Context.—

Point-of-care testing (POCT) is inherently spatial, that is, performed where needed, and intrinsically temporal, because it accelerates decision-making. POCT efficiency and effectiveness have the potential to facilitate antimicrobial resistance (AMR) detection, decrease risks of coinfections for critically ill patients with coronavirus infectious disease 2019 (COVID-19), and improve the cost-effectiveness of health care.

Objectives.—

To assess AMR identification by using POCT, describe the United States AMR Diagnostic Challenge, and improve global standards of care for infectious diseases.

Data Sources.—

PubMed, World Wide Web, and other sources were searched for papers focusing on AMR and POCT. EndNote X9.1 (Clarivate Analytics) consolidated abstracts, URLs, and PDFs representing approximately 500 articles were assessed for relevance. Panelist insights at Tri•Con 2020 in San Francisco and finalist POC technologies competing for a US $20,000,000 AMR prize are summarized.

Conclusions.—

Coinfections represent high risks for COVID-19 patients. POCT potentially will help target specific pathogens, refine choices for antimicrobial drugs, and prevent excess morbidity and mortality. POC assays that identify patterns of pathogen resistance can help tell us how infected individuals spread AMR, where geospatial hotspots are located, when delays cause death, and how to deploy preventative resources. Shared AMR data “clouds” could help reduce critical care burden during pandemics and optimize therapeutic options, similar to use of antibiograms in individual hospitals. Multidisciplinary health care personnel should learn the principles and practice of POCT, so they can meet needs with rapid diagnostic testing. The stakes are high. Antimicrobial resistance is projected to cause millions of deaths annually and cumulative financial loses in the trillions by 2050.

Objectives

The objectives of this article are to assess identification of antimicrobial resistance (AMR), using point-of-care testing (POCT), and to glean future directions from progress of the AMR Diagnostic Challenge promoted by the National Institutes of Health (NIH) and the Biomedical Advanced Research and Development Agency (BARDA).1 

The AMR Diagnostic Challenge seeks to reduce the use of antibiotic regimens that generate “superbugs,”2  for which new drugs are sorely lacking, and to improve global standards of therapeutic care for infectious diseases by diminishing AMR threats to survival. These threats include coinfections in patients with coronavirus infectious disease 2019 (COVID-19) who do not respond to antimicrobials.

Antimicrobial Resistance Diagnostic Challenge

Rationale

In the United States, antibiotic-resistant bacteria cause at least 2.8 million infections and more than 35,000 deaths each year.3  Bacterial, fungal, and viral coinfections contribute to COVID-19 morbidity and mortality. Rapid POC solutions that determine AMR in human samples will help combat the development and spread of drug-resistant bacteria.1 

Table 1 presents the 5 technologies and finalists for the $20 million AMR Diagnostic Challenge prize, the largest ever offered by the United States government. Competitors are creating innovative and novel diagnostics that identify and characterize antibiotic-resistant bacteria and/or distinguish between viral and bacterial infections to reduce unnecessary use of antibiotics, a major cause of antibiotic resistance.

Table 1

Finalist Projects in the NIH/BARDA Antimicrobial Resistance Point-of-Care Testing Grand Challenge

Finalist Projects in the NIH/BARDA Antimicrobial Resistance Point-of-Care Testing Grand Challenge
Finalist Projects in the NIH/BARDA Antimicrobial Resistance Point-of-Care Testing Grand Challenge

Vision

The AMR Diagnostic Challenge is a joint effort between NIH and the Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR) in support of the National Action Plan for Combating Antibiotic Resistant Bacteria.4  NIH's National Institute of Allergy and Infectious Diseases and ASPR's BARDA are each contributing $10 million to the prize.

The vision is that with real-time detection, health care providers will be able to identify infecting pathogens and resistance factors quickly, perhaps in as little as 1 hour, rather than days, and use the knowledge to tailor treatment for each individual patient. In one study of critically ill COVID-19 patients, 50% who died had a dangerous secondary infection.5 

The AMR Diagnostic Challenge supports the POCT theme of the House Energy and Commerce Committee and the Senate Homeland Security and Government Affairs Committee letter dated June 9, 2015, and sent to the Comptroller General of the US Governmental Accountability Office.6  Congress wants to improve the cost-effectiveness of American health care by helping providers to rapidly target antimicrobial therapy for improved patient outcomes.

