Evolution of Superbugs: A Healthcare Nightmare

Almost each week brings news of a hospital or clinic reporting the detection of a drug-resistant microorganism. In addition to difficult-to-treat viral infections, such as the ever-changing human and avian influenza viruses, an increasing number of bacteria have been developing resistance to existing antibiotics, resulting in the development of “superbugs.” This creates a complex healthcare problem, one that can prove catastrophic for patients and healthcare employees while generating healthcare costs that could have been avoided.

The National Institute of Allergy and Infectious Diseases recently reported an epidemiological study conducted by scientists at the National Institutes of Health that tracked the evolution of a Klebsiella pneumoniae superbug species (Sequence type 258, ST258; carbapenemresistant) using genomic sequencing.¹ The study surprisingly identified 2 different lineages for ST258 K pneumonia contrary to previous belief that the resistant species spread from 1 ancestor, based on differences in the sequence of the bacterial envelope (outer coat), which interacts with the host immune system. This study highlights the importance of genomics in drug development (see cover story); in this case, antibiotics.

According to the Infectious Diseases Society of America, antibiotics, antivirals, and other antimicrobials have saved lives worldwide but are losing their effectiveness to resistance.² Both viruses and bacteria have the ability to adapt and evolve based on environmental cues, and exposure to antimicrobials triggers resistance mechanisms in the organisms. The more an antibiotic is used, the more likely it will be ineffective in the future. Although this is inevitable to some degree, over prescription and improper use of antimicrobials play an important role in resistance development.²

Facts and Figures

In early March of this year, the Centers for Disease Control and Prevention (CDC) released an update on the current status of antibiotic-resistant microorganisms in the United States.³ CDC estimates that antibiotic-resistant infections affect at least about 2 million Americans, resulting in about 23,000 deaths per year. These resistant bacteria have been classified by the CDC as urgent, serious, and concerning threats (Table). Antibiotic-resistant infections necessitate prolonged and/or costlier treatments treatments, extended hospital stays, additional doctors’ visits and healthcare use, and ultimately result in increased disability and death compared with treatable infections. Although the number is difficult to estimate, antibiotic resistance costs the United States approximately $20 billion per year in direct healthcare costs, with loss of productivity amounting to an additional $35 billion per year.^2,3

Globally, multidrugresistant tuberculosis (MDR-TB) and methicillin-resistant Staphylococcus aureus (MRSA) are the major concerns, among others. In 2011, there were 630,000 reported cases of MDR-TB among the estimated 12 million cases of TB, while 3.7% of new cases and 20% of previously treated cases are estimated to have MDR-TB.⁴ Overuse of antibiotics, both in humans and in livestock, is an extremely important determinant of this growing threat of resistant microbes (Figure), and regulatory agencies such as the CDC and the US Food and Drug Administration (FDA) have published guidelines to regulate the process and to gain a better handle on the problem.^3,5 An FDA report published late in 2013 recommends judicious use of medically important antibiotics in food-producing animals; the indiscreet use of antibiotics important in human infections among livestock could overexpose the bacteria to those drugs and contribute to resistance.

The FDA strongly recommends veterinary oversight to assure appropriate use of these antimicrobials. A recent commentary published in the Journal of the American Medical Association, and coauthored by Anthony Fauci, MD, highlights that although bacterial resistance has been an evolutionary mechanism, it has been exacerbated by the misuse and overuse of antibiotics.⁶ The authors also mirror the CDC’s and FDA’s concern about the contributions of the agricultural sector by pointing to the fact that veterinary use dominates about 75% of the antibiotic use in the United States, primarily to improve the animals’ resistance to disease and increase their weight.⁶

Recent Evidence of Increased Resistance

Carbapenem-resistant Enterobacteriaceae (CRE) have been on the rise in Canada and have proved fatal, forcing hospitals to step up screening efforts. However, the outbreaks have not been widely reported, keeping the general population as well as other hospitals and clinics in the dark.⁷

A research report published last year monitored the antimicrobial resistance patterns of healthcare-associated infections (HAIs) between 2009 and 2010 in the United States, which included central line—associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections (SSIs). Nearly 20% of the pathogens reported from all HAIs by 2039 hospitals inclu-ded the following MDR organisms: MRSA (8.5%), vancomycin-resistant Enterococcus (3%), extended-spectrum cephalosporin-resistant K pneumoniae and K oxytoca (2%), E coli (2%), and Enterobacter spp. (2%); carbapenem-resistant P aeruginosa (2%), K pneumoniae/K oxytoca (<1%), E coli (<1%), and Enterobacter spp. Although there wasn’t a substantial increase from the previous 2 years, MDR gram-negative phenotype, a rising threat, was reported by several facilities.⁸

