By Peter Teska and Jim Gauthier
The discovery of penicillin and subsequent generations of antibiotics has been heralded as one of the biggest medical discoveries in history. Yet shortly after his discovery of penicillin in 1928, Fleming warned of the dangers of resistance. This fear has since been proven to be accurate. Within a few years of the introduction of each new class of antibiotics, resistance was detected, helping drive the need for development of the next blockbuster antibiotic.
The pace of introducing new antibiotics has slowed to a crawl, but within the last decade, bacterial resistance to antibiotics appears to have grown at a more rapid pace, leading to concerns about the “end of the antibiotic era” being on the horizon.
A paper recently accepted for publication in the journal Antimicrobial Agents and Chemotherapy (McGann 2016) has increased this concern as an organism isolated in a patient in the United States was shown to be resistant to colistin, even though the patient was not receiving colistin. Colistin is rarely used in the U.S. due to side effects and is considered an antibiotic of last resort.
McGann reports that during routine culturing of the urine of a 49-year-old female from Pennsylvania with no travel history in the previous five months, it was determined that the patient was suffering from an Escherichia coli infection. Per facility policy, the bacterium was tested for resistance to a range on antibiotics. Through this testing, it was determined that the isolate was an Extended Spectrum Beta Lactamase (ESBL)-producing phenotype and, consistent with facility policy, it was further tested for colistin susceptibility among other antibiotics. It was shown to be resistant to colistin in addition to other antibiotics.
Since the patient has never taken colistin, the authors theorized that a plasmid (small segments of DNA not part of the bacteria’s chromosome) containing the resistance gene was shared by another Enterobacteriaceae which enabled this E. coli to develop colistin resistance. This theory suggests that strains of bacteria may trade plasmids, spreading wide antibiotic resistance, which is quite different than previous thinking where the bacteria needed to be exposed to the antibiotic to develop resistance.
In 2013, the Centers for Disease Control and Prevention (CDC) published a report on antibiotic threats in the United States. The CDC estimates that more than 2 million people acquire a serious infection that is resistant to one or more antibiotics, resulting in at least 23,500 deaths annually in the U.S. They also estimate that within the U.S., at least 50 percent of the antibiotics prescribed are either not needed or are not optimally effective as prescribed.
The report further discusses how some Gram-negative bacteria are becoming increasingly resistant to nearly all drugs that would be used for treatment. Members of the Enterobacteriaceae (along with Pseudomonas species and Acinetobacter species) are specifically called out as they can cause serious infections and are commonly healthcare associated, which is concerning for the healthcare industry.
The list below from the CDC report summarizes the current concerns with existing classes of antibiotics and Gram-negative bacteria.
• β-lactams: Gram-negative bacteria have developed several pathways of resistance and ESBL-producing bacteria can break down the antibiotics before they can be effective.
• Penicillin, amino-penicillins, early generation cephalosporins (a β-lactam subclass): These drugs are rarely used for Gram negative bacteria as resistance is widespread.
• β-lactamase inhibitor combinations (a β-lactam subclass): These drugs are important for treating Gram negative infections, but resistance is increasing.
• Extended spectrum Cephalosporins (a β-lactam subclass): These drugs have been the cornerstone for treating Gram negative infections for 20 years, but resistance is increasing.
• Carbapenems (a β-lactam subclass): Currently the antibiotic of last resort for Gram negative bacterial infections, the rise of carbapenem resistance in the last decade, especially in Enterobacteriaceae – Carbapenem Resistant Enterobacteriaceae (CRE) is concerning because once a bacteria becomes resistant to carbapenems, it generally becomes resistant to all β-lactam antibiotics. Other bacteria are Carbapenemase-producing organisms (CPO) such as Acinetobacter species and some Pseudomonas species.
• Fluoroquinolones: A broad spectrum antibiotic, but resistant bacteria developed quickly with increased use.
• Aminoglycosides: Often used with β-lactam drugs for Gram negative infections, but growing resistance and concerns about side effects makes these less prescribed.
• Tetracyclines and Glycyclines: Not considered a first line treatment option, but with increasing resistance in other classes of antibiotics, use is increasing.
• Polymyxins (includes colistin): This is an older class of antibiotics, but has toxicity concerns, which reduce its use.
In the same report, the CDC detailed the classes of microorganisms that were of highest concern and assigned a threat level (urgent, serious and concerning). Listed with each organism is the number of annual cases and deaths in the U.S.
