3.2.2 Extended spectrum β-lactamases

In Section 1.2 you saw how β-lactamases can hydrolyse β-lactam antibiotics in order to destroy them. The first β-lactamase to be identified was penicillinase. As its name suggests, penicillinase can hydrolyse penicillin but not cephalosporins. In the 1980s, a new group of β-lactamase enzymes were detected in Europe that hydrolyse cephalosporins. Because of their ability to hydrolyse a wider range of β-lactams, the name for these enzymes is extended spectrum β-lactamase (ESBL).

In the next activity, you will look at how the presence of ESBLs in E. coli is associated with cephalosporin resistance.

Activity 4 Cephalosporin resistance and ESBLs

Timing: Allow 20 minutes

The data in this activity are from Pfizer’s antimicrobial testing leadership and surveillance (ATLAS) (Pfizer, 2017).

E. coli bacteria were isolated from infections and tested to determine whether they produced ESBLs and whether they were resistant to cephalosporins. Figure 6 shows the percentage of ESBL- and non-ESBL-producing E. coli isolates that were resistant to the cephalosporin cefepime between 2004 and 2016.

Note that this figure compares ESBL-producing and non-ESBL-producing isolates for resistance to cefepime. However, it does not give any information on the number of E. coli isolates that produce ESBLs. As you will see in the case study in Week 4, the percentage of ESBL-producing E. coli isolates in the UK during this period remained below 15% (BSAC UK, 2014).

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Figure 6 Cefepime resistance of E. coli isolates in the UK between 2004 and 2016 (Data from Pfizer, 2017).

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This figure comprises a bar graph showing cefepime resistance of E. coli isolates in the UK between 2004 and 2016. The horizontal axis is labelled year and is marked from 2004 to 2016 in 1-year intervals except between 2004 and 2007 where no data is included. The vertical axis is labelled resistant (%) and is marked from 0 to 100 in intervals of 10. The blue bars represent E. coli isolates that contain ESBLs. The red bars represent E. coli isolates that do not contain ESBLs. The blue bars are much larger than the red bars in all years. The blue bars range from 50% in 2004 and 2013 to 100% in 2007 and 2008. The red bars never exceed 10%.

Figure 6 Cefepime resistance of E. coli isolates in the UK between 2004 and 2016 (Data from Pfizer, 2017).

Now answer the following questions based on the data in Figure 6.

1 How has the proportion of (a) ESBLs and (b) non-ESBLs resistant to cefepime changed over time?

Answer

(a) ESBL-producing E. coli have higher levels of resistance to cefepime than non-ESBL-producing E. coli isolates over the entire period. In 2004, approximately 50% of ESBL isolates were resistant. This increased to a peak of approximately 100% in 2007 and 2008. Resistance decreased between 2008 and 2009 and then rose again until 2011. Resistance reached its lowest level in 2013 before increasing again. Resistance never fell below 50% with the lowest levels in 2004 and 2013.

(b) non-ESBL producing bacteria display hardly any resistance to cefepime with low levels of resistance (less than 10%) only being observed in 2007, 2009, 2012 and 2015.

2 Explain the difference in resistance between ESBL- and non-ESBL-producing E. coli?

Answer

The presence of an ESBL in ESBL-producing E. coli results in the hydrolysis, and therefore destruction, of cefepime. Since cefepime can no longer inhibit PBP, these bacteria are resistant. Non-ESBL-producing E. coli lack the ESBL and cannot hydrolyse cefepime, therefore it can exert its bactericidal effects by binding to and inhibiting its target PBP.

3 Do you think the expression of ESBLs is a major determinant of resistance to cephalosporins in E. coli?

Answer

Resistance to cefepime remains between 50 and 100% in ESBL-producing E. coli whereas almost all non-ESBL-producing bacteria are susceptible to cefepime. This suggests that the presence of an ESBL is a major determinant of cephalosporin resistance.

Since they were first described in the early 1980s, the frequency of infections caused by ESBL-producing bacteria has been increasing (Figure 7). Resistance to cephalosporins limits the treatment options for these infections. Consequently, ESBLs represent an ever-growing healthcare challenge.

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Figure 7 Frequency of ESBL-positive E. coli isolates in the UK from 2001 to 2016 (Data from BSAC UK, 2014).

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This figure comprises a line graph showing the frequency of ESBL-positive E. coli isolates in the UK between 2001 and 2016. The horizontal axis is labelled year and is marked from 2000 to 2016 in 2-year intervals. The vertical axis is labelled ESBL-positive isolates (%) and is marked from 0 to 14 in intervals of 2. The line crosses the horizontal axis at 2001 and slopes upwards to a peak at 13% in 2006. It then slopes downwards to 6% in 2011 before slopping upwards again to 12% in 2013. It ends at 10% in 2016.

Figure 7 Frequency of ESBL-positive E. coli isolates in the UK from 2001 to 2016 (Data from BSAC UK, 2014).

Several ESBL classes have been identified. Of them, the CTX-M class of ESBLs, has become the most common worldwide. You will learn more about the origin and spread of CTX-M ESBLs in the case study in Week 4.