Resistance mechanisms

Similar to E. coli, K. pneumoniae can be resistant to multiple antimicrobial agents, and resistance traits are frequently acquired through plasmids. In contrast to E. coli, K. pneumoniae has a chromosomally encoded class A beta-lactamase and is thus intrinsically resist-ant to aminopenicillins. Moreover, this organism readily acquires plasmid-mediated resistance determinants.

Many novel ESBL variants were initially identified in K.  pneumoniae and were only subsequently found in E. coli. Since the resistance mechanisms do not differ significantly from those described for E. coli, readers should refer to the E. coli section (3.1, above) for further details.

Carbapenems have been widely used in many coun-tries due to the increasing rate of ESBL-producing Enterobacteriaceae, resulting in the emergence of resist-ance to these agents, especially in K. pneumoniae. In Europe, K. pneumoniae with carbapenemase KPC, NDM, OXA-48-like, or VIM production has been reported, although with greatly varying prevalence. The high-est rates were reported in Mediterranean and Balkan countries.

3.2.3 Antimicrobial susceptibility

• More than a third of the K. pneumoniae isolates reported to EARS-Net in 2015 were resistant to at least one antimicrobial group under surveillance, and combined resistance to multiple antimicrobial groups was common. The most common resistance phenotype was combined resistance to three key antimicrobial groups: fluoroquinolones, third-gen-eration cephalosporins and aminoglycosides.

• The EU/EEA population-weighted mean per-centages of resistance in K. pneumoniae to fluoroquinolones, third-generation cephalospor-ins, aminoglycosides and carbapenems, as well as combined resistance to fluoroquinolones, third-generation cephalosporins and aminoglycosides, all increased significantly between 2012 and 2015.

• There were wide inter-country differences in the percentage of carbapenem-resistant K. pneu-moniae. The three countries with the highest of carbapenem resistance (Greece, Italy and Romania) also contributed the vast majority of the isolates with combined carbapenem and poly-myxin resistance.

• A north to east/south gradient was noted for most antimicrobial groups, with lower resistance per-centages in K. pneumoniae reported from northern countries and higher percentages from the eastern and southern parts of Europe.

Fluoroquinolones

For 2015, 30 countries reported 22 358 K. pneumoniae isolates with AST information for fluoroquinolones (cip-rofloxacin, levofloxacin or ofloxacin). The number of isolates reported per country ranged from 35 to 2 332 (Table 3.7).

The EU/EEA population-weighted mean percentage showed a significantly increased trend for the period 2012–2015, from 25.3 % in 2012 to 29.7 % in 2015 (Table 3.7).

National percentages of resistant isolates ranged from 2.9 % (Iceland) to 70.0 % (Slovakia) in 2015 (Table  3.7 and Figure 3.6). Trends for the period 2012–2015 were calculated for the 29 countries reporting at least 20 isolates per year during the full reporting period.

Significantly increasing trends were observed for five countries (France, Ireland, Romania, Spain and the United Kingdom). These trends remained significant when considering only data from laboratories reporting consistently for all four years. Significantly decreas-ing trends were observed for Austria, Denmark and Germany. These trends remained significant when considering only data from laboratories reporting con-sistently for all four years.

Third-generation cephalosporins

For 2015, 30 countries reported K. pneumoniae isolates with AST information for third-generation cephalospor-ins (cefotaxime, ceftriaxone or ceftazidime). The number of isolates reported per country ranged from 36 to 2 338 (Table 3.8).

The trend for the EU/EEA population-weighted mean percentage increased significantly for the period 2012–

2015, from 25.8 % in 2012 to 30.3 % in 2015 (Table 3.8).

National percentages of resistant isolates ranged from zero (Iceland) to 75.0 % (Bulgaria) in 2015 (Table 3.8, Figure 3.7). Trends for the period 2012–2015 were calcu-lated for the 29 countries reporting at least 20 isolates per year during the full reporting period. Significantly increasing trends were observed for Cyprus, Finland and the United Kingdom. For Finland, the trend did not remain significant when considering only data from lab-oratories reporting consistently for all four years.

Significantly decreasing trends were observed for five countries (Denmark, Germany, Greece, Hungary and Lithuania). For Germany, the trend did not remain sig-nificant when considering only data from laboratories reporting consistently for all four years.

ESBL percentages for K. pneumoniae were calculated based on data from 23 countries. Only data from labo-ratories reporting ESBL results for all isolates identified as resistant to third-generation cephalosporins (51 % of the laboratories reporting AST data for third-genera-tion cephalosporin in K. pneumoniae), and only data from countries reporting at least 10 such isolates were included. Among the K. pneumoniae isolates resistant to third-generation cephalosporins and meeting the inclu-sion criteria, 85.3 % were ascertained as ESBL-positive by the laboratories in 2015. ESBL results might not be directly comparable between countries as there are national differences in the definition of ESBL. The pres-ence of ESBL might also be masked by carbapenemases such as MBLs and KPCs, and/or severe permeability defects [18].

Aminoglycosides

For 2015, 30 countries reported 22 301 K. pneumoniae isolates with AST information for aminoglycosides (gen-tamicin and/or tobramycin). The number of isolates reported per country ranged from 36 to 2 337 (Table 3.9).

The trend for the EU/EEA population-weighted mean percentage increased significantly for the period 2012–

2015, from 21.5 % in 2012 to 22.5 % in 2015 (Table 3.9).

