NA | NA | NA | NA |
| Penicillin (oral) | ≤0.06 | 0.12–2 | ≥2 | ≤0.06 | 0.12–2 | ≥4 | NA | NA | NA | NA | NA | NA | NA |
| SXTd | ≤0.5 | 1–2 | ≥4 | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤0.5 | 1 | ≥2 | ≤0.5 |
| S. pneumoniae | H. influenzae | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CLSI (mg/L) | EUCAST (mg/L) | CLSI (mg/L) | EUCAST (mg/L) | ||||||||||
| Antimicrobial | S | I | R | S | I | R | S | I | R | S | I | R | PK/PD (S only) |
| Amoxicillin | ≤2 | 4 | ≥8 | NA | NA | NA | NA | NA | NA | ≤2 | – | ≥4 | ≤2 (≤4) |
| AMCa | ≤2 | 4 | ≥8 | NA | NA | NA | ≤4 | – | ≥8 | ≤2 | – | ≥4 | ≤2 (≤4) |
| Ampicillin | NA | NA | NA | NA | NA | NA | ≤1 | 2 | ≥4 | ≤1 | – | ≥2 | NA |
| Azithromycin | ≤0.5 | 1 | ≥2 | ≤0.25 | 0.5 | ≥1 | ≤4 | – | – | ≤0.12 | 0.25–4 | ≥8 | ≤0.12 |
| Cefaclor | ≤1 | 2 | ≥4 | ≤0.03 | 0.06–0.5 | ≥1 | ≤8 | 16 | ≥32 | NA | NA | NA | ≤0.5 |
| Ceftriaxone | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤2 | – | – | ≤0.12 | – | ≥0.25 | ≤1 |
| Cefuroximeb | ≤1 | 2 | ≥4 | ≤0.25 | 0.5 | ≥1 | ≤4 | 8 | ≥16 | ≤0.12 | 0.25–1 | ≥2 | ≤1 |
| Clarithromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | ≤8 | 16 | ≥32 | ≤1 | 2–32 | ≥64 | ≤0.25 |
| Erythromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | NA | NA | NA | NA | NA | NA | ≤0.25 |
| Levofloxacin | ≤2 | 4 | ≥8 | ≤2 | – | ≥4 | ≤2 | – | – | 0.06 | – | 0.12 | ≤2 |
| Moxifloxacin | ≤1 | 2 | ≥4 | ≤0.5 | – | ≥1 | ≤1 | – | – | 0.12 | – | 0.25 | ≤1 |
| Penicillin (iv non-meningitis) | ≤2 | 4 | ≥8 | NAc | NAc | NAc | NA | NA | NA | NA | NA | NA | NA |
| Penicillin (oral) | ≤0.06 | 0.12–2 | ≥2 | ≤0.06 | 0.12–2 | ≥4 | NA | NA | NA | NA | NA | NA | NA |
| SXTd | ≤0.5 | 1–2 | ≥4 | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤0.5 | 1 | ≥2 | ≤0.5 |
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable.
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,12 which is the same as CLSI for H. influenzae and one dilution higher for S. pneumoniae.
Breakpoints used are for cefuroxime axetil.
EUCAST do not give intravenous 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.
Trimethoprim/sulfamethoxazole was tested at a 1:19 trimethoprim to sulfamethoxazole ratio; breakpoints are expressed as the trimethoprim component.
MIC breakpoints (mg/L) used for S. pneumoniae and H. influenzae isolates
| S. pneumoniae | H. influenzae | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CLSI (mg/L) | EUCAST (mg/L) | CLSI (mg/L) | EUCAST (mg/L) | ||||||||||
| Antimicrobial | S | I | R | S | I | R | S | I | R | S | I | R | PK/PD (S only) |
| Amoxicillin | ≤2 | 4 | ≥8 | NA | NA | NA | NA | NA | NA | ≤2 | – | ≥4 | ≤2 (≤4) |
| AMCa | ≤2 | 4 | ≥8 | NA | NA | NA | ≤4 | – | ≥8 | ≤2 | – | ≥4 | ≤2 (≤4) |
| Ampicillin | NA | NA | NA | NA | NA | NA | ≤1 | 2 | ≥4 | ≤1 | – | ≥2 | NA |
| Azithromycin | ≤0.5 | 1 | ≥2 | ≤0.25 | 0.5 | ≥1 | ≤4 | – | – | ≤0.12 | 0.25–4 | ≥8 | ≤0.12 |
| Cefaclor | ≤1 | 2 | ≥4 | ≤0.03 | 0.06–0.5 | ≥1 | ≤8 | 16 | ≥32 | NA | NA | NA | ≤0.5 |
| Ceftriaxone | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤2 | – | – | ≤0.12 | – | ≥0.25 | ≤1 |
| Cefuroximeb | ≤1 | 2 | ≥4 | ≤0.25 | 0.5 | ≥1 | ≤4 | 8 | ≥16 | ≤0.12 | 0.25–1 | ≥2 | ≤1 |
| Clarithromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | ≤8 | 16 | ≥32 | ≤1 | 2–32 | ≥64 | ≤0.25 |
| Erythromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | NA | NA | NA | NA | NA | NA | ≤0.25 |
| Levofloxacin | ≤2 | 4 | ≥8 | ≤2 | – | ≥4 | ≤2 | – | – | 0.06 | – | 0.12 | ≤2 |
| Moxifloxacin | ≤1 | 2 | ≥4 | ≤0.5 | – | ≥1 | ≤1 | – | – | 0.12 | – | 0.25 | ≤1 |
| Penicillin (iv non-meningitis) | ≤2 | 4 | ≥8 | NAc | NAc | NAc | NA | NA | NA | NA | NA | NA | NA |
| Penicillin (oral) | ≤0.06 | 0.12–2 | ≥2 | ≤0.06 | 0.12–2 | ≥4 | NA | NA | NA | NA | NA | NA | NA |
| SXTd | ≤0.5 | 1–2 | ≥4 | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤0.5 | 1 | ≥2 | ≤0.5 |
| S. pneumoniae | H. influenzae | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CLSI (mg/L) | EUCAST (mg/L) | CLSI (mg/L) | EUCAST (mg/L) | ||||||||||
| Antimicrobial | S | I | R | S | I | R | S | I | R | S | I | R | PK/PD (S only) |
| Amoxicillin | ≤2 | 4 | ≥8 | NA | NA | NA | NA | NA | NA | ≤2 | – | ≥4 | ≤2 (≤4) |
| AMCa | ≤2 | 4 | ≥8 | NA | NA | NA | ≤4 | – | ≥8 | ≤2 | – | ≥4 | ≤2 (≤4) |
| Ampicillin | NA | NA | NA | NA | NA | NA | ≤1 | 2 | ≥4 | ≤1 | – | ≥2 | NA |
| Azithromycin | ≤0.5 | 1 | ≥2 | ≤0.25 | 0.5 | ≥1 | ≤4 | – | – | ≤0.12 | 0.25–4 | ≥8 | ≤0.12 |
| Cefaclor | ≤1 | 2 | ≥4 | ≤0.03 | 0.06–0.5 | ≥1 | ≤8 | 16 | ≥32 | NA | NA | NA | ≤0.5 |
| Ceftriaxone | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤2 | – | – | ≤0.12 | – | ≥0.25 | ≤1 |
