Antibiotic prescribing declined by just 5 per cent between 2012 and 2016 but there are grounds for optimism in the fight to protect us from an antibiotic apocalypse.

Earlier this year, the Government introduced a target that aims to halve healthcare-associated bacteraemias caused by Escherichia coli, Klebsiella species and Pseudomonas aeruginosa by April 2021.

It is a laudable aim as the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) report published in October noted that resistance continues to rise and that antibiotic prescribing fell by just 5 per cent between 2012-2016. For example, the incidence of E. coli bacteraemia increased by 24.3 per cent compared to 2012, leading to 40,272 cases in 2016.

The ESPAUR report noted that urinary tract infections (UTIs) were probably responsible for about half of E. coli bacteraemias. Based on 1,007,684 urine samples, 2.7 and 3.2 per cent of isolates from community and acute settings respectively were resistant to nitrofurantoin, but 34 and 37 per cent were resistant to trimethoprim and 12 and 15 per cent to ciprofloxacin – a therapeutic mainstay for complicated or upper UTI (pyelonephritis).

Current guidelines recommend microbiologically testing urine from patients who fail treatment, experience frequent or recurrent UTIs or who are likely to have a resistant infection. Public Health England (PHE) suggests using nitrofurantoin rather than trimethoprim as empiric UTI treatment before laboratory results are available. PHE advocates trimethoprim only when there is a low risk of resistance.

Small decline

Despite widespread concern, as we have already seen, antibiotic prescribing declined by just 5 per cent between 2012 and 2016 (based on defined daily doses per 1,000 inhabitants a day). The number of antibiotic prescriptions dispensed in general practice fell by 13 per cent, largely reflecting a decline in the use of penicillins.

Secondary care, on the other hand, has not seen a “sustained reduction in total antibiotic prescribing” although hospitals used less ultra-broad spectrum antibiotics between 2015 and 2016. Prescribing of piperacillin/tazobactam and carbapenems both fell by 4 per cent.

“This is the first step in reducing antibiotic use in hospitals. Focusing on using these antibiotics appropriately is key to preventing the emergence and spread of carbapenem-resistant Gram-negative bacteria,” the report says.

Antimicrobial stewardship also seems to be working. During the first two years of NHS England’s Quality Premium, 88 per cent of CCGs reduced antibiotic consumption and 83 per cent cut broad-spectrum antibiotic use.

New antibiotics

Although it is early days, new drugs to tackle infections may be just around the corner. Spanish scientists, for example, recently designed molecules that attack small areas (called microdomains) of lipid and protein in the membrane of Staphylococcus aureus.¹

“These microdomains in the cell membrane, called lipid rafts, are crucial because they form many protein complexes related to resistance to antibiotics,” says author Daniel López from the National Centre for Biotechnology, Madrid.

“The molecules we have designed make all these proteins stop working and become disorganised. In short, they succeed in making a resistant bacteria stop being resistant.”

Disrupting the assembly of these microdomains disables penicillin-resistance in MRSA. The researchers suggest using these molecules in combination with antibiotics because “resistance would be disassembled before aiming a direct attack on the bacteria with a common antibiotic”.

Dr López suggests that resistance is unlikely. Removing the lipid rafts does not itself undermine bacterial survival and, therefore, does not impose the evolutionary pressure that drives resistance.

Cell walls a target

Another new strategy² focuses on bacterial cell walls. “The cell wall is a mesh, like a fishing net, made up largely of peptidoglycan, a polymerised blend of sugars and amino acids associated with peptides,” says lead author Andréa Dessen from the Institute of Structural Biology in Grenoble, France and the National Bioscience Laboratory in Brazil.

In capsule-shaped bacilli, a multiprotein complex called the elongasome ensures that the daughter cells have an elongated cell wall. The researchers isolated the central part of the complex formed by two proteins (PBP2 and MreC) that maintain the bacteria’s shape and growth. MreC, for instance, acts as ‘scaffolding’ during elongation of the cell wall.

Mutant versions of MreC were then engineered with alterations in the region that interfaces with PBP2. The modified protein no longer formed the complex.

H. pylori genetically modified to express mutant MreC did not become ‘capsule shaped’ and died rapidly.

“This knowledge can be used to seek molecules capable of interrupting the interaction between these proteins and thereby kill the bacillus,” says Dr Dessen. In principle, the strategy is effective only against species with elongated cell walls – but this includes Acinetobacter baumannii (an important multi-resistant micro-organism in hospitals globally) and K. pneumoniae.

The proportion of K. pneumoniae isolates resistant to common antibiotics remained fairly stable between 2012 and 2016, says ESPAUR. Nevertheless, in 2016, 27.5 per cent of isolates showed resistance to co-amoxiclav and the number of patients with resistant infections increased. For example, 510 people presented with K. pneumoniae resistant to third-generation cephalosporins in 2012, compared to 790 in 2016.

“A woman recently hospitalised in the US died from infection by a strain of K. pneumoniae that is resistant to 26 different antibiotics,” Dr Dessen concludes. “The problem of drug resistant bacteria is serious and hasn’t been given proper attention by either governments or the pharmaceutical industry. We can no longer ignore it.”

Another new strategy for antibiotic development focuses on bacterial cell walls

<sup>References
1. Cell DOI:10.1016/j.cell.2017.10.012
2. Nat Comms DOI:10.1038/s41467-017-00783-2</sup>