Alleviating the burden of antimicrobial resistance (AMR)

The threat of antimicrobial resistance to global health is at an accelerating rate. As we have seen over the past couple of years especially with the COVID-19 pandemic, managing a global healthcare crisis requires planning, collaboration, and concise communication. So how do we address something like antimicrobial resistance (AMR), which is extremely complex and difficult to target all at once? The approach must  be multi-faceted and taken step by step.

‘Antimicrobial’ is an umbrella term for medicines such as antibiotics, antifungals, antivirals and antiparasitics that prevent and treat infections in humans, as well as animals and plants. Antimicrobial resistance occurs when bacteria, viruses, fungi, and parasites evolve and no longer respond to conventional antimicrobial treatments, making infections harder and harder to treat – in some cases leaving no treatment options available [1].

AMR occurs naturally over time, usually due to genetic mutations. (Think of what we have already experienced with the mutation of coronavirus or that there’s a new influenza vaccination every year.) A couple of the strongest drivers of AMR include the misuse and overuse of antimicrobials, lack of awareness and lack of legislative action.

In a recent comprehensive study of bacterial AMR, researchers stated that bacterial AMR is a health problem whose magnitude is at least as large as major diseases such as HIV and malaria, and could be potentially much greater. The study concluded that in 2019, an estimated 4.95 million deaths were associated with drug-resistant infections, with lower respiratory infections, bloodstream infections, intra-abdominal infections and urinary tract infections making up the top four infectious syndromes [2].

Urinary tract infections (UTIs) occur frequently across the globe, with an estimated 150 million cases a year.  It is the most frequent bacterial infection amongst women, with recurrent infections being a problem for 25–30% of women who experience an initial infection. Unfortunately, UTIs are also fairly common amongst hospital patients, accounting for 40% of hospital-acquired infections [3]. For uncomplicated UTIs, there are both holistic and medical treatments, or a combination of both, that are recommended by healthcare professionals. Prescription antibiotics will almost always cure a UTI, so treatment is usually straightforward; although in recent years this has become more complicated due to the over prescription of broad-spectrum antibiotics. In fact, UTIs are  the fourth highest contributor to deaths associated with bacterial antimicrobial resistance [2].

To screen for a UTI, the dipstick is the most frequently used method. This method picks up the presence of nitrite, a product derived by certain nitrogenic species (e.g., Escherichia, Proteus, Klebsiella). However, some pathogens do not generate nitrite (e.g., Enterococcus, Gonococcus, Staphylococcus, Pseudomonas), meaning that nitrite is not always a reliable parameter to screen a suspected UTI. Therefore, if typical symptoms are present, a negative dipstick result is insufficient to rule out an infection [4].

Although it may not be time- or cost-effective, urine culture remains a very important test in the context of UTI diagnostics, particularly for isolating the infectious microorganism. From a positive urine culture, species identification and antibiotic susceptibility testing can determine the sensitivity and resistance of specific pathogens to a range of antibiotics so healthcare providers can prescribe the proper treatment [5]. This is not yet standard practice across the globe, and it may be difficult to imagine forcing patients to wait for proper treatment whilst they are in pain, but making this transition could have a huge impact on the fight against AMR.

Being able to quickly exclude UTIs at point-of-care settings could help to reduce the number of antibiotics being prescribed unnecessarily, especially when considering that up to 80% of suspected UTI cases turn out to be negative [6]. Therefore, a fast and reliable method to exclude UTIs can be a driver for laboratory workflow improvements and antimicrobial stewardship.

The UF-Series from Sysmex utilises fluorescence flow cytometry, which is a technology that allows negative UTI samples to be ruled out, culture plating and general workload can in turn be optimised. There is also the possibility to utilise bacteria information flags which can indicate positive samples containing Gram-negative bacteria for Direct Antibiotic Susceptibility Testing (dAST). dAST on the positive urine samples can reduce response time for an antibiotic profile by up to 24 hours, and thus contribute to reduced empiric use of antibiotics and shorter overall treatment [7].

The question of whether the inflammation is infectious or non-infectious is a vital one and one of the daily challenges that clinicians have to answer every day. And if it is an infection, whether it is viral or bacterial is the next critical piece of information because this would determine the necessity of an antimicrobial.

