Bacterial resistance and antibiotic therapy

In the literature, the term antibiotic resistance (ABR) generally refers to bacterial

pathogens that were once susceptible to an antibiotic, but which have since acquired resistance (8). The World Health Organisation (WHO) has raised concerns that if the increasing rates of the ABR are not controlled, we may reach a post-antibiotic era where common infections that have until now been easily treated, may become lethal (8). These concerns are supported by data from a recent WHO report which indicated a dramatic increase in the rates of ABR in common infectious diseases, such as urinary tract infection and pneumonia, both community and hospital-acquired infections (8). Of these resistant bacteria, the most commonly identified resistant pathogens that are associated with poor clinical outcomes are referred to as the “ESKAPE” pathogens (87):  Enterococcus faecium  Staphylococcus aureus  Klebsiella pneumoniae  Acinetobacter baumanii  Pseudomonas aeruginosa  Enterobacter species

The rates of ABR for five bacterial pathogens (Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium) have been investigated in Europe over four years from 2002 to 2006. The report estimated that the overall rate of resistance for these pathogens increased by 6.4% annually (88). Another report from the United States (US) found that the rate of hospitalisation with vancomycin‐resistant

Enterococcus faecium (VRE) has almost tripled from 3.6 to 9.5 cases per 100 000 population over the period 2003 to 2006 (89). A report from the Centers for Diseases Control and

10 Prevention (CDC) indicated that carbapenem-resistant Enterobacteriaceae (CRE) has risen

over the last decade, from 1.2% of strains in 2001 to 4.2% in 2011 (90).

The rise in ABR has become a public health concern worldwide due to the impact this has on patients’ clinical outcomes and healthcare costs (91-95). With respect to mortality rates associated with ABR, data from the USA estimated almost 23,000 deaths per year due to infections were caused by resistant pathogens (45). Studies indicate that mortality rates among patients who are infected with MRSA are higher than that among those who are infected with methicillin-susceptible Staphylococcus aureus (MSSA) (96-99). Other studies that investigated the mortality rates among patients in 1265 ICU from 75 countries, found that the mortality rate for patients with MRSA was almost 9% greater than those who were

infected with the MSSA (29.1% vs 20.5%, respectively) (100).An observational study conducted on patients with blood infections caused by Enterococcus faecium found that patients who were infected with VRE had higher mortality rates than those who were infected with vancomycin-susceptible pathogens (101).Moreover, patients who are infected with ABR pathogens are more likely to stay longer in hospital (8). Mauldin et al. investigated the impact of infections caused antibiotic-resistant Gram negative pathogens on the LOS compared to antibiotic-susceptible Gram-negative pathogens. The authors showed that the LOS increased significantly, by 23.8% for patients with resistant pathogens (p < 0.001) (102). In another study, de Kraker et al. found that LOS was on average eight days longer among patients with bacteraemia caused by infection with Escherichia coli resistant to third-

generation cephalosporins, compared to patients with susceptible strains of the same pathogen (103).

The costs of treating infections caused by resistant bacteria are believed to be

consistently greater than for infections caused by susceptible pathogens. In their study of 662 hospitalised patients with an infection caused by gram-negative bacteria, Mauldin et al.

11 reported that the estimated direct healthcare costs for patients with resistant pathogens were

29.3% higher than the costs of susceptible pathogens (102). Another study examining the healthcare costs of 725 hospitalised patients with infections caused by S aureus found that estimated total healthcare costs for patients with resistant pathogens were more than twice that for those patients with susceptible organisms ($34,657 vs $15,923 respectively; p < 0.001) (104). A study looking at 5,699 hospitalised patients found that the total cost was almost $10,000 more when a patient was infected with one of the ESKAPE pathogens (105).

One of the major concerns regarding ABR is that use of antibiotics is now integral to many aspects modern medical practice and without access to reliable antibiotic therapy this may be jeopardised. For example, antibiotics play a major part in cancer treatments, general surgery and organ transplantations (45). In their review article, Smith and Coast stated that losing antibiotic effectiveness to treat common infections would put the era of modern medicine in danger and this would lead us to return to the pre-antibiotic era (106).

A large and growing body of literature has examined the association between antibiotic consumption and increased rate of ABR (29, 107-110). Prior exposure to antibiotics is considered as the major cause of the emergence and rise of ABR. In an investigation on the consumption of antibiotics in the outpatient settings of 26 European countries, it has been shown that ABR rates were higher in countries who consumed more antibiotics (Figure 1.3) (29).

12

Figure 1.3: Correlation between out-patient penicillin consumption and prevalence of penicillin S pneumoniae-resistant incidence among European countries. Reproduced with permission (29).

DID: defined daily dose per 1000 inhabitants daily

AT, Austria; BE, Belgium; HR, Croatia; CZ, Czech Republic; DK, Denmark; FI, Finland; FR, France; DE, Germany; HU, Hungary; IE, Ireland; IT, Italy; LU, Luxembourg; NL, The Netherlands; PL, Poland; PT, Portugal; SI, Slovenia; ES, Spain; UK, England only.

Whilst the use of any antibiotic may lead to the emergence of resistance, the use of certain antibiotics may be associated with a particularly significant increase in the rate of some resistant microorganism. For example, Bergman et al. conducted a study in which they tested

S. pneumoniae isolates to indicate the rates of resistance to penicillin and macrolides (111). The data was then compared against the local consumption of macrolides and cephalosporins

13 in the 18 participating hospitals. The authors found that there was a significant association

between increase macrolide usage, azithromycin in particular, and the increase of macrolide- resistant S pneumonoae. Furthermore, a connection between increase use of cephalosporins and a rise of penicillin-resistant S pneumoniae was indicated. Therefore, the authors

highlighted the importance of avoiding unnecessary use of these agents.

Studies have been conducted to examine the effect of controlling broad-spectrum antibiotic use on ABR in some bacterial pathogens. For example, an Australian national

restriction on the use of fluoroquinolones in human and animals was associated with reduction of the emergence of resistant E coli (112). Another example comes from Finland, where a decrease in the national consumption of macrolides in the outpatient setting was associated with a significant decrease in the detection of macrolide-resistant group A streptococci (113). It has also been shown that restriction of carbapenem antibiotics was associated with

significant reduction of the rate of carbapenem-resistant Pseudomonas aeroginosa in 22 US teaching hospitals, where restriction was applied (114). Kaki et al. conducted a systematic review on the impact of quality improvement initiatives in critical care units to improve antibiotic prescribing (115). From the 24 analysed studies, 13 evaluated the impact on ABR; where the authors concluded that most of those interventions have been significantly

associated with reduce resistance of key ICU pathogens.

Based on the wealth of literature available regarding ABR, four core actions have been proposed in order to tackle the problem (45, 116):

 Preventing the occurrence of infection and the spread of the ABR.  Tracking resistant microorganisms

 Assisting pharmaceutical industries in developing new antibiotics and new diagnostic tests for resistant bacteria

14  Implementing antimicrobial stewardship (AMS)

Although the first three core actions are important strategies, it is beyond the scope of this thesis to discuss these topics in depth and the focus will hereafter be on AMS.