Hospitals themselves are not meeting the standards necessary to protect patients, and the population in general, from these preventable and potentially fatal infections.⁹ Evaluation of 1600 intensive care units in 975 hospitals across the United States found that about 10% of hospitals did not have a checklist to prevent bloodstream infections ($0.6 billion to $2.7 billion annual cost10), 25% did not have a checklist to prevent ventilator pneumonia ($0.8 billion to $1.5 billion annual cost¹¹), and 33% did not have a policy to prevent catheter-associated urinary tract infections⁹ ($565 million annual cost¹²).

Which Patients Are Most at Risk?

Hospitals and clinics are definitely the primary sites of evolution of antibioticresistant microbes. However, specific cohorts of patients are more vulnerable to these infections than others. Cancer patients have a repressed immune system (immunocompromised), with a low white blood cell count, following chemotherapy and radiation, and are often at an increased risk for developing an infection. Further, hospitalized patients are frequently subjected to procedures that disrupt the body’s natural barriers (finger sticks, bone marrow aspirations, and venipunctures). Independent of treatment, some cancer patients may have immune problems that predispose them to certain infections.³

Patients who receive cardiac bypass, joint replacements, and other complex surgeries are at risk of SSIs, which can slow the recovery time and may even lead to additional complications.³ SSI is estimated in 1% to 3% of patients undergoing surgery,¹³ and recovery obviously depends on the type of organism responsible for the infection. Patients with rheumatoid arthritis may also be more susceptible to infections, and the anti-inflammatory agents used in treatment can further suppress the patient’s immune system.³

Dialysis patients are also at a greater risk for acquiring bloodstream infections, due to the increased use of catheters and needles in these patients. Multidrug-resistant organisms have been increasingly shown to colonize dialysis patients at significantly higher rates than in patients with other healthcare exposures. The practices used in hospitals and dialysis centers have not been

successful in curbing these infections.^3,14 Those receiving organ or bone marrow transplants represent another highly vulnerable category of patients. Immunosuppressant treatment over an extended period of time in these patients increases their risk of infection.

Statistics estimate that 1% of organs transplanted in the United States every year transfer a disease (infection or cancer) from the donor to the recipient. Further, infection-associated complications in organ transplant patients are more common with liver and pancreas transplant, but not so much with heart transplant.^3,15

Most Common Errors Encountered in Prescription Practices

According to the CDC, nearly 50% of hospitalized patients are administered an antibiotic for at least 1 day of their stay, to treat lung infections, urinary tract infections, and infections suspected to be caused by drug-resistant Staphylococcus bacteria such as MRSA. Most doctors were found to prescribe antibiotics without adequately testing the patient (ordering cultures) for the presence of specific bacteria.16 According to Shira I. Doron, MD, antimicrobial steward and associate hospital epidemiologist at the Tufts Medical Center, “It is important to evaluate whether a patient is infected with or is only colonized by a particular species of bacterium.”

Being conservative in this respect could actually prove useful since powerful does not necessarily mean efficient with respect to bacterial infections. Studies have shown that patients treated with broad-spectrum antibiotics are 3 times more suseptible to infection to an even more resistant germ.¹⁶ Treating a patient with a broad-spectrum antibiotic for a non-threatening infection results in unnecessary exposure of the other bacteria in the patient’s body to that antibiotic, increasing the chances of resistance development,” said Doron.

Steps Being Implemented to Combat the Burgeoning Problem

Physicians can help get a better grip on the situation by following certain rules and practices. Some specific recommendations by the CDC are:

• Identify the bacterium by ordering of treatment with the antibiotic cultures

• Ensure appropriate dose and period

• Assess the patient within 48 hours and adjust the dose or stop treatment¹⁷

The CDC recommends participation by all the stakeholders, including the federal and state governments, local hospital CEOs and medical officers, doctors and hospital staff, and patients themselves.¹⁷

The bottom line is that all involved, especially physicians, should be educated on the pitfalls of overprescribing, and health authorities at both the state and federal level should develop a prescription tracking system.

