The rise and rise of antimicrobial resistance in Gram-negative bacteria

Antimicrobial resistance is a major threat to the delivery of effective care and already causes 700 000 excess deaths per year worldwide. International consensus on action to combat antimicrobial resistance was reached in 2015. Australia is implementing a national strategy. The clinical consequences of antimicrobial resistance are seen most acutely in multi-drug resistant Gram-negative bacterial infections, where they cause increased mortality and morbidity and threaten the delivery of once routine medical care. The solution to antimicrobial resistance is complex and multifaceted. Antimicrobial stewardship, that is optimising the use of the antibiotics we currently have, is the most rapidly deployable mitigation. Several novel antibiotics with activity against a range of drug-resistant bacteria are now available clinically, leading to hope that innovative solutions will reduce the impact of resistance. It is critical that these new drugs are protected from inappropriate use.

Critical to the survival of microorganisms on Earth is their ability to evade destruction by mutation of key effector genes, leading to adaptation and selective evolution. Antimicrobial resistance (AMR) emerged billions of years ago in nature, unrelated to human use of antimicrobials¹. Most human pathogenic bacteria develop AMR to antibiotics within a few years of their first use. For example, the Florey group demonstrated penicillinases able to hydrolyse penicillin in Staphylococcus aureus in 1940, before clinical use in humans². Penicillin resistance leading to clinical treatment failure was described in 1942³. The selection of antimicrobial resistance is inevitable whether or not antimicrobial use is appropriate, but interventions that impede this process can delay the onset of AMR as a public health problem. In some cases, AMR gene mutations lead to a ‘fitness cost’ to the organism so that, with time, they are less able to compete with non-resistant, ‘wild-type’ organisms and reversion to susceptibility occurs.

AMR is recognised as one of the major threats to the health and wellbeing of humans on a global scale. It is estimated that 700 000 people now die every year as a consequence of AMR. This may result in an estimated 0.06–3.1% decline in world Gross Domestic Product by 2050 if current trends continue⁴. In 2015, the General Assembly of the United Nations endorsed a declaration to take broad, coordinated international action to address the root causes of antimicrobial resistance across human and animal health and agriculture.

In Australia, the importance of AMR is recognised in the First National Antimicrobial Resistance Strategy 2015–2019, in which seven objectives to reduce AMR are established⁵. When released in 2015, the Australian Strategy was a world leader. A second strategy is due in 2020.

In this review, we choose to focus on AMR in Gram-negative bacteria such as including Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli and other Enterobacteriales as we feel this is the most urgent aspect of the AMR crisis. High risk infections including pneumonia, bloodstream infection, urinary tract and intra-abdominal sepsis are often caused by Gram-negative bacteria. Gram-negatives are a common cause of rapidly progressive septic shock, leading to death in as little as 12 hours from the onset of illness, particularly in immunocompromised patients. Currently, treatment of Gram-negative infection is ‘empirical’ in the first 48 hours, that is, the selection of treatment is based on knowledge of the likely organisms and resistance spectrum based on population data and often therefore requires use of broad-spectrum therapy until culture and susceptibility results become available.

Common resistance mechanisms among Gram-negative organisms include: beta-lactamase production leading to lysis of beta-lactam antibiotics; target-enzyme mutations; porin mutations; and drug efflux pumps⁶. Multiple, simultaneously acquired resistance mechanisms are readily transmitted by plasmids between organisms and across different species, leading to multiple-drug resistant (MDR) organisms. Beta-lactamase production is clinically divided into those that hydrolyse third-generation cephalosporins, known as extended spectrum beta-lactamases (ESBLs), and those that hydrolyse and carbapenems such as meropenem, known as carbapenemases⁷. ESBLs are now found in 15–25% of Enterobacteriales responsible for hospital acquired infections in the United States and Europe, with rates much higher reported in Asia and South America⁸. Australia has observed a relatively low frequency caused by MDR-pathogens with ceftriaxone resistance in E. coli and Klebsiella pneumoniae seen in 3.2% and 3.6% of community isolates, respectively⁹. The proportion in hospital-acquired infection is likely to be higher.

Clinical outcomes are worse in individuals infected with MDR-Gram-negative bacteria. In the critically ill population with ESBL bloodstream infection, 30-day mortality ranges 7–23.3%^10,11. Individuals with carbapenemase-producing Klebsiella pneumoniae infection have a mortality of 33–50%¹². Similar adverse outcomes are described with P. aeruginosa and other Enterobacteriales^13,14. Contributors to worse outcomes in this patient group include delay in effective antibiotic therapy, increased antimicrobial toxicity and presence of significant comorbidities. Rectal colonisation with ESBL-producing Enterobacteriales is associated with increased risk of hospital acquired pneumonia, bacteraemia and urinary tract infection with the same organism¹⁵. A recent study identified multi-drug resistant Gram-negative colonisation as an independent predictor of death in the ICU at 28 days, although other studies contradict this finding^11,16. Colonised patients have both longer hospital and intensive care unit stays, as well as experience an increased exposure to broad-spectrum antibiotics, further selecting AMR¹¹.