The NIH-BARDA Challenge differs from “DISARM” (Developing an Innovative Strategy for AMR), a legislative initiative to fund targeted antibiotics in hospitals,7  and from the “AMR Challenge,” a long-term program administered by the Centers for Disease Control and Prevention (CDC) to accelerate the fight against AMR.8  This effort has recruited more than 350 organizations across the globe committed to slow AMR.

Timeline

The deadline for submission of Step 1 concepts was January 9, 2017. Semifinalists each received $50,000. Step 2 was open to semifinalists and others who wished to enter the competition anew. Finalists were announced in December 2018, and each received $100,000 to develop prototypes. Now, the competition is in the third and final Step 3 with planned culmination on July 31, 2020.1  The remaining prize pool is about $19,000,000.

Winners must have tested in vitro diagnostic prototypes, using 2 independent Clinical Laboratory Improvement Amendments (CLIA)–certified laboratories to assess the performance of their assays compared to the performance claims for US Food and Drug Administration (FDA)–approved assays. Two of the Challenge finalists recently presented their research in a panel moderated by the author at the Tri•Con Cambridge Healthtech Symposium held in San Francisco, on March 3, 2020, just before lockdown and safe spacing (social distancing) orders in that city.

Obviously, not all 5 finalists can win, but the United States and other countries, especially settings in limited-resource countries, will benefit because of the anticipated success of numerous new inventions spinning off from all the 3 steps and some emerging successfully from the commercial pipeline. Please see the Challenge “FAQ” Web page for additional details of Step 3 and the process of evaluating the technologies.9 

NOMENCLATURE

Geospatial Science

Geospatial science identifies and leverages the power of location data.10  Location data embody a geographic dimension. Location intelligence is the process of turning geographic data into insights for decision-making. POCT is pivotal to quick decision-making, triage, and quarantine. A spatial care path is the most efficient route taken by the patient when receiving definitive care in a small-world network. A geospatial care path adds geographic and topographic coordinates, physical sites, and quantitative metrics to the health care small-world network.

Hotspots

A “hotspot” is a topographic area or region of unusual danger to personal or public health. People in the community may be at extreme risk during an outbreak of a highly infectious disease that spreads quickly, as we are witnessing with the COVID-19 pandemic. Additionally, dangerous situations, such as civil strife and war, belligerent political attitudes, and hacking of computers used in vaccine research and development, may complicate the control of hotspots, rendering them even more difficult to address medically, quell socially, and stop quickly.

Point-of-Care Testing

Point-of-care testing, defined as diagnostic testing at or near the site of patient care, is inherently spatial, that is, performed at points of need, and also intrinsically temporal, because it produces fast actionable results. This definition does not depend on the size or format of the handheld, portable, or transportable instrument, test module (eg, for a smartphone), or assay design. POCT encompasses near-patient testing, rapid diagnostic tests (eg, lateral flow), disposable test strips, and in situ, ex vivo, in vivo, and on vivo monitoring (eg, pulse oximeters, wearables, and remote temperature monitoring).

The “Cape Cod” group codified this definition,11  which first appeared in standard dictionaries of the English language years ago. The Point-of-Care Testing Center for Teaching and Research (POCT•CTR) wrote the original Wikipedia article.12  Historical terms include alternate site testing, testing outside the clinical laboratory, point-of-need testing, rapid diagnostic test, and others, now mostly abandoned in favor of the simplified concept above that professionals, laypersons, and politicians alike recognize, especially now during the pandemic when POC strategies have moved to the frontline of medical rapid response in communities throughout the world.

Coronavirus

Disease nomenclature enables analysis of prevention, spread, transmissibility, severity, and treatment. Virus names based on genetic structure facilitate development of diagnostic tests, vaccines, and medicines. SARS-CoV-2 is the virus, and COVID-19, the disease it causes. The virus name reflects genetic relationship with the coronavirus responsible for the SARS outbreak in 2003. However, the 2 viruses differ in symptoms, signs, transmission, and severity. For example, the estimated mortality rates are 10% for SARS and 0.25% to 3% for COVID-19, while COVID-19 is transmitted more easily owing to higher viral load in the nose and throat shortly after symptoms develop.

