Optimizing Antimicrobial Prescribing Through Diagnostic Improvement

Many barriers in antimicrobial stewardship (AMS) are shared between high-income countries (HIC) and low- and middle-income countries (LMIC). Overly broad-spectrum medications are often prescribed due to fear of not covering a specific pathogen with narrow-spectrum antibiotics while waiting for cultures.

Lack of awareness of adverse events related to antibiotic prescription also applies to LMIC settings, such as nephrotoxicity, increased risk of Clostridium difficile infection, selection of drug-resistant species, and other side effects. However, many challenges are unique to or experienced more often by healthcare workers in resource-limited settings.

In this review, we aim to discuss current challenges in hospital-based AMS provision in low- and high-resource settings.

Diagnostic work

Blood cultures and samples from infectious sites should be collected as soon as possible near the onset of infection. In sepsis, vasopressor or immunocompromised patients, it is not appropriate to delay antibiotic initiation to collect samples because clinical outcomes remain the primary concern.

In recent years, many tests have been developed with the aim of providing faster results: point-of-care antimicrobial susceptibility testing, rapid tests to identify extended-spectrum β-lactamase (ESBL), carbapenemases, and polymyxin resistance. colistin, for example. Non-culture methods, including nucleic acid amplification technologies, transcriptomic testing, and predictive biomarkers, also aid in the diagnosis of sepsis.

Although there are no studies, to our knowledge, that evaluate the impact of incorporating such technologies using clinical outcomes, reducing the time to diagnosis could improve the clinical outcomes of patients with sepsis and ultimately reduce the duration of the hospital stay. Diagnostic resources represent an important difference between low- and high-resource settings.

Optimizing patient surveillance to shorten diagnosis time, improving diagnostic methods through rapid testing, and strengthening communication between microbiologists and treating physicians is key to reducing diagnosis time and providing timely treatment.

 Choice of empirical treatment and the importance of local epidemiological data

It is well known that antibiotics should be started as soon as possible when sepsis is suspected or confirmed, ideally within the first hour.

This poses a major challenge in low- and middle-income countries where rates of multidrug-resistant (MDR) infections are increasing, even for community-acquired infections.

Choosing the appropriate empirical treatment implies not losing sight of the causative pathogen and, at the same time, avoiding the use of potentially toxic and unnecessarily broad-spectrum drugs. Knowing the local epidemiology of antimicrobial resistance is essential, particularly in urgent settings such as septic shock. However, surveillance of multidrug-resistant microorganisms is suboptimal in LMIC.

The use of protocols based on local microbiological data is associated with an increase in appropriate antimicrobial administration; Therefore, AMS programs should highlight the importance of collecting adequate surveillance data and making it available to caregivers, as well as providing training to medical personnel to adapt empiric therapy to local epidemiology.

Proper dosing regimens and selective pressure

 Fear of complications associated with antibiotics, such as nephrotoxicity , often leads to prescribing low-dose antibiotics or skipping loading doses, particularly with respect to those that are widely recognized for their common and serious side effects.

Although the complications of overdose of antimicrobial regimens are widely known, the risks are likely to be frequently overlooked. Instead of preventing complications, underdosing provides selective pressure that facilitates the emergence of multidrug-resistant microorganisms. The development of objective tools that aim to improve appropriate prescription is increasingly important.

 Antimicrobial options

Increased rates of multidrug-resistant (MDR) infections have been reported worldwide; LMICs not only face the challenge of lower availability of antibiotic options, but also experience higher rates of MDR organisms and often have suboptimal surveillance. In Brazil, for example, there has been an increase in MDR Pseudomonas aeruginosa in recent years, as well as for methicillin-resistant Staphylococcus aureus ,  vancomycin-resistant enterococci , and carbapenemase-producing Enterobacteriaceae .

Despite alarming rates of multidrug-resistant infections, access to new antimicrobials is poor in low- and middle-income countries (LMICs).

This poses a challenge for all care professionals in low-resource settings, particularly in critical care units and emergency departments where time to therapy is a major issue. Alternative combination regimens for MDR infections often rely on nephrotoxic drugs, such as polymyxins, in a setting where multiple events contribute to kidney injury.