AMR in Gram-negatives significantly impairs healthcare delivery, particularly in vulnerable patient groups. Haematopoietic stem cell transplant recipients with a carbapenem-resistant K. pneumoniae infection had a mortality rate of 64% in one Italian study¹⁷. In areas with a high prevalence of carbapenem-resistant Enterobacteriales (CRE), Pseudomonas aeruginosa (CRP) and Acinetobacter baumannii (CRAB), such as India and the Middle East, delivery of much healthcare currently seen as routine is under threat. This includes solid organ and haematopoietic stem cell transplantation; cancer chemotherapy; surgery involving implantation of prosthetic material and intensive care. A multinational cohort study showed that patients with ESBL-Enterobacteriaecae colonisation prior to colorectal surgery had an increased risk of deep surgical site infection¹⁸. Gram-negative multi-drug resistance is associated with increased inpatient costs in patients with bloodstream infection¹⁹.

The response to AMR is complex, requiring improved clinical practice, education of healthcare workers and the community, targeted clinical and translational research, enhanced surveillance, rapid diagnosis, and novel antimicrobials. The response must adopt a ‘One Health’ approach including human and veterinary medicine, agricultural and environmental management.

Sadly, the Australian community has an addiction to antibiotics, using more antibiotics per head of population than almost any other country²⁰. Antimicrobial stewardship (AMS) – ensuring the quality use of the antimicrobials to prevent inappropriate use whilst optimising outcomes of infection – is the most rapidly deployable response to slow the further emergence of AMR. Mandated by hospital accreditation, AMS is much more developed and effective in hospital settings in Australia, compared with community settings where most antibiotic use occurs. Interventions that include both persuasive educational and restrictive governance components are the most successful. AMS interventions need to be multidisciplinary including specific medical, nursing and pharmacy components. Patient and community engagement including mass-marketing campaigns are essential.

Most Australian microbiology laboratories have developed extensive capabilities in the timely identification of resistant Gram-negatives, although detection of some resistance mechanisms is technically difficult. However, national standardised reporting and notification of AMR is not established, impeding surveillance efforts and rapid public health response to emerging AMR threats in Australia.

The development of new antimicrobials to combat AMR has languished until recently. In the USA, the GAIN (Generating Antibiotic Incentives Now) Act and the European Union’s Innovative Medicines Initiative (IMI) ND4BB (New Drugs for Bad Bugs) provide financial incentives and streamlined processes encouraging pharmaceutical companies to develop antibiotics, leading to the release of two new antibiotics in the past five years and over 30 compounds in active development²¹.

Several promising novel agents are now available or in late-stage development for MDR-Gram-negative organisms. Ceftolozane/tazobactam is a novel cephalosporin combined with a beta-lactamase inhibitor, notable for its potent activity against MDR-P. aeruginosa²². Ceftazidime/avibactam is a combination agent comprising a third-generation cephalosporin with the novel beta-lactamase inhibitor avibactam, which protects ceftazidime from hydrolysis from many serine beta-lactamases. Notably ceftazidime/avibactam has potent activity against CPE-producing KPC carbapenemases, but not metallo-beta lactamases²³. These agents are available and in use in Australia. Multiple other beta lactam/beta lactamase inhibitor combinations are in development.

Cefiderocol is a novel siderophore cephalosporin with a broad spectrum of activity against Gram-negative organisms. A side chain uses the organisms’ iron transport system to be transported intracellularly²⁴. Cefiderocol has been shown to be active against ESBL-producing organisms including those containing metallo-beta lactamases. It is also potent against MDR Acinetobacter baumanii, P. aeruginosa and Stenotrophomonas maltophilia. A study examining cefiderocol in the setting of serious infections caused by carbapenem-resistant organisms is underway²⁵.

A novel aminoglycoside, plazomicin is active in vitro against CPE and ESBL-Enterobacteriales isolates. In a randomised controlled trial comparing plazomicin with meropenem for the treatment of cUTI, plazomicin showed non-inferiority for clinical and microbiological cure²⁶. A study examining the use of plazomicin for serious infections caused by carbapenem resistant Enterobacteriales was unfortunately terminated early due to difficulties with recruitment²⁷.

Recent progress in drug development will provide clinicians with additional options for treating infections caused by multi-drug resistant Gram-negative organisms. However, reports of clinical failure and the development of antimicrobial resistance have already been reported to the new agents²⁸. Optimal AMS is essential to preserve the effectiveness of novel antibiotics.

AMR in Gram-negatives is an urgent, important threat to global health. Co-ordinated global action on the clinical, governance and research is underway but requires markedly increased investment. Recently, several exciting novel agents with activity against MDR Gram-negatives have emerged. There is hope that human innovation will limit the consequences of this potentially catastrophic problem.

Dr Wright is an investigator on a clinical trial sponsored by Shionogi Inc. Dr Stewart and Dr Hajkowicz declare no conflicts of interest.