| Cefuroximeb | ≤1 | 2 | ≥4 | ≤0.25 | 0.5 | ≥1 | ≤4 | 8 | ≥16 | ≤0.12 | 0.25–1 | ≥2 | ≤1 |
| Clarithromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | ≤8 | 16 | ≥32 | ≤1 | 2–32 | ≥64 | ≤0.25 |
| Erythromycin | ≤0.25 | 0.5 | ≥1 | ≤0.25 | 0.5 | ≥1 | NA | NA | NA | NA | NA | NA | ≤0.25 |
| Levofloxacin | ≤2 | 4 | ≥8 | ≤2 | – | ≥4 | ≤2 | – | – | 0.06 | – | 0.12 | ≤2 |
| Moxifloxacin | ≤1 | 2 | ≥4 | ≤0.5 | – | ≥1 | ≤1 | – | – | 0.12 | – | 0.25 | ≤1 |
| Penicillin (iv non-meningitis) | ≤2 | 4 | ≥8 | NAc | NAc | NAc | NA | NA | NA | NA | NA | NA | NA |
| Penicillin (oral) | ≤0.06 | 0.12–2 | ≥2 | ≤0.06 | 0.12–2 | ≥4 | NA | NA | NA | NA | NA | NA | NA |
| SXTd | ≤0.5 | 1–2 | ≥4 | ≤1 | 2 | ≥4 | ≤0.5 | 1–2 | ≥4 | ≤0.5 | 1 | ≥2 | ≤0.5 |
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole; S, susceptible; I, intermediate; R, resistant; NA, not applicable.
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,12 which is the same as CLSI for H. influenzae and one dilution higher for S. pneumoniae.
Breakpoints used are for cefuroxime axetil.
EUCAST do not give intravenous 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.
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 between 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
A total of 279 S. pneumoniae isolates were collected from three different centres in Russia from 2014–16. Most pneumococci came from sputum (n = 107; 38.4%) and sinuses (n = 102; 36.6%). Less frequently, isolates were from bronchoalveolar lavage (n = 36; 12.9%), middle ear effusion (n = 23; 8.2%), endotracheal aspirate (n = 7; 2.5%) and blood (n = 3; 1.1%). One isolate was from an undisclosed respiratory source. Most isolates (n = 232; 83.2%) came from children (aged ≤12 years), 42 (15.1%) were from adult patients (13–64 years) and 3 (1.1%) were from elderly patients (aged ≥65 years). Two isolates were from patients of unknown age.
Summary MIC and susceptibility data for all 279 S. pneumoniae isolates are shown in Table 2. MIC distribution data are given in Table 3.
MIC and susceptibility data for S. pneumoniae isolates (n = 279)
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina,b | 0.03 | 1 | ≤0.015 | >8 | 92.8 | 2.2 | 5.0 | 92.8 (95.0) | NA | NA | NA |
| AMCa,b | ≤0.015 | 1 | ≤0.015 | 8 | 95.0 | 2.2 | 2.9 | 95.0 (97.1) | NA | NA | NA |
| Azithromycin | 0.12 | >2 | ≤0.03 | >2 | 68.8 | 0.0 | 31.2 | 54.5 | 68.5 | 0.4 | 31.2 |
| Cefaclor | 1 | >4 | ≤0.03 | >4 | 76.7 | 3.6 | 19.7 | 21.5 | 0.4 | 21.2 | 78.5 |
| Ceftriaxone | 0.03 | 1 | ≤0.015 | >4 | 94.6 | 1.4 | 3.9 | 94.6 | 84.2 | 11.8 | 3.9 |
| Cefuroxime axetil | ≤0.12 | 4 | ≤0.12 | >4 | 85.0 | 1.4 | 13.6 | 85.0 | 78.5 | 2.9 | 18.6 |
| Clarithromycin | ≤0.015 | >1 | ≤0.015 | >1 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Erythromycin | 0.03 | >0.5 | 0.03 | >0.5 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Levofloxacin | 1 | 1 | ≤0.25 | 2 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Moxifloxacin | 0.12 | 0.25 | 0.06 | 0.25 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Penicillin (oral) | ≤0.06 | 2 | ≤0.06 | >4 | 67.0 | 20.4 | 12.5 | NA | 67.0 | 26.2 | 6.8 |
| Penicillin (iv non-meningitis) | ≤0.06 | 2 | ≤0.06 | >4 | 93.2 | 4.7 | 2.2 | NA | NA | NA | NA |
| SXT | 0.5 | > 2 | ≤0.06 | >2 | 67.7 | 12.9 | 19.4 | 67.7 | 68.1 | 12.5 | 19.4 |
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina,b | 0.03 | 1 | ≤0.015 | >8 | 92.8 | 2.2 | 5.0 | 92.8 (95.0) | NA | NA | NA |
| AMCa,b | ≤0.015 | 1 | ≤0.015 | 8 | 95.0 | 2.2 | 2.9 | 95.0 (97.1) | NA | NA | NA |
| Azithromycin | 0.12 | >2 | ≤0.03 | >2 | 68.8 | 0.0 | 31.2 | 54.5 | 68.5 | 0.4 | 31.2 |
| Cefaclor | 1 | >4 | ≤0.03 | >4 | 76.7 | 3.6 | 19.7 | 21.5 | 0.4 | 21.2 | 78.5 |
| Ceftriaxone | 0.03 | 1 | ≤0.015 | >4 | 94.6 | 1.4 | 3.9 | 94.6 | 84.2 | 11.8 | 3.9 |
| Cefuroxime axetil | ≤0.12 | 4 | ≤0.12 | >4 | 85.0 | 1.4 | 13.6 | 85.0 | 78.5 | 2.9 | 18.6 |
| Clarithromycin | ≤0.015 | >1 | ≤0.015 | >1 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Erythromycin | 0.03 | >0.5 | 0.03 | >0.5 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Levofloxacin | 1 | 1 | ≤0.25 | 2 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Moxifloxacin | 0.12 | 0.25 | 0.06 | 0.25 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Penicillin (oral) | ≤0.06 | 2 | ≤0.06 | >4 | 67.0 | 20.4 | 12.5 | NA | 67.0 | 26.2 | 6.8 |
| Penicillin (iv non-meningitis) | ≤0.06 | 2 | ≤0.06 | >4 | 93.2 | 4.7 | 2.2 | NA | NA | NA | NA |
| SXT | 0.5 | > 2 | ≤0.06 | >2 | 67.7 | 12.9 | 19.4 | 67.7 | 68.1 | 12.5 | 19.4 |
AMC, amoxicillin/clavulanate; SXT, trimethoprim/sulfamethoxazole; min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; NA, not applicable.
Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.
Based on EUCAST guidelines, for isolates categorized as intermediate to ampicillin, oral treatment by using ampicillin, amoxicillin, or amoxicillin/clavulanic acid should be avoided. 7/279 S. pneumoniae isolates had intermediate resistance to ampicillin.
MIC and susceptibility data for S. pneumoniae isolates (n = 279)
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina,b | 0.03 | 1 | ≤0.015 | >8 | 92.8 | 2.2 | 5.0 | 92.8 (95.0) | NA | NA | NA |
| AMCa,b | ≤0.015 | 1 | ≤0.015 | 8 | 95.0 | 2.2 | 2.9 | 95.0 (97.1) | NA | NA | NA |
| Azithromycin | 0.12 | >2 | ≤0.03 | >2 | 68.8 | 0.0 | 31.2 | 54.5 | 68.5 | 0.4 | 31.2 |
| Cefaclor | 1 | >4 | ≤0.03 | >4 | 76.7 | 3.6 | 19.7 | 21.5 | 0.4 | 21.2 | 78.5 |
| Ceftriaxone | 0.03 | 1 | ≤0.015 | >4 | 94.6 | 1.4 | 3.9 | 94.6 | 84.2 | 11.8 | 3.9 |
| Cefuroxime axetil | ≤0.12 | 4 | ≤0.12 | >4 | 85.0 | 1.4 | 13.6 | 85.0 | 78.5 | 2.9 | 18.6 |
| Clarithromycin | ≤0.015 | >1 | ≤0.015 | >1 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Erythromycin | 0.03 | >0.5 | 0.03 | >0.5 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Levofloxacin | 1 | 1 | ≤0.25 | 2 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Moxifloxacin | 0.12 | 0.25 | 0.06 | 0.25 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Penicillin (oral) | ≤0.06 | 2 | ≤0.06 | >4 | 67.0 | 20.4 | 12.5 | NA | 67.0 | 26.2 | 6.8 |
| Penicillin (iv non-meningitis) | ≤0.06 | 2 | ≤0.06 | >4 | 93.2 | 4.7 | 2.2 | NA | NA | NA | NA |
| SXT | 0.5 | > 2 | ≤0.06 | >2 | 67.7 | 12.9 | 19.4 | 67.7 | 68.1 | 12.5 | 19.4 |
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina,b | 0.03 | 1 | ≤0.015 | >8 | 92.8 | 2.2 | 5.0 | 92.8 (95.0) | NA | NA | NA |
| AMCa,b | ≤0.015 | 1 | ≤0.015 | 8 | 95.0 | 2.2 | 2.9 | 95.0 (97.1) | NA | NA | NA |
| Azithromycin | 0.12 | >2 | ≤0.03 | >2 | 68.8 | 0.0 | 31.2 | 54.5 | 68.5 | 0.4 | 31.2 |
| Cefaclor | 1 | >4 | ≤0.03 | >4 | 76.7 | 3.6 | 19.7 | 21.5 | 0.4 | 21.2 | 78.5 |
| Ceftriaxone | 0.03 | 1 | ≤0.015 | >4 | 94.6 | 1.4 | 3.9 | 94.6 | 84.2 | 11.8 | 3.9 |
| Cefuroxime axetil | ≤0.12 | 4 | ≤0.12 | >4 | 85.0 | 1.4 | 13.6 | 85.0 | 78.5 | 2.9 | 18.6 |
| Clarithromycin | ≤0.015 | >1 | ≤0.015 | >1 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Erythromycin | 0.03 | >0.5 | 0.03 | >0.5 | 68.8 | 0.0 | 31.2 | 68.8 | 68.8 | 0.0 | 31.2 |
| Levofloxacin | 1 | 1 | ≤0.25 | 2 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Moxifloxacin | 0.12 | 0.25 | 0.06 | 0.25 | 100 | 0.0 | 0.0 | 100 | 100 | – | 0.0 |
| Penicillin (oral) | ≤0.06 | 2 | ≤0.06 | >4 | 67.0 | 20.4 | 12.5 | NA | 67.0 | 26.2 | 6.8 |
| Penicillin (iv non-meningitis) | ≤0.06 | 2 | ≤0.06 | >4 | 93.2 | 4.7 | 2.2 | NA | NA | NA | NA |
| SXT | 0.5 | > 2 | ≤0.06 | >2 | 67.7 | 12.9 | 19.4 | 67.7 | 68.1 | 12.5 | 19.4 |
AMC, amoxicillin/clavulanate; SXT, trimethoprim/sulfamethoxazole; min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; NA, not applicable.
Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.
Based on EUCAST guidelines, for isolates categorized as intermediate to ampicillin, oral treatment by using ampicillin, amoxicillin, or amoxicillin/clavulanic acid should be avoided. 7/279 S. pneumoniae isolates had intermediate resistance to ampicillin.