In settings where MDR infections are highly prevalent, particularly polymyxin-resistant gram-negative bacteria and vancomycin-resistant gram-positive bacteria, the acquisition of new beta-lactams/beta-lactamase inhibitors (BLBLI) and cephalosporins should be considered a priority.

De-escalation

De -escalation consists of replacing a broad-spectrum empirical therapy with a narrow-spectrum one followed by its suspension; It could also include reducing the amount of antimicrobials in a combination therapy. One of the goals of AMS is to reduce the use of broad-spectrum drugs wherever possible, reducing selective pressure and ultimately rates of multidrug-resistant microorganisms.

De-escalation may be possible in more than a third of patients with ventilator-acquired pneumonia (VAP) and has been associated with higher survival rates in several studies; Obtaining respiratory samples before starting antimicrobial therapy is key to making de-escalation possible.

Knowledge of local epidemiology and prevalence of resistance and the use of rapid antimicrobial susceptibility tests help in context.

In some groups of patients who have serious underlying conditions, such as hematological and transplant patients, de-escalation could be challenging considering the need for very broad-spectrum empiric therapies; Furthermore, the presence of neutropenia discourages physicians from narrowing the antimicrobial spectrum. Clinical biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) could indicate when it is safe to de-escalate in lung transplant patients presenting with an episode of acute respiratory failure where it would be difficult to differentiate early between graft dysfunction and pneumonia.

Continuing medical education on antimicrobial therapy, improving communication between microbiologists and treating physicians, as well as optimizing surveillance can help empower frontline clinicians to provide safe reduction.

 Shorten the duration of treatment

 Recent studies indicate that shortening the duration of treatment for infections in intensive care is safe for most patients.

Treatment of ventilator-associated pneumonia for a short period (8 versus 15 days) did not affect clinical outcomes; Additionally, a review on the duration of treatment for sepsis found that regimens for up to 7 days could be as safe as those taking up to two weeks. However, the provision of shorter antimicrobial courses should not be applied in a “one size fits all” approach and should be done on a case-by-case basis.

Guidelines on antimicrobial treatment could provide important tools on when to decide on a shorter duration, combining source control, use of biomarkers (when available), antimicrobial susceptibility, and severity of infection.

 The importance of diversity

Antimicrobial stewardship (AMS) programs should play a key role in promoting antimicrobial diversity, ensuring greater heterogeneity. Low diversity, with predominant use of one class of antibiotic, is facilitating the emergence of resistance. The predominance of carbapenems has been associated with carbapenem-resistant Acinetobacter baumannii , while ESBL has emerged with the predominant use of third-generation cephalosporins.

AMS programs and the importance of continuing education

Antimicrobial stewardship ( AMS) is resource-intensive and depends on a very complex health system structure that encompasses infection prevention and control (ICP), which for once depends, among other factors, on the physical capacity of the facilities, laboratory resources, infection surveillance and epidemiology, medical and nursing education, antibiotic availability and post-prescription surveillance. All of these factors, much less available in low- and middle-income countries, have an impact on management and these differences should not be overlooked.

Hospitals in LMIC have less formal AMS and IPC programs, fewer antibiotic options available, and shorter distances between beds, where single patient rooms are reported less frequently, impacting infection prevention and posing a challenge for separate patients with MDR infections from those admitted for other reasons.

Although more than 3/4 of ICU patients receive antibiotics, prescriptions and dosing regimens are often inadequate.

Therefore, training in antimicrobial therapy should be incorporated as a core competency for internists, intensive care physicians, and emergency physicians, who must be trained to make decisions about antimicrobial treatment in a timely manner. Considering the dynamic nature of local antimicrobial resistance and infection prevalence patterns, it is important that such competencies are continually updated.

 Antimicrobial stewardship ( AMS) in the post-COVID era

The SARS-CoV-2 pandemic posed a major challenge to providing adequate AMS due to a combination of excessive workload, overcrowded intensive care units, unprecedented numbers of patients requiring invasive respiratory support for long periods (with consequent high rates of hospital-associated infections) and difficult diagnostic tests.

In a recent publication, 77.2% of institutions in low- and middle-income countries had active AMS programs. Surprisingly, a shortage of infectious disease specialists is common in this setting due to limited resources. Therefore, the role of the internist in promoting efforts in LMIC, assuming leadership tasks and clinical training in antibiotic optimization in the post-COVID19 era, is notable.