The World Health Organization (WHO) is responsible for human disease preparedness, response, and nomenclature in the International Classification of Diseases. China called the outbreak, “Novel Coronavirus Pneumonia,” based on its primary clinical manifestation diagnosed initially by chest radiography and CT scan (eg, multifocal pneumonia), since neither reliable nor accurate antigen or antibody testing was available in Wuhan, the original epicenter.

METHODS

Research Scope

This article assesses the importance of AMR and its association with POCT. Numerous sources identified through the old and newly designed versions of PubMed dealt with the general areas of AMR. Papers assessed totaled ∼500. Chronologic and relevance searches were limited to rapid response and POCT in relation to COVID-19 and coinfections.

Only those publications explicitly discussing or integrating POCT or closely related mobile technologies, and conceptually relevant geospatial AMR concepts, obtained in a separate search, are tabulated here. Biothreat agents (eg, Bacillus anthracis and Yersinia pestis) and COVID-19 virus coinfections were excluded.

Data Sources

PubMed, the World Wide Web, and other timely sources were gathered and assessed, along with key updates, papers, chapters, government documents, maps, flowcharts, schematics, and geospatial concepts. EndNote X9.1 (Clarivate Analytics; https://clarivate.com/, accessed July 22, 2020) consolidated literature entries and automatically retrieved papers as URLs and PDFs placed in groups. The CDC open access report, Antibiotic Resistance Threats in the United States, 2019,3  provided relevant AMR data and illustrations.

Confounding Risks

The rapidly growing COVID-19 literature was analyzed for infectious disease risk factors. Geospatial science articles were assessed previously for geospatial relevance to POCT and closely related mobile technologies.13  Molecular diagnostics for highly infectious threats can be found in a recent book chapter14  and comprehensive analysis published elsewhere.15,16  Point-of-care strategies for defeating the COVID-19 pandemic were summarized in a recent open access paper accepted by this journal and posted as an early online release on April 13, 2020.17 

THREATS, THEIR IMPACT, AND POCT

Table 2 summarizes the recent outcomes of the so-called superbugs that threaten to kill untold numbers of people in the next 30 years, because the current antibiotic armamentarium will become increasingly ineffective and irrelevant to survival.3,18 Table 3, drawn from the CDC scheme of priorities,3  categorizes the resistant organisms as urgent, serious, concerning, and emerging. The CDC criteria used to assign threat levels comprise clinical impact, economic impact (when available), incidence, 10-year projection of incidence (new infections during the next 10 years), transmissibility (how easily a germ spreads or causes infections), availability of effective antibiotics, and barriers to prevention.

Table 2

The Impact of Worldwide Ubiquitous Antimicrobial Resistant Superbugs

The Impact of Worldwide Ubiquitous Antimicrobial Resistant Superbugs
The Impact of Worldwide Ubiquitous Antimicrobial Resistant Superbugs
Table 3

Urgent, Serious, Concerning, and Emerging Antimicrobial Resistant Threats

Urgent, Serious, Concerning, and Emerging Antimicrobial Resistant Threats
Urgent, Serious, Concerning, and Emerging Antimicrobial Resistant Threats

Experts say the antibiotic era has already come to a close. The facts presented here support that view and document the shocking extent of the problem. The Center for Disease Dynamics, Economics, and Policy generated interactive AMR maps and bar graphs that illustrate the geospatial distribution of AMR.19 Table 4 presents the economic impact and lives lost from the top 10 threats identified by the CDC.3  It is easy to understand the motivation of the Congressional Committees when they singled out AMR as one of the worst enemies to public welfare in the United States. The solution recommended is rapid multiplex POCT.