MIC distribution data for S. pneumoniae isolates (n = 279)
| Antimicrobial | Number of isolates at MIC (mg/L) | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | ≤0.12 | 0.12 | ≤0.25 | 0.25 | 0.5 | >0.5 | 1 | >1 | 2 | >2 | 4 | >4 | 8 | >8 | |
| Amoxicillin | 115 | 71 | 13 | 26 | 4 | 4 | 19 | 7 | 6 | 9 | 5 | ||||||||
| AMC | 189 | 12 | 17 | 9 | 5 | 12 | 12 | 9 | 6 | 8 | |||||||||
| Azithromycin | 3 | 15 | 134 | 39 | 1 | 87 | |||||||||||||
| Cefaclor | 1 | 1 | 2 | 7 | 49 | 154 | 10 | 6 | 49 | ||||||||||
| Ceftriaxone | 1 | 176 | 23 | 13 | 14 | 8 | 29 | 4 | 6 | 5 | |||||||||
| Cefuroxime | 202 | 17 | 8 | 10 | 4 | 21 | 17 | ||||||||||||
| Clarithromycin | 142 | 49 | 1 | 9 | 78 | ||||||||||||||
| Erythromycin | 163 | 28 | 1 | 87 | |||||||||||||||
| Levofloxacin | 1 | 8 | 263 | 7 | |||||||||||||||
| Moxifloxacin | 52 | 174 | 53 | ||||||||||||||||
| Penicillin | 187 | 17 | 18 | 7 | 15 | 16 | 13 | 6 | |||||||||||
| SXT | 1 | 99 | 27 | 62 | 1 | 35 | 54 | ||||||||||||
| Antimicrobial | Number of isolates at MIC (mg/L) | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | ≤0.12 | 0.12 | ≤0.25 | 0.25 | 0.5 | >0.5 | 1 | >1 | 2 | >2 | 4 | >4 | 8 | >8 | |
| Amoxicillin | 115 | 71 | 13 | 26 | 4 | 4 | 19 | 7 | 6 | 9 | 5 | ||||||||
| AMC | 189 | 12 | 17 | 9 | 5 | 12 | 12 | 9 | 6 | 8 | |||||||||
| Azithromycin | 3 | 15 | 134 | 39 | 1 | 87 | |||||||||||||
| Cefaclor | 1 | 1 | 2 | 7 | 49 | 154 | 10 | 6 | 49 | ||||||||||
| Ceftriaxone | 1 | 176 | 23 | 13 | 14 | 8 | 29 | 4 | 6 | 5 | |||||||||
| Cefuroxime | 202 | 17 | 8 | 10 | 4 | 21 | 17 | ||||||||||||
| Clarithromycin | 142 | 49 | 1 | 9 | 78 | ||||||||||||||
| Erythromycin | 163 | 28 | 1 | 87 | |||||||||||||||
| Levofloxacin | 1 | 8 | 263 | 7 | |||||||||||||||
| Moxifloxacin | 52 | 174 | 53 | ||||||||||||||||
| Penicillin | 187 | 17 | 18 | 7 | 15 | 16 | 13 | 6 | |||||||||||
| SXT | 1 | 99 | 27 | 62 | 1 | 35 | 54 | ||||||||||||
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole.
MIC distribution data for S. pneumoniae isolates (n = 279)
| Antimicrobial | Number of isolates at MIC (mg/L) | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | ≤0.12 | 0.12 | ≤0.25 | 0.25 | 0.5 | >0.5 | 1 | >1 | 2 | >2 | 4 | >4 | 8 | >8 | |
| Amoxicillin | 115 | 71 | 13 | 26 | 4 | 4 | 19 | 7 | 6 | 9 | 5 | ||||||||
| AMC | 189 | 12 | 17 | 9 | 5 | 12 | 12 | 9 | 6 | 8 | |||||||||
| Azithromycin | 3 | 15 | 134 | 39 | 1 | 87 | |||||||||||||
| Cefaclor | 1 | 1 | 2 | 7 | 49 | 154 | 10 | 6 | 49 | ||||||||||
| Ceftriaxone | 1 | 176 | 23 | 13 | 14 | 8 | 29 | 4 | 6 | 5 | |||||||||
| Cefuroxime | 202 | 17 | 8 | 10 | 4 | 21 | 17 | ||||||||||||
| Clarithromycin | 142 | 49 | 1 | 9 | 78 | ||||||||||||||
| Erythromycin | 163 | 28 | 1 | 87 | |||||||||||||||
| Levofloxacin | 1 | 8 | 263 | 7 | |||||||||||||||
| Moxifloxacin | 52 | 174 | 53 | ||||||||||||||||
| Penicillin | 187 | 17 | 18 | 7 | 15 | 16 | 13 | 6 | |||||||||||
| SXT | 1 | 99 | 27 | 62 | 1 | 35 | 54 | ||||||||||||
| Antimicrobial | Number of isolates at MIC (mg/L) | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | ≤0.12 | 0.12 | ≤0.25 | 0.25 | 0.5 | >0.5 | 1 | >1 | 2 | >2 | 4 | >4 | 8 | >8 | |
| Amoxicillin | 115 | 71 | 13 | 26 | 4 | 4 | 19 | 7 | 6 | 9 | 5 | ||||||||
| AMC | 189 | 12 | 17 | 9 | 5 | 12 | 12 | 9 | 6 | 8 | |||||||||
| Azithromycin | 3 | 15 | 134 | 39 | 1 | 87 | |||||||||||||
| Cefaclor | 1 | 1 | 2 | 7 | 49 | 154 | 10 | 6 | 49 | ||||||||||
| Ceftriaxone | 1 | 176 | 23 | 13 | 14 | 8 | 29 | 4 | 6 | 5 | |||||||||
| Cefuroxime | 202 | 17 | 8 | 10 | 4 | 21 | 17 | ||||||||||||
| Clarithromycin | 142 | 49 | 1 | 9 | 78 | ||||||||||||||
| Erythromycin | 163 | 28 | 1 | 87 | |||||||||||||||
| Levofloxacin | 1 | 8 | 263 | 7 | |||||||||||||||
| Moxifloxacin | 52 | 174 | 53 | ||||||||||||||||
| Penicillin | 187 | 17 | 18 | 7 | 15 | 16 | 13 | 6 | |||||||||||
| SXT | 1 | 99 | 27 | 62 | 1 | 35 | 54 | ||||||||||||
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole.
Overall, 93.2% (260/279) of S. pneumoniae were penicillin susceptible, 4.7% (13/279) were penicillin intermediate and 2.2% (6/279) were penicillin resistant by CLSI penicillin intravenous (iv) (non-meningitis) breakpoints. However, based on CLSI penicillin oral breakpoints or EUCAST breakpoints only 67.0% (187/279) were penicillin susceptible.
S. pneumoniae isolates were 100% susceptible to levofloxacin and moxifloxacin by all three breakpoints. Amoxicillin and amoxicillin/clavulanic acid susceptibility was 92.8%–97.1% by CLSI or PK/PD breakpoints (no EUCAST breakpoints are available). Ceftriaxone was similarly effective, with 94.6% (264/279) of isolates susceptible by CLSI and PK/PD breakpoints, but less active (84.2%) by EUCAST criteria due to the lower EUCAST breakpoint. Cefuroxime was slightly less active, with 85% (237/279) of isolates susceptible by CLSI and PK/PD breakpoints and 78.5% (219/279) by EUCAST breakpoints. Cefaclor, on the other hand, had some activity by CLSI standards (76.7% susceptible; 214/279) but was poorly active (21.5% susceptible; 60/279) by PK/PD breakpoints and only 0.4% of isolates were susceptible (1/279) by EUCAST breakpoints.