National percentages of resistant isolates ranged from zero (Iceland) to 66.5 % (Slovakia) in 2015 (Table 3.9 and Figure 3.8). Trends for the period 2012–2015 were calcu-lated for the 29 countries reporting at least 20 isolates per year during the full reporting period. Significantly increasing trends were observed for Cyprus, Finland and the United Kingdom. For Finland, the trend did not remain significant when considering only data from laboratories reporting consistently for all four years.

Significantly decreasing trends were observed for five

countries (Denmark, Germany, Greece, Hungary and Lithuania). For Germany, the trend did not remain sig-nificant when considering only data from laboratories reporting consistently for all four years.

Susceptibility data for amikacin were less frequently reported than for gentamicin and/or tobramycin and gen-erally showed lower resistance. A total of 15 421 isolates had susceptibility data for both amikacin and gentamicin and/or tobramycin (69.1 % of the isolates included in the aminoglycoside group analysis). Among isolates with resistance to either gentamicin or tobramycin, 17.2 % of the isolates were also resistant to amikacin.

Carbapenems

For 2015, 30 countries reported 21 749 K. pneumo-niae isolates with AST information for carbapenems (doripenem, imipenem or meropenem). The number of isolates reported per country ranged from 35 to 2 244 (Table 3.10).

The trend for the EU/EEA population-weighted mean percentage increased significantly for the period 2012–

2015, from 6.2 % in 2012 to 8.1 % in 2015 (Table 3.10).

The national percentages of resistant isolates ranged from zero (Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Luxembourg and Sweden) to 61.9 % (Greece) (Table 3.10, Figure 3.9). Trends for the period 2012–2015 were calculated for the 29 countries reporting at least 20 isolates per year during the full four-year period.

Significantly increasing trends were observed for four countries (Croatia, Portugal, Romania and Spain). For Romania, the trend did not remain significant when considering only data from laboratories reporting con-sistently for all four years. Significantly decreasing trends were observed for Hungary and Slovakia. For Slovakia, the trend did not remain significant when considering only data from laboratories reporting con-sistently for all four years.

Combined resistance to third-generation cephalospor-ins, fluoroquinolones and aminoglycosides

For 2015, 30 countries reported 21 871 K. pneumoniae isolates with sufficient AST information to determine combined resistance to third-generation cephalospor-ins, fluoroquinolones and aminoglycosides. The number of isolates reported per country ranged from 35 to 2 324 (Table 3.11).

The trend for the EU/EEA population-weighted mean percentage increased significantly for the period 2012–

2015, from 17.7 % in 2012 to 18.6 % in 2015 (Table 3.11).

National percentages of resistant isolates ranged from zero (Iceland) to 59.6 (Slovakia) in 2015 (Table 3.11 and Figure 3.10). Trends for the period 2012–2015 were calcu-lated for the 29 countries reporting at least 20 isolates per year during the full four-year period. A significantly increasing trend was observed for Finland, a trend that did not remain significant when considering only data from laboratories reporting consistently for all four years. Significantly decreasing trends were observed

Figure 3.6. Klebsiella pneumoniae. Percentage (%) of invasive isolates with resistance to fluoroquinolones, by country, EU/EEA countries, 2015

Luxembourg Malta 10% to < 25%

25% to < 50%

≥ 50%

No data reported or fewer than 10 isolates Not included

< 1%

1% to < 5%

5% to < 10%

Liechtenstein Non-visible countries

Figure 3.7. Klebsiella pneumoniae. Percentage (%) of invasive isolates with resistance to third-generation cephalosporins, by country, EU/EEA countries, 2015

Luxembourg 10% to < 25%

25% to < 50%

≥ 50%

No data reported or fewer than 10 isolates Not included

< 1%

1% to < 5%

5% to < 10%

Liechtenstein Non-visible countries

and Lithuania). For Denmark, the trend did not remain significant when considering only data from laboratories reporting consistently for all four years.

The trend for the EU/EEA population-weighted mean percentage increased significantly for the period 2012–

2015, from 17.7 % in 2012 to 18.6 % in 2015 (Table 3.11).

Other resistance combinations and resistance to other antimicrobial groups

Of the 21 141 isolates (92.3 % of all K. pneumoniae iso-lates) tested for all antimicrobial groups under regular EARS-Net surveillance (fluoroquinolones, third-genera-tion cephalosporins, aminoglycosides and carbapenems) in 2015, more than one third (36.6 %) were resistant to at least one antimicrobial group. Among the resistant isolates, combined resistance to third-generation ceph-alosporins, fluoroquinolones and aminoglycosides was the most common resistance phenotype, more frequent than isolates with single resistance to antimicrobial group or two antimicrobial groups together. Overall, 4.7 % of all K. pneumoniae isolates were resistant to all groups under EARS-Net surveillance (Table 3.12).

Twenty-one countries reported AST data for polymyx-ins for a total of 6 029 isolates (26.3 % of all reported K. pneumoniae isolates) in 2015. Only six countries reported polymyxin AST data for more than half of the reported K. pneumoniae isolates. Overall, 8.8 % of the K. pneumoniae isolates were resistant to polymyxins.

Among carbapenem-resistant isolates also tested for resistance to polymyxins (26.5 % of all isolates with carbapenem AST information), 31.9 % were resistant to polymyxins, whereas only 2.6 % of the carbapenem-susceptible isolates were resistant to polymyxins. The vast majority (95 %) of the isolates with combined car-bapenem and polymyxin resistance were reported from Greece and Italy.

Due to the low number of isolates tested, potential sequential testing and differences in the use of labo-ratory methodology used to determine susceptibility, these findings should be interpreted with caution and may not be representative of Europe as a whole.