Table 4

Top 10 Antimicrobial Resistance Threats and Levels by Number of Cases

Top 10 Antimicrobial Resistance Threats and Levels by Number of Cases
Top 10 Antimicrobial Resistance Threats and Levels by Number of Cases

Now that rapid diagnostic testing has risen to the forefront of strategies for fighting the COVID-19 pandemic,17  several experienced academic laboratories and commercial entrepreneurs should be able to more easily generate POC solutions for AMR. Government and private support, such as the new so-called Manhattan Project for COVID-19,20  target and promote the most promising of the technologies, and also consider coinfections, which extend intensive care unit (ICU) stays, saturate critical care resources, and lead to excess mortality.

POINT-OF-CARE SOLUTIONS

Table 5 summarizes published POC strategies and concepts2154  underlying rapid response testing, detection of AMR, and susceptibility assessment. A multitude of technical approaches and creative POC solutions have been introduced by academic and commercial inventors,2154  including novel innovations for determining phenotypic antibiotic susceptibility, distinguishing bacterial from viral infections, and differentiating ordinary influenza from COVID-19.17  Gonzalez and McElvania32  published a very positive assessment of rapid diagnostic testing for children, including group A Streptococcus, respiratory viruses, and syndromic multiplex respiratory panels. Table 5 concludes with a synopsis of the symposium and AMR panel discussion held in San Francisco in March 2020.53,54 

Table 5

Point-of-Care Strategies and Concepts for Antimicrobial Resistance and Antibiotic Susceptibility Testing

Point-of-Care Strategies and Concepts for Antimicrobial Resistance and Antibiotic Susceptibility Testing
Point-of-Care Strategies and Concepts for Antimicrobial Resistance and Antibiotic Susceptibility Testing

Point-of-care solutions comprise small portable testing platforms, smartphone modules, molecular diagnostics, biosensors, mass measurements, single cell biometric analysis, and several others.2154  Variety seems to be the most prominent and creative characteristic of work completed to date. With a few exceptions, such as MRSA (methicillin-resistant Staphylococcus aureus),50  tuberculosis (discussed later), and importantly, pediatric infectious diseases,32  widespread commercial reduction to practice (building beyond conception) in practical and environmentally robust formats that one might find implemented for onsite diagnosis in clinics, emergency rooms, and hospitals has yet to fully appear. Nonetheless, some reports, such as that of Hubner et al,24  point to the cost-effectiveness of POC AMR detection.

Table 6 lists POC projects, concepts, and solutions for ARM testing intended for sexually transmitted diseases (STDs),5572  while Table 7 covers tuberculosis (TB)7381  and Table 8 covers urinary tract infections (UTIs).8296  It is no surprise that progress is substantial for STDs5572  in view of societal impact, reasonable for TB7381  considering the deployment of relatively rapid Cepheid instrument and other solutions badly needed in Africa, and promising for UTIs and associated phenotypic antibiotic susceptibility testing,8296  because of the relatively straightforward urine sample matrix and ease of analysis compared to whole blood and other specimen types.

Table 6

Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Sexually Transmitted Diseases

Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Sexually Transmitted Diseases
Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Sexually Transmitted Diseases
Table 7

Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Tuberculosis

Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Tuberculosis
Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Tuberculosis
Table 8

Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Urinary Tract Infections

Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Urinary Tract Infections
Point-of-Care Diagnostics and Strategies for Antimicrobial Resistance and Antibiotic Susceptibility Testing—Urinary Tract Infections

Regarding STDs, Fingerhuth et al60  arrived at a very interesting and perhaps unique conclusion about POCT: “POC with high sensitivity to detect AMR can keep gonorrhea treatable longer than culture or NAAT (nucleic acid amplification tests). POC tests without reliable resistance detection should not be introduced, because they can accelerate the spread of antibiotic-resistant gonorrhoea.” In a limited resource setting, Verwijs et al70  found targeted POCT improved performance of WISH (a health interview for women) and excelled relative to WHO-recommended syndromic algorithms.

Shafiee et al57  and Duarte et al59  addressed POCT for human immunodeficiency virus (HIV) and concluded that more POC CD4+ T-lymphocyte count, viral load, and resistance testing is necessary to offset the increasing infectiveness of antiretroviral regimens. Rhee et al56  observed that in the context of a public health approach to antiviral drugs for HIV, a reliable POC genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive protease-inhibitor–containing regimens.