In a more concrete effort, CDC has requested annual funding of $30 million in the president’s 2015 budget to launch the Detect and Protect Against Antibiotic Resistance Initiative (AR Initiative), to detect and track patterns, respond to outbreaks, prevent spread of resistant bacteria, and discover newer antibiotics.¹⁷ The agency estimates that the AR Initiative could result in a 50% reduction in healthcare associated C difficile ($2 billion in healthcare savings), 50% reduction in healthcare-associated carbapenem-resistant Enterobacteriaceae (CRE) infections, 30% reduction in healthcare-associated MDR Pseudomonas, 30% reduction in MRSA, and a 25% reduction in MDR Salmonella infections.

Doron told Evidence-Based Immunology and Infectious Disease that at Tufts, a 2-pronged approach is being followed: antimicrobial stewardship and infection prevention. The antimicrobial

stewardship program, led by Doron, involves dedicated staff and resources to ensure adequate usage of antimicrobials. A strict restriction on antimicrobial usage is monitored by a concurrent review of all prescribed antibiotics by members of the stewardship program, and by adequate intervention as deemed necessary.

Electronic order sets on the Medical Centers computers help physicians decide which antibiotics to prescribe and at what dose, based on the patient’s test results, to ensure appropriate administration of antimicrobials. This program, initiated in 2001, resulted in a cost-saving of $5 to $10 million over a 10-year period. “For infection prevention, the focus is on hygienic practices,” said Doron. Hand hygiene, clean environment, use of personal protective equipment (laboratory coats, gloves, etc) by the staff, and a mandatory flu vaccine are high on the agenda.

Improved Diagnostics and Drugs?

Multicollaborative efforts between researchers at academic institutes, hospitals, government laboratories, regulatory authorities, and the biotechnology/pharmaceutical industry would play an important role in developing novel approaches to diagnosing and treating emerging MDR infections.

A new reverse transcription polymerase chain reaction (RT-PCR)-based diagnostic tool was recently reported, by scientists at the Institute for Genome Sciences and Policy at Duke University, to diagnose acute respiratory viral infections, which could help prevent unwarranted antibacterial use. The diagnostic platform developed by the group proved 89% sensitive and 94% specific when used to test samples from 102 individuals who arrived at the emergency department with fever.¹⁸

With the giant leaps achieved in the world of genomic technologies, studies are being conducted at the Broad Institute in Cambridge, Massachusetts, to identify useful antibacterial compounds naturally produced by 20 species of actinomycetes.⁶ Other novel drugs being developed include peptidomimetics, new aminoglycosides and their derivatives, FimH inhibitors, and nanoparticles

of zinc oxide, iron oxide, and copper oxide.¹⁹

Going Forward

A recent panel discussion hosted by the Harvard School of Public Health (“Battling Drug-Resistant Superbugs: Can We Win?”) brought together a physician, an epidemiologist, a pharmacoepidemiologist, and a CDC representative. Some of the issues that concerned the panelists included, of course, the over-prescription of antibiotics by doctors, lack of adherence by patients, and overuse of antibiotics in livestock. The panelists recommended both hospital stewardship programs and community education to battle the problem of resistant mircoorganisms. They also recommended legal changes that would allow longer patent periods for pharmaceutical companies that develop new antibiotics.²⁰ The government did act on the “providing incentives” front by introducing a law in 2012 called the Generating Antibiotics Incentive Now (GAIN), which provides 5 years of patent protection from generics along with an accelerated FDA approval for antibiotics against specific bacteria.²¹ (see commentary on page SP179).

Monitoring unnecessary antibiotic use will also translate into greater cost savings for the healthcare system, as shown by the example set by the University of Maryland Medical Center (UMMC) in Baltimore. UMMC saved $3 million in its annual budget following a 7-year antimicrobial stewardship program, which identified when and which antibiotics are appropriate, resulting in

about a 50% cut in antibiotic spending per patient with no impact on the quality of care. However, with the end of the program in 2008, antimicrobial costs added $2 million to the budget by year 2010.²²

US Republican Janet Adkins introduced an infection-control bill in the House Health Quality Subcommittee to create a new website that would track infection-resistant bacterial infections.

“The objective of the bill…was simply to make this information to Floridians. So when there is an outbreak of this antibiotic-resistant threat, the Floridians have a single place that they can go to to find out where those outbreaks are occurring,” said Adkins.²³

The problem at hand is enormous, but a combination of improved surveillance (by regulatory agencies as well as the individual clinics/hospitals), patient education, improved diagnostic tests, and the development of newer approaches to eliminate bacteria would be the best strategy.