‘Inflammation’ describes the body’s immunovascular response, irrespective of the cause. It is our body’s natural defence against damaged cells, physical or chemical agents, allergens, or pathogenic organisms. The term ‘infection’ is used when pathogenic organisms invade the tissue of a host organism, multiply, and the affected tissue reacts to these organisms and the toxins they produce. Infections are caused by microorganisms such as viruses, bacteria, parasites, or fungi or by the toxins that these microorganisms produce.

It is useful to differentiate inflammation and infection as there are also many pathological situations where inflammation is not driven by microbial invasion – for example, trauma, ischaemia, or autoimmune diseases. There are also pathological situations where microbial invasion does not result in a classic inflammatory response.

Fast and efficient differentiation between various inflammatory conditions is clinically very important because the treating physician needs to decide on appropriate therapy for the patient – ideally without delay. A correct differential diagnosis of suspected infections by clinical examination, biochemical markers and microbiological blood cultures is both costly and time-consuming. However, if the laboratory has a fast initial indication, certain follow-up tests could be avoided. This means the physician can start – or, with treatment already begun, adapt or discontinue – treatment faster [8].

Available on the Sysmex XN-Series haematology analysers, the Extended Inflammation Parameters (EIP) are diagnostic parameters that support the measurement of immune cell activation. The recognition of immune response patterns supports the differentiation between inflammation and infection, different pathogenic causes of infection and the different types of an immune response. The EIP can help clinicians with the diagnosis, treatment and monitoring of patients with inflammatory disorders by

• supporting the differentiation between inflammation and infection [9-11],
• supporting the differentiation between different pathogenic causes of infection (e.g., bacterial, viral) [9, 12-14],
• supporting the differentiation between different types of immune response: early innate, cellular or humoral immune response. This information may help to identify the stage of infection [10, 15-16].

Thus, the EIP provide valuable insights into inflammatory conditions [17].

Malaria, for some, may present as a faraway tropical disease, but for others is indeed an everyday challenge. It remains one of the most important public health concerns globally, with more than 241 million malaria cases and 627,000 malaria deaths reported worldwide in 2020, according to the latest report from the World Health Organization (WHO) [18]. Travelling and migration though have brought malaria to the doorsteps of virtually every country on the planet.

Early and accurate diagnosis is a critical aspect of efforts to control not only malaria but also the rate of AMR. The WHO recommendation is for all suspected malaria cases to have a parasitological test, either microscopy or a rapid diagnostic test (RDT), to avoid presumptive therapy based on clinical suspicion alone and to minimise unnecessary exposure to anti-malarial drugs.

Up to 90% of fevers in sub-Saharan Africa are treated presumptively as malaria in the formal health sector and it is estimated that only 20% of people buying first-line antimalarials in the retail sector have malaria [19]. Diagnostic testing to confirm a malaria infection before treatment begins is crucial, but not always available.

Sysmex, building on its haematology expertise, can help laboratories and clinics identify a malaria infection with confidence, guiding treatment decisions and evaluating treatment success. The XN-31 analyser is an ideal modality for the precise recognition and rapid automated enumeration of malaria parasitaemia, independent of the skill of the operator or species involved. In a 2019 study, the XN-31 detected the actual parasite and not any by-product, such as antigens, haemozoin or phagocytosed parasites within white blood cells, making it more suitable for malaria detection compared to RDTs and other indirect automated methods [20]. Furthermore, concurrent measurement of a complete blood count (CBC) is a unique feature that provides valuable data for clinical correlation.

Complex problems require complex solutions – and AMR is a complex problem. At governmental and policy level, there are many points to be considered. Guidance should be provided on infection prevention and management, as well as the implementation of antibiotic stewardship programmes. Accordingly, from the top policy level, awareness campaigns should be promoted amongst the general public and the physicians who treat them. One of the crucial levels in between is addressing how the diagnostics industry can improve solutions to provide specific and rapid diagnostic tools.

Reproduced by kind permission of Health Europa, www.healtheuropa.eu © Health Europa 2022.