Some Table 6 entries directly or indirectly reflect past or ongoing work of NIH-BARDA finalists (see Table 1). They include the projects of Tsalik et al,31,37  Affinity Biosensors,47  and Klaris Diagnostics49  in Table 5; multiplex solid-phase melt curve analysis for POC detection of HIV-1 by Clutter et al66  in Table 6; and uropathogen identification and phenotypic antimicrobial susceptibility testing by the Gau group (Altobelli et al,87  Chen et al,88,89  Liu et al,90  Lu et al,91  Mach et al,92  and Pan et al93) in Table 8. Of course, the majority of the Diagnostic Challenge predated COVID-19 and even earlier, Cooke et al97  predicted the need for POCT for antibacterial use in respiratory tract infections.

Details published may not correspond to the methods or sophistication of finalists' emerging technologies (see Table 1). While the author was on the NIH-BARDA Step 1 and Step 2 review panels, competing inventions are strictly confidential, and only publically accessible information is provided here. One must wait until the prize is awarded to see the exciting POC solutions that the Diagnostic Challenge inspired!

Meanwhile, Yang and Rothman98  have explained the uses, limitations, and future applications of rapid diagnostics for infectious diseases in acute care settings. The POCT•CTR and 6 other chapter author teams in Global Point of Care99  cover POCT for infectious diseases in disasters, emergencies, and public health resilience. Hays et al38  propose “mix and match” (see Table 5) designed to encourage the implementation of rapid infectious disease and AMR POCT in transnational medical environments for use in the fight against increasing antimicrobial resistance. Several authors recognize the importance of stewardship and surveillance, which go hand-in-hand with AMR POCT.

GEOSPATIAL SPREAD OF ANTIMICROBIAL RESISTANCE

The speed of worldwide dissemination of SARS-CoV-2, lack of preparation for such a crisis, and absence of planning for adequate diagnostic testing17  has taught us that the same mistakes should not be made with AMR. While AMR is evolving on an apparently slower and less perceptible, but inexorable timetable, the problem has spread in patches and in nationally confluent regions across the globe, as the reader can see from the interactive maps cited earlier.19  The Diagnostic Challenge is stimulating awareness, research, and development of rapid POC diagnosis. Examples of the macrospatial and microspatial geographic chases that have begun follow.

Figure 1 illustrates the global geospatial distribution of Candida auris.3  The CDC ranks this fungus as an “urgent” threat (the gravest category), because (1) it is multidrug-resistant, with some strains resistant to all 3 available classes of antifungals, (2) it can cause significant outbreaks in health care facilities, (3) some common health care disinfectants are less effective at eliminating it, and (4) it can be carried on patients' skin without causing infection, allowing spread to others.3  In fact, a remarkable feature is the way it has become a global problem because of its ability to spread easily between people, including patients in long-term care facilities, similar to the sites of highly vulnerable patients hit severely by COVID-19.

Figure 1

Unique geospatial spread of Candida auris resistance to US hotspots. As shown in the top right corner, the Centers for Disease Control and Prevention ranks Candida auris as an urgent threat, the top threat level after serious and concerning.

Figure 1

Unique geospatial spread of Candida auris resistance to US hotspots. As shown in the top right corner, the Centers for Disease Control and Prevention ranks Candida auris as an urgent threat, the top threat level after serious and concerning.

Candida auris represents an example of global macrospatial translocation (see Figure 1) of a threat with almost no therapeutic defense. A recent review100  of POCT for Candida species concluded, “Despite considerable advances for candidiasis detection, the development of simple, compact and portable POC diagnostics (including lab on a chip devices) for rapid and precise testing that automatically performs cell lysis, nucleic acid extraction, purification, and detection still remains a challenge.” On the other hand, there is a promising nanogold immunodiagnostic assay for rapid on-site detection of invasive Aspergillosis, even in resource-limited settings,101  important because of the unusual geospatial distribution and antifungal pressure producing local hotspots of azole resistance102  that disseminate from farm and field through health care small-world networks.