Susceptibility to clarithromycin and erythromycin was seen in 68.8% (192/279) of isolates by CLSI, EUCAST and PK/PD breakpoints. Susceptibility to azithromycin was also 68.8% by CLSI breakpoints but there were slightly lower susceptibility rates, of 68.5% (191/279) and 54.5% (152/279), using EUCAST and PK/PD breakpoints, respectively. Susceptibility to trimethoprim/sulfamethoxazole was similar to that seen with macrolides and oral penicillin: 67.7% (189/279) by CLSI or PK/PD breakpoints and 68.1% (190/279) by EUCAST breakpoints.
Antibiotic susceptibility in S. pneumoniae was also compared according to specimen source, age group and penicillin susceptibility using CLSI breakpoints. There was no significant difference in antibiotic susceptibility based on patient age (data not shown). When comparing specimen sources, significant differences were only found between isolates from sinus (n = 102) and sputum (n = 107) for oral penicillin (55.9% and 75.7% susceptible, respectively, P = 0.003) and cefaclor (68.6% and 83.2%, respectively, P = 0.015), and between isolates from sinus (n = 102) and bronchoalveolar lavage (n = 36) for penicillin (55.9% and 75.0%, respectively, P = 0.049). Susceptibility to the test antimicrobials for isolates stratified by penicillin susceptibility (CLSI oral breakpoints only) is shown in Figure 1. As stated above, all isolates were susceptible to levofloxacin and moxifloxacin, so penicillin susceptibility clearly had no effect on the activity of these antibacterials. All penicillin-susceptible isolates were susceptible to ≥90% of the other antibacterials tested. Amoxicillin, amoxicillin/clavulanic acid or ceftriaxone retained full activity against penicillin-intermediate isolates, but all other antibacterials studied, except fluoroquinolones, showed significantly less activity against penicillin-intermediate isolates compared with penicillin-susceptible isolates (P < 0.0001). Furthermore, all antibacterials tested, except fluoroquinolones, were significantly less active against penicillin-resistant isolates compared with penicillin-intermediate isolates (P value ranged from 0.0005 to <0.0001).
Percentage susceptibility rates (with 95% CI) for antimicrobials against S. pneumoniae according to penicillin susceptibility (CLSI oral breakpoints): PSSP, penicillin-susceptible S. pneumoniae; PISP, penicillin-intermediate S. pneumoniae; PRSP, penicillin-resistant S. pneumoniae. *Susceptibility to amoxicillin, amoxicillin/clavulanic acid or ceftriaxone was significantly lower in PRSP than in PISP or in PSSP (P < 0.0001). **Susceptibility to cefuroxime or cefaclor was significantly lower in PISP or in PRSP compared with PSSP and in PRSP compared with PISP (all P < 0.0001). ***Susceptibility to the macrolides and trimethoprim/sulfamethoxazole was significantly lower in PISP or in PRSP compared with PSSP (P < 0.0001) and PRSP compared with PISP (P ≤ 0.001).
H. influenzae
A total of 279 H. influenzae isolates were collected from three different centres in Russia from 2014 to 2016. Infection origins of the isolates included sputum (n = 142; 50.9%), followed by sinuses (n = 97; 34.8%), bronchoalveolar lavage (n = 14; 5.0%), endotracheal aspirate (n = 7; 2.5%), middle ear effusion (n = 6; 2.2%) and blood (n = 4; 1.4%). Nine isolates (3.2%) were from an undisclosed respiratory source. Most isolates (n = 172; 61.6%) came from children, 91 (32.6%) were from adult patients (13–64 years) and 16 (5.7%) were from elderly patients. Forty-three isolates were β-lactamase positive (43/279; 15.4%) and 236 (84.6%) were β-lactamase negative. None was β-lactamase-negative-ampicillin-resistant (BLNAR) by CLSI breakpoints (ampicillin MIC ≥4 mg/L), but two were BLNAR by EUCAST breakpoints (ampicillin MIC ≥2 mg/L).
Summary MIC and susceptibility data for all 279 H. influenzae isolates are shown in Table 4. MIC distribution data are given in Table 5.
MIC and susceptibility data for H. influenzae isolates (n = 279)
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina | ≤2 | 64 | ≤2 | >128 | NA | NA | NA | 81.0 (84.2) | 81.0 | – | 19.0 |
| AMCa | 1 | 2 | 0.12 | 4 | 100 | – | 0.0 | 97.5 (100) | 97.5 | – | 2.2 |
| Ampicillin | 0.25 | 64 | ≤0.06 | >128 | 83.9 | 0.7 | 15.4 | NA | 83.9 | – | 16.1 |
| Azithromycin | 2 | 2 | ≤0.06 | 8 | 99.3 | – | – | 2.2 | 2.2 | 97.1 | 0.7 |
| Cefaclor | 4 | 16 | ≤0.5 | >32 | 87.8 | 8.6 | 3.6 | 1.4 | NA | NA | NA |
| Ceftriaxone | ≤0.03 | ≤0.03 | ≤0.03 | 0.06 | 100 | – | – | 100 | 100 | – | 0.0 |
| Cefuroxime | 1 | 2 | 0.06 | 16 | 98.2 | 1.1 | 0.7 | 76.0 | 0.4 | 75.6 | 24.0 |
| Clarithromycin | 8 | 16 | ≤1 | >16 | 53.4 | 43.4 | 3.2 | 0.0 | 0.4 | 99.6 | 0.0 |
| Levofloxacin | 0.015 | 0.03 | ≤0.004 | >2 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| Moxifloxacin | 0.015 | 0.03 | 0.008 | >1 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| SXT | 0.25 | >2 | ≤0.015 | >2 | 62.7 | 2.9 | 34.4 | 62.7 | 62.7 | 1.4 | 35.8 |
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina | ≤2 | 64 | ≤2 | >128 | NA | NA | NA | 81.0 (84.2) | 81.0 | – | 19.0 |
| AMCa | 1 | 2 | 0.12 | 4 | 100 | – | 0.0 | 97.5 (100) | 97.5 | – | 2.2 |
| Ampicillin | 0.25 | 64 | ≤0.06 | >128 | 83.9 | 0.7 | 15.4 | NA | 83.9 | – | 16.1 |
| Azithromycin | 2 | 2 | ≤0.06 | 8 | 99.3 | – | – | 2.2 | 2.2 | 97.1 | 0.7 |
| Cefaclor | 4 | 16 | ≤0.5 | >32 | 87.8 | 8.6 | 3.6 | 1.4 | NA | NA | NA |
| Ceftriaxone | ≤0.03 | ≤0.03 | ≤0.03 | 0.06 | 100 | – | – | 100 | 100 | – | 0.0 |
| Cefuroxime | 1 | 2 | 0.06 | 16 | 98.2 | 1.1 | 0.7 | 76.0 | 0.4 | 75.6 | 24.0 |
| Clarithromycin | 8 | 16 | ≤1 | >16 | 53.4 | 43.4 | 3.2 | 0.0 | 0.4 | 99.6 | 0.0 |
| Levofloxacin | 0.015 | 0.03 | ≤0.004 | >2 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| Moxifloxacin | 0.015 | 0.03 | 0.008 | >1 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| SXT | 0.25 | >2 | ≤0.015 | >2 | 62.7 | 2.9 | 34.4 | 62.7 | 62.7 | 1.4 | 35.8 |
AMC, amoxicillin/clavulanate; SXT, trimethoprim/sulfamethoxazole; min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; NA, not applicable.
Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.
MIC and susceptibility data for H. influenzae isolates (n = 279)
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina | ≤2 | 64 | ≤2 | >128 | NA | NA | NA | 81.0 (84.2) | 81.0 | – | 19.0 |
| AMCa | 1 | 2 | 0.12 | 4 | 100 | – | 0.0 | 97.5 (100) | 97.5 | – | 2.2 |
| Ampicillin | 0.25 | 64 | ≤0.06 | >128 | 83.9 | 0.7 | 15.4 | NA | 83.9 | – | 16.1 |
| Azithromycin | 2 | 2 | ≤0.06 | 8 | 99.3 | – | – | 2.2 | 2.2 | 97.1 | 0.7 |
| Cefaclor | 4 | 16 | ≤0.5 | >32 | 87.8 | 8.6 | 3.6 | 1.4 | NA | NA | NA |
| Ceftriaxone | ≤0.03 | ≤0.03 | ≤0.03 | 0.06 | 100 | – | – | 100 | 100 | – | 0.0 |
| Cefuroxime | 1 | 2 | 0.06 | 16 | 98.2 | 1.1 | 0.7 | 76.0 | 0.4 | 75.6 | 24.0 |
| Clarithromycin | 8 | 16 | ≤1 | >16 | 53.4 | 43.4 | 3.2 | 0.0 | 0.4 | 99.6 | 0.0 |
| Levofloxacin | 0.015 | 0.03 | ≤0.004 | >2 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| Moxifloxacin | 0.015 | 0.03 | 0.008 | >1 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| SXT | 0.25 | >2 | ≤0.015 | >2 | 62.7 | 2.9 | 34.4 | 62.7 | 62.7 | 1.4 | 35.8 |
| Susceptibility using indicated breakpoints | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC (mg/L) | CLSI | PK/PD | EUCAST | ||||||||
| Antimicrobial | 50% | 90% | min | max | %S | %I | %R | %S | %S | %I | %R |
| Amoxicillina | ≤2 | 64 | ≤2 | >128 | NA | NA | NA | 81.0 (84.2) | 81.0 | – | 19.0 |
| AMCa | 1 | 2 | 0.12 | 4 | 100 | – | 0.0 | 97.5 (100) | 97.5 | – | 2.2 |
| Ampicillin | 0.25 | 64 | ≤0.06 | >128 | 83.9 | 0.7 | 15.4 | NA | 83.9 | – | 16.1 |
| Azithromycin | 2 | 2 | ≤0.06 | 8 | 99.3 | – | – | 2.2 | 2.2 | 97.1 | 0.7 |
| Cefaclor | 4 | 16 | ≤0.5 | >32 | 87.8 | 8.6 | 3.6 | 1.4 | NA | NA | NA |
| Ceftriaxone | ≤0.03 | ≤0.03 | ≤0.03 | 0.06 | 100 | – | – | 100 | 100 | – | 0.0 |
| Cefuroxime | 1 | 2 | 0.06 | 16 | 98.2 | 1.1 | 0.7 | 76.0 | 0.4 | 75.6 | 24.0 |
| Clarithromycin | 8 | 16 | ≤1 | >16 | 53.4 | 43.4 | 3.2 | 0.0 | 0.4 | 99.6 | 0.0 |
| Levofloxacin | 0.015 | 0.03 | ≤0.004 | >2 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| Moxifloxacin | 0.015 | 0.03 | 0.008 | >1 | 99.6 | – | – | 99.6 | 98.6 | – | 1.4 |
| SXT | 0.25 | >2 | ≤0.015 | >2 | 62.7 | 2.9 | 34.4 | 62.7 | 62.7 | 1.4 | 35.8 |
AMC, amoxicillin/clavulanate; SXT, trimethoprim/sulfamethoxazole; min, minimum; max, maximum; S, susceptible; I, intermediate; R, resistant; NA, not applicable.
Amoxicillin and amoxicillin/clavulanic acid PK/PD susceptibility at high dose shown in parentheses.