The spread of extended-spectrum β-lactamase–producing Enterobacteriaceae represents an example of community microspatial translocation (Figure 2). The CDC ranks this threat as serious, justified by adverse outcomes—197,400 hospitalized in 1 year; 9100 deaths; and $1.2 billion in health care cost.3  Community-associated infections constitute 47% of the total, while community onset with recent health care exposure, long-term care facility onset, and hospital onset are 34%, 14%, and 5%, respectively. Fortunately, there is at least some progress in POC assays for antibiotic sensitivity for this superbug. See Huang et al23  regarding rapid electrochemical detection, and Lee et al26  for a microfluidic device in Table 5.

Figure 2

Extended-spectrum β-lactamase–producing Enterobacteriaceae hotspots within US communities.

Figure 2

Extended-spectrum β-lactamase–producing Enterobacteriaceae hotspots within US communities.

While it is now somewhat dated, the 2015 WHO report “Worldwide Country Situation Analysis: Response to Antimicrobial Resistance”103  provides additional insight into geospatial dissemination of AMR, progress and plans to stop it, and means of surveillance for bacteria, as well as TB, malaria, influenza, and HIV. One serious problem identified was the widespread practice of broad-spectrum antimicrobial administration without prescription, which is rampant geographically in the Americas, Southeast Asia, and the Western Pacific. Geospatial care paths in these regions may lack microbiology or sensitivity testing capabilities.

The report also stated (p 14): “Only one of the African countries that responded reported having a national plan, whereas having a comprehensive, funded national plan is one of the best ways to control antimicrobial resistance.” Other limited-resource regions had the same deficiency. Additionally (p 37), “…in many (countries) poor laboratory capacity, infrastructure and data management prevented effective surveillance.” “The sale of antimicrobial medicines without prescription was widespread, and many countries lacked standard treatment guidelines for healthcare workers.” There was no strategic plan for POC AMR testing.

In 2017, the WHO identified pathogens for which new effective antibiotics are badly needed.104  The 3 deemed most critical were carbapenem-resistant Acinetobacter baumannii, third-generation cephalosporin-resistant Enterobacteriaceae (CRE), and Pseudomonas aeruginosa. In 2019, the CDC categorized the first two as urgent and the third, serious.3 Acinetobacter threatens the microspatial environment of hospitalized patients, because it contaminates facility surfaces and shared medical equipment. Patients who require devices (eg, catheters) and those taking long courses of antibiotics are most at risk for CRE infections. Pseudomonas was associated with a hotspot in Mexico where in 2018 twenty surgery patients subsequently brought the pathogen to several states in the United States. Unfortunately, POC methods for these pathogens have yet to be fully explored and should be integrated into worldwide surveillance and efforts to enhance awareness of AMR.105 

Of the 21 threats on the CDC list (see Table 3), additional AMR papers (not associated with POCT) that addressed geospatial distribution included analysis of Streptococcus pneumoniae serotypes in the United States,106 Salmonella hotspots in the Democratic Republic of the Congo,107  and febrile illness in Asia.108  The authors of the Asia study summed up the problem nicely: “More investment in developing accurate and affordable diagnostic tests for rural Asia and their independent evaluation are needed. Enhanced AMR surveillance and openly accessible databases of geography-specific AMR data would inform policy on empirical and specific therapy. More investment in innovative strategies facilitating infectious disease surveillance in remote rural communities would be an important component of poverty reduction and improving public health.”108 

COINFECTIONS AND AMR RISK FOR COVID-19 PATIENTS

Table 9 summarizes coinfections in COVID-19 patients. Wuhan investigators noted that the antibiotic use rate of 49% to 100% intended for infections was greater in COVID-19 patients than the reported incidence of infections.5  In their experience, infection control protocols aimed at preventing the transmission and cross-infection of SARS-CoV-2 among patients, and not necessarily at preventing bacterial or fungal secondary infection. They observed secondary infection in 15% of COVID-19 patients overall and 1% of survivors, but notably, 50% of nonsurvivors.5,109 

Table 9

COVID-19 Coinfections, Secondary Infections, and Nosocomial Infections

COVID-19 Coinfections, Secondary Infections, and Nosocomial Infections
COVID-19 Coinfections, Secondary Infections, and Nosocomial Infections

In the Wuhan patient population studied by Zhou et al,109  100% (54 of 54) of nonsurvivors had sepsis, and 70% had septic shock. Others had cardiovascular risk factors. The median time from start of illness to death or discharge was 18.5 days in nonsurvivors and 22.0 days in survivors, roughly matching the duration of viral shedding. Coinfections increase the burden on ICU resources, while prolonged viral shedding increases risks to both clinical and laboratory staff. Coinfections also included other viruses.

One can hypothesize that bacterial, fungal, and viral coinfections contribute substantially to adverse outcomes in COVID-19 patients, and next, predict that POC solutions, such as those in Tables 5 through 8, would benefit not only patients, but also personnel, biosafety, and workflow. According to Chinese investigators (see Table 9), conventional microbiologic workup of specimens from COVID-19 patients incurs significant risk of aerosols and contact transmission for health care providers, for whom personal protective equipment has been in short supply.

In Wuhan and elsewhere in China, these and other considerations initially led to omission of pathogen workup in the laboratory.5,109  Additionally, conventional workup of fungal infections, such as C auris, typically is prolonged, possibly longer to result than the documented median ICU stay. Candida auris is a common hospital-acquired fungal infection in ICUs and one of the most resistant pathogens.110  Workup of Candida species and their resistance spectrum challenges even the most sophisticated technologies.111  Besides pulmonary coinfections and ventilator-acquired infections, heart failure, hypertension, acute cardiac injury, and diabetes add to COVID-19 patient risk.5,109 

Radiologic findings in COVID-19 patients comprise multifocal consolidative opacities, septal thickening, and development of a “crazy paving pattern,” with the greatest severity of computed tomography findings visible around day 10 after symptom onset.112  This builds a strong case for research, invention, and design of POC technologies that provide rapid multiplex pathogen and AMR testing to include the spectrum of bacterial and fungal pulmonary threats to COVID-19 patients documented in Table 9. If necessary for personnel safety, this testing could be performed in isolation laboratories, similar to those we designed for Ebola virus disease.14,15,113 

CONCLUSIONS AND FUTURE VISION

The COVID-19 pandemic is proving, like Ebola epidemics in Africa,15,16  that POC strategies are essential to deal with real-time crises.17  Subtle AMR pathogens are progressively knocking out therapeutic options. Editorials and expert opinions summarized in Table 10 warn of incipient acceleration of AMR, because of the widespread use of broad-spectrum antimicrobials for critically ill patients hospitalized during the COVID-19 pandemic.

Table 10

Expert Opinions Regarding the Global Acceleration of Antimicrobial Resistance

Expert Opinions Regarding the Global Acceleration of Antimicrobial Resistance
Expert Opinions Regarding the Global Acceleration of Antimicrobial Resistance

Evolving knowledge of critically ill COVID-19 patients likely will reveal compounding challenges, that is, details of the deadly synergy of SARS-CoV-2 cytokine storm + bacteria/fungus/virus coinfections (see Table 9) + resistance to antimicrobial and antifungal drugs. One can envision using multiplex POCT (Figure 3) for rapid diagnoses that decrease ICU burden, fatality rates, and excess mortality. Judging from progress to date, exciting advances in POC technologies will help navigate 21st century diagnostic challenges and save lives.

Figure 3

Multiplex diagnostics for antimicrobial resistance. Abbreviations: POC, point-of-care; POCT, point-of-care testing.

Figure 3

Multiplex diagnostics for antimicrobial resistance. Abbreviations: POC, point-of-care; POCT, point-of-care testing.

POCT has proven potential to target specific pathogens, refine choices for antimicrobials, and avoid indiscriminate use of antibiotic drugs. Point-of-care assays that identify patterns of pathogen resistance tell us how infected individuals spread AMR, where geospatial hotspots are located, and when to deploy preventative resources, especially in limited-resource countries that lack adequate microbiology laboratory resources.