MIC distribution data for all H. influenzae isolates (n = 279)
| Drug | Number of isolates at MIC (mg/L) | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.008 | ≤0.015 | 0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | 0.12 | 0.25 | ≤0.5 | 0.5 | ≤1 | 1 | >1 | ≤2 | 2 | >2 | 4 | 8 | 16 | >16 | 32 | >32 | 64 | 128 | >128 | |
| Amoxicillin | 226 | 9 | 3 | 5 | 10 | 1 | 25 | |||||||||||||||||||
| AMC | 2 | 51 | 86 | 77 | 57 | 6 | ||||||||||||||||||||
| Ampicillin | 5 | 28 | 120 | 10 | 71 | 2 | 1 | 3 | 2 | 2 | 8 | 2 | 25 | |||||||||||||
| Azithromycin | 2 | 4 | 1 | 11 | 117 | 121 | 21 | 2 | ||||||||||||||||||
| Cefaclor | 4 | 11 | 66 | 103 | 61 | 24 | 8 | 2 | ||||||||||||||||||
| Ceftriaxone | 275 | 4 | ||||||||||||||||||||||||
| Cefuroxime | 1 | 11 | 99 | 101 | 45 | 17 | 3 | 2 | ||||||||||||||||||
| Clarithromycin | 1 | 3 | 15 | 130 | 121 | 9 | ||||||||||||||||||||
| Levofloxacin | 16 | 182 | 56 | 21 | 2 | 1 | 1 | |||||||||||||||||||
| Moxifloxacin | 38 | 174 | 46 | 17 | 2 | 1 | 1 | |||||||||||||||||||
| SXT | 19 | 15 | 30 | 58 | 50 | 3 | 4 | 4 | 96 | |||||||||||||||||
| Drug | Number of isolates at MIC (mg/L) | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.008 | ≤0.015 | 0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | 0.12 | 0.25 | ≤0.5 | 0.5 | ≤1 | 1 | >1 | ≤2 | 2 | >2 | 4 | 8 | 16 | >16 | 32 | >32 | 64 | 128 | >128 | |
| Amoxicillin | 226 | 9 | 3 | 5 | 10 | 1 | 25 | |||||||||||||||||||
| AMC | 2 | 51 | 86 | 77 | 57 | 6 | ||||||||||||||||||||
| Ampicillin | 5 | 28 | 120 | 10 | 71 | 2 | 1 | 3 | 2 | 2 | 8 | 2 | 25 | |||||||||||||
| Azithromycin | 2 | 4 | 1 | 11 | 117 | 121 | 21 | 2 | ||||||||||||||||||
| Cefaclor | 4 | 11 | 66 | 103 | 61 | 24 | 8 | 2 | ||||||||||||||||||
| Ceftriaxone | 275 | 4 | ||||||||||||||||||||||||
| Cefuroxime | 1 | 11 | 99 | 101 | 45 | 17 | 3 | 2 | ||||||||||||||||||
| Clarithromycin | 1 | 3 | 15 | 130 | 121 | 9 | ||||||||||||||||||||
| Levofloxacin | 16 | 182 | 56 | 21 | 2 | 1 | 1 | |||||||||||||||||||
| Moxifloxacin | 38 | 174 | 46 | 17 | 2 | 1 | 1 | |||||||||||||||||||
| SXT | 19 | 15 | 30 | 58 | 50 | 3 | 4 | 4 | 96 | |||||||||||||||||
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole.
MIC distribution data for all H. influenzae isolates (n = 279)
| Drug | Number of isolates at MIC (mg/L) | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.008 | ≤0.015 | 0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | 0.12 | 0.25 | ≤0.5 | 0.5 | ≤1 | 1 | >1 | ≤2 | 2 | >2 | 4 | 8 | 16 | >16 | 32 | >32 | 64 | 128 | >128 | |
| Amoxicillin | 226 | 9 | 3 | 5 | 10 | 1 | 25 | |||||||||||||||||||
| AMC | 2 | 51 | 86 | 77 | 57 | 6 | ||||||||||||||||||||
| Ampicillin | 5 | 28 | 120 | 10 | 71 | 2 | 1 | 3 | 2 | 2 | 8 | 2 | 25 | |||||||||||||
| Azithromycin | 2 | 4 | 1 | 11 | 117 | 121 | 21 | 2 | ||||||||||||||||||
| Cefaclor | 4 | 11 | 66 | 103 | 61 | 24 | 8 | 2 | ||||||||||||||||||
| Ceftriaxone | 275 | 4 | ||||||||||||||||||||||||
| Cefuroxime | 1 | 11 | 99 | 101 | 45 | 17 | 3 | 2 | ||||||||||||||||||
| Clarithromycin | 1 | 3 | 15 | 130 | 121 | 9 | ||||||||||||||||||||
| Levofloxacin | 16 | 182 | 56 | 21 | 2 | 1 | 1 | |||||||||||||||||||
| Moxifloxacin | 38 | 174 | 46 | 17 | 2 | 1 | 1 | |||||||||||||||||||
| SXT | 19 | 15 | 30 | 58 | 50 | 3 | 4 | 4 | 96 | |||||||||||||||||
| Drug | Number of isolates at MIC (mg/L) | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.008 | ≤0.015 | 0.015 | ≤0.03 | 0.03 | ≤0.06 | 0.06 | 0.12 | 0.25 | ≤0.5 | 0.5 | ≤1 | 1 | >1 | ≤2 | 2 | >2 | 4 | 8 | 16 | >16 | 32 | >32 | 64 | 128 | >128 | |
| Amoxicillin | 226 | 9 | 3 | 5 | 10 | 1 | 25 | |||||||||||||||||||
| AMC | 2 | 51 | 86 | 77 | 57 | 6 | ||||||||||||||||||||
| Ampicillin | 5 | 28 | 120 | 10 | 71 | 2 | 1 | 3 | 2 | 2 | 8 | 2 | 25 | |||||||||||||
| Azithromycin | 2 | 4 | 1 | 11 | 117 | 121 | 21 | 2 | ||||||||||||||||||
| Cefaclor | 4 | 11 | 66 | 103 | 61 | 24 | 8 | 2 | ||||||||||||||||||
| Ceftriaxone | 275 | 4 | ||||||||||||||||||||||||
| Cefuroxime | 1 | 11 | 99 | 101 | 45 | 17 | 3 | 2 | ||||||||||||||||||
| Clarithromycin | 1 | 3 | 15 | 130 | 121 | 9 | ||||||||||||||||||||
| Levofloxacin | 16 | 182 | 56 | 21 | 2 | 1 | 1 | |||||||||||||||||||
| Moxifloxacin | 38 | 174 | 46 | 17 | 2 | 1 | 1 | |||||||||||||||||||
| SXT | 19 | 15 | 30 | 58 | 50 | 3 | 4 | 4 | 96 | |||||||||||||||||
AMC, amoxicillin/clavulanic acid; SXT, trimethoprim/sulfamethoxazole.
All isolates were susceptible to ceftriaxone by all three breakpoint guidelines. Amoxicillin/clavulanic acid susceptibility was also 100% by CLSI and high-dose PK/PD breakpoints and 97.5% by EUCAST and low-dose PK/PD breakpoints. Levofloxacin and moxifloxacin susceptibility was 99.6% (278/279) for CLSI and PK/PD breakpoints, and slightly lower at 98.6% (275/279) with EUCAST breakpoints. Cefuroxime susceptibility was 98.2% (274/279) by CLSI, 76.0% (212/279) by PK/PD, but only 0.4% by EUCAST (1/279) breakpoints. Similarly, cefaclor susceptibility was considerably higher by CLSI (87.8%; 245/279) than by PK/PD (1.4%; 4/279) criteria; no EUCAST breakpoints are available. For azithromycin the same breakpoint guideline variability was observed, with high susceptibility using CLSI criteria (99.3%; 277/279), but greatly reduced susceptibility by PK/PD and EUCAST breakpoints (2.2%; 6/279). This breakpoint difference was also shown with clarithromycin susceptibility, although activity was much lower: 53.4% susceptible (149/279) by CLSI, 0% susceptible by PK/PD and 0.4% susceptible (1/279) by EUCAST. Trimethoprim/sulfamethoxazole susceptibility was 62.7% (175/279) by all three breakpoint categories.