Coinfections present high risks for COVID-19 patients and complicate ICU stays. Shared AMR geospatial “clouds” could help diminish critical care burden during pandemics and optimize therapeutic options, similar to use of antibiograms in individual hospitals. Multidisciplinary health care personnel should learn the principles and practice of POCT so they can meet these diagnostic testing needs.

If the most dire forecasts prove true, AMR could become the “newdemic”114  of the 21st century, signifying a medical crisis out of control, especially in crowded and heavily populated metropolises like New York City, and requiring concerted national and international effort to avoid large medical, economic, and social losses. On the other hand, if POC solutions are developed in time and applied across the economic strata of resource-rich and resource-poor settings and countries, AMR spread might be curtailed.

Primary care physicians write most of the antibiotic prescriptions. Typically, they feel under pressure to generate them, but lack the tools necessary for rapid differential diagnosis. This dilemma calls for POC strategies that quickly differentiate viral from bacterial causes of fever. If bacterial, then diagnostic tests should immediately identify the pathogen and its AMR profile. Adequate evidence and timely decision-making call for multiplex, but affordable POCT. The tables highlight novel POC approaches for UTIs, STDs, and TB. Progress is substantial, but the POC solutions should include phenotypic susceptibility testing where appropriate. Fortunately, Diagnostic Challenge finalists address some of these key issues (see Table 1).

Point-of-care instruments often serve as default testing methods in limited-resource community hospitals. Environmental conditions may not be well controlled where diagnostic testing is performed in tiny laboratories, emergency rooms, clinics, and primary care clinics in tropical and harsh settings. Point-of-care diagnostics, reagents, and quality control supplies must be environmentally robust, certified for the conditions encountered, and monitored. Environmental stresses, such as high or low temperature or humidity can cause both false-negative and false-positive POC test results.115119  Environmental stress research is pivotal to national security and to successfully defeating AMR, as well as the COVID-19 pandemic.

Point-of-care inventions (see Tables 5 through 8), novel molecular diagnostics,120  biomarker prediction platforms,121  and other interesting innovations can bridge resource gaps in limited-resource nations and facilitate physician knowledge of targeted antibiotic therapy, community AMR, and COVID-19 hotspots. The stakes are high. AMR is projected to cause millions of deaths annually and cumulative financial losses in the trillions by 2050.18,164  These human and economic penalties will sap national budgets, shift more spending to the health care sector, elevate inequities if not uniformly distributed, and determine the fate of future civic and public health leaders.

Pharmaceutical companies formed a $1 billion AMR Action Fund for new antibiotics, invested $164 million in early pipeline development, and gathered $500 million for a university consortium.164  The Disarm Act of 2019 and Pasteur Act of 2020 increase reimbursement.164  The potential for huge economic losses from AMR organisms justify substantial investments, realistically, multiples of the $20,000,000 Diagnostic Challenge prize. However, the prize is a good starting point to motivate creative diagnostic technologies and badly needed POC geospatial solutions. We will not be free from new threats, as illustrated by the discovery of drug-resistant Neiserria meningitidis now spreading in the United States.165 

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Author notes

This work is supported by the Point-of-Care Testing Center for Teaching and Research (POCT•CTR) and by Dr Kost, its director. The author thanks the creative students who participate in the POCT•CTR and contribute substantially to knowledge in point-of-care (POC). The author also is grateful to have received a Fulbright Scholar Award 2020–2021 that will support POC geospatial research in ASEAN Member States and lectures throughout Asia. Figures and tables are provided courtesy and permission of Knowledge Optimization, Davis, California.

Competing Interests

The author has no relevant financial interest in the products or companies described in this article.

Portions of the content were introduced during an invited presentation at Tri•Con, Cambridge Healthtech; March 3, 2020; San Francisco, California.

Devices must comply with jurisdictional regulations in specific countries, operator use limitations based on patient conditions, federal and state legal statutes, hospital accreditation requirements, and emergency decrees. Not all POC devices presented are US Food and Drug Administration (FDA) cleared for use in the United States. FDA polices are in flux. Please check with manufacturers for the current status of diagnostics and POC tests within the relevant national domain of use.