Antibiotic susceptibility in H. influenzae was also compared according to specimen source and patient age group. There was no significant difference in antibiotic susceptibility based on patient age (data not shown). Percentage susceptibility data (CLSI breakpoints) by specimen source are shown in Figure 2. For most antibacterials there was no significant difference in susceptibility by specimen source, but trimethoprim/sulfamethoxazole susceptibility was significantly lower for isolates from sinus specimens than those from bronchoalveolar lavage specimens (P = 0.001) or sputum samples (P = 0.005).
Percentage susceptibility rates (with 95% CI) for antimicrobials against H. influenzae by specimen source according to CLSI breakpoints. *Trimethoprim/sulfamethoxazole susceptibility was significantly lower in isolates from sinus specimens than in bronchoalveolar lavage (BAL) specimens (P = 0.001) or in sputum specimens (P = 0.005).
Discussion
Increasing antimicrobial resistance is a serious global problem that restricts empirical treatment options, which are essential for community-acquired respiratory tract infections. SOAR surveys antimicrobial resistance in key respiratory pathogens and is currently conducted throughout the Middle East, Africa, Latin America, Asia-Pacific and the Commonwealth of Independent States countries and has been running since 2002. It was established to provide information on local resistance patterns among the two most common pulmonary pathogens, S. pneumoniae and H. influenzae.
In this study, with lower oral dosing, 67.0% of pneumococci from Russia were found to be penicillin susceptible using CLSI oral breakpoints. Therefore, higher iv dosing is required to ensure positive clinical outcomes with penicillin. However, for many patients with community-acquired respiratory tract infections, oral therapy is desirable and fluoroquinolones (100% susceptible) and amoxicillin/clavulanic acid (≥95.0% susceptible) remain the optimum choices. However, fluoroquinolones are not recommended for the treatment of paediatric patients. Cefuroxime is also available orally but susceptibility was lower, at 85.0% (CLSI or PK/PD breakpoints) and 78.5% (EUCAST). Based on CLSI breakpoints, 68.8% of the pneumococci were susceptible to the macrolides azithromycin and clarithromycin, and although these agents can be given orally, they do not provide sufficient coverage. Trimethoprim/sulfamethoxazole was also poorly active against pneumococci (∼68% susceptible). In addition, those isolates resistant to oral penicillin were also highly resistant to all other classes of antibiotic apart from fluoroquinolones, which further restricts therapeutic choices, especially for children, who cannot be given fluoroquinolones.
H. influenzae from Russia were generally more susceptible to antimicrobial agents than S. pneumoniae, but nevertheless β-lactamase prevalence was high (15.4%), with associated ampicillin resistance. As would be expected, amoxicillin/clavulanic acid overcame resistance due to β-lactamases. The higher rate of resistance to amoxicillin when compared with ampicillin for H. influenzae (Table 4) is surprising and may reflect a technical issue with determination of amoxicillin MICs. If only BLNAR and β-lactamase-producing isolates are considered as amoxicillin resistant, the proportion of amoxicillin-susceptible isolates rises from 81% to 83.9%. In addition, resistance to fluoroquinolones according to EUCAST criteria was observed in four H. influenzae isolates from Russia. Following CLSI recommendations, susceptibility to azithromycin was 99.3% but analysis by both PK/PD and EUCAST breakpoints indicated only 2.2% susceptibility. This effect was also shown for clarithromycin, with a reduction in susceptibility from 53.4% by CLSI to 0% and 0.4% by PK/PD and EUCAST breakpoints, respectively. This effect is not restricted to macrolides, because the CLSI susceptibility of cefuroxime was 98.2%, which dropped to ∼76% using PK/PD and EUCAST breakpoints. Similarly, cefaclor susceptibility was 87.8% by CLSI, but only 1.4% by PK/PD criteria (EUCAST do not have H. influenzae breakpoints).
Furthermore, cefaclor susceptibility also varied in S. pneumoniae, with susceptibility 76.7% by CLSI criteria but 21.5% by PK/PD and 0.4% by EUCAST breakpoints. The variability in antimicrobial susceptibility using different breakpoints is confusing and makes it difficult for clinicians to interpret antimicrobial resistance data. Therefore it would be very helpful if breakpoints were harmonized.
As with S. pneumoniae, susceptibility of H. influenzae to trimethoprim/sulfamethoxazole was low (62.7% overall by all guidelines) but this significantly differed depending on the specimen source, ranging from 48.5% susceptible in sinus specimens to 92.9% susceptible in bronchoalveolar lavage specimens.
Published susceptibility data for non-invasive pneumococci collected in 2009–13 from paediatric hospitals in Moscow showed penicillin non-susceptibility at 28%, macrolide resistance at 26% and trimethoprim/sulfamethoxazole resistance at 57%, using EUCAST breakpoints.13 Data from a recent global surveillance study show high resistance rates in pneumococci from Russia (macrolides 56% resistance and trimethoprim/sulfamethoxazole resistance 47%).3 These data confirm a high level of antibiotic resistance in pneumococci from Russia. It has been reported recently that self-prescription of antibiotics is common in Russia (Saint Petersburg),14 and as this practice is considered a risk factor for increased antibiotic resistance15 it may be a reason for the low antibiotic susceptibility observed in Russia. However, antibiotic susceptibility rates are higher in H. influenzae isolates from Russia, as shown in the current study and elsewhere.3 This may relate to this pathogen being less commonly associated with CAP than S. pneumoniae or simply be because the two pathogens have differing microbiological characteristics.
SOAR has also recently published data from the 2011–13 survey in nearby Ukraine, where antibiotic resistance in S. pneumoniae and H. influenzae was considerably lower than that observed in Russia.4 This confirms the need to continue antibiotic resistance surveillance on a national basis as resistance even within the same region can vary considerably from country to country.
Acknowledgements
We thank Gudrun Maechler and Olena Sopko for reviewing the manuscript and Leghnina Margarita/Marina Avetisyan 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. 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.