• Urgent Threats
- Clostridium difficile (250,000 cases, 14,000 deaths)
- Carbapenem-resistant Enterobacteriaceae (CRE) (9,300 cases, 610 deaths)
- Neisseria gonorrhea (246,000 cases, fewer than five deaths)
• Serious Threats
- Multi-drug resistant Acinetobacter (7,300 cases, 500 deaths)
- Drug-resistant Campylobacter (310,000 cases, 28 deaths)
- Fluconazole-resistant Candida (3,400 cases, 220 deaths)
- Extended Spectrum β-lactamase producing Enterobacteriaceae (ESBL) (26,000 cases, 1,700 deaths)
- Vancomycin-resistant Enterococcus (VRE) (20,000 cases, 1,300 deaths)
- Multidrug-resistant Pseudomonas aeruginosa (6,700 cases, 440 deaths)
- Drug-resistant Non-Typhoid Salmonella (100,000 cases, 40 deaths)
- Drug-resistant Salmonella serotype typhi (3,800 cases, fewer than five deaths)
- Drug-resistant Shigella (27,000 cases, fewer than five deaths
- Methicillin-resistant Staphylococcus aureus (MRSA) (80,000 cases, 11,000 deaths)
- Drug-resistant Streptococcus pneumoniae (1,200,000 cases, 7,000 deaths)
- Drug-resistant Tuberculosis (1,042 cases, 50 deaths)
• Concerning Threats
- Vancomycin-resistant Staphylococcus aureus (VRSA) (fewer than five cases, fewer than five deaths)
- Erythromycin-resistant Group A Streptococcus (1,300 cases, 160 deaths)
- Clindamycin-resistant Group B Streptococcus (7,600 cases, 440 deaths)
The range of bacteria-causing infections and the large number of infections across these bacteria presents treatment challenges for physicians. When fighting a problem as complex as antibiotic resistance, it is appropriate to consider a multi-factor approach as multiple actions will likely be required to have a significant impact on this issue.
The list below was generated from multiple sources in an attempt to identify some potential levers to impact antibiotic resistance. Many of these actions would require prolonged efforts with the involvement of a number of different parties, yet broad strategy with numerous actions is the only strategy likely to have significant impact.
1. Antibiotic stewardship: An antibiotic stewardship program can help limit resistance developing within healthcare by ensuring patients receive the right antibiotic, for the right indication, using the proper route for the ideal length of time. Once an organism is identified as causing an infection, and tested for antibiotic susceptibility, it is prudent to switch to a less broad-spectrum antibiotic if possible so that normal flora organisms are not damaged. In the community, many of the antibiotics currently being prescribed for people have little clinical value for a range of reasons, including giving antibiotics to people who have viral infections or using antibiotics that are ineffective against the bacteria causing the infection. It’s important to consider strategies and tactics to prevent additional resistance from developing within the community, and to monitor people to ensure they take all their doses to limit the development of antibiotic-resistant strains.
2. Reduced use of antibiotics in animals: The CDC report highlights that many of the antibiotics given to animals are prophylactic or growth promoting, rather than in response to an actual illness. These antibiotics can potentially contribute to bacteria developing resistance. If the antibiotic remains in the animal meat after slaughter, low levels of the antibiotic can provide time for organisms to evolve resistance.
3. Prevention of infections: Vaccinations, hand hygiene, effective environmental cleaning and disinfection and the use of barriers (gloves, gowns and masks) can all have a significant impact on how bacteria are transmitted between people. If fewer people become sick, fewer antibiotics will be prescribed, giving the bacteria fewer chances to develop resistance. Better education around hand hygiene, cleaning and disinfection and the use of gloves, gowns and masks can help protect other people around someone who is sick.
4. Tracking and better testing: Testing patients with infections can help determine the antibiotic resistance of the organisms causing their infections. Healthcare professionals should share information on highly-resistant organisms with the CDC and other authorities to determine the prevalence of antibiotic resistance. Rapid tests may be needed to determine whether people have true bacterial infections which can lead to faster treatment and proper use of antibiotics. Rapid tests should also be developed to identify the resistance of the bacteria to current antibiotics, making treatment easier for physicians.
5. Healthcare staff decolonization: Many healthcare workers are colonized with antibiotic-resistant bacteria. Routine testing would allow for identification and decolonization for these workers, reducing the spread of resistant bacteria. This could also lead to more resistance, however, depending on how decolonization is carried out.
6. Development of new antibiotics: There are a number of challenges with this strategy. First, the discovery of the current library of antibiotics may mean that there are only a few drugs yet to be discovered. New antibiotic-producing organisms are being investigated by looking to new sources such as our oceans. Second, developing any new drug is expensive and time consuming. This would be no exception. Third, drug companies look at the potential for use to decide whether to spend money on the development of a drug. A drug that is used daily for the rest of a person’s life, such as a cholesterol-lowering medicine is attractive to develop. A new antibiotic would only be used for infections, which would hopefully clear up. Also, a new antibiotic is unlikely to be widely used because of concerns about bacteria developing resistance. Thus developing antibiotics is not financially attractive for drug companies. Governments may need to provide a significant financial incentive to offset the small revenue likely to be associated with a new antibiotic.
The continued spread of antibiotic resistance in bacteria is cause for significant concern. As the bacteria continue to evolve more effective resistance, the healthcare provider’s options for antibiotic therapy are increasingly limited. Discuss implementing several or all of the above recommendations within your organization to help slow the development of further resistance.
Peter Teska is a global infection prevention application expert with Sealed Air’s Diversey Care division and can be reached at firstname.lastname@example.org. Jim Gauthier is a senior clinical advisor with Diversey Care and can be reached at email@example.com.
McGann P, Snesrud E, Maybank R, et al. Escherichia coli harboring mcr-1 and blaCTX-M on a novel IncF plasmid: First report of mcr-1 in the USA. Antimicrob Agents Chemother, 2016. Published online. doi:10.1128/AAC.01103-16. Downloaded from http://aac.asm.org/content/early/2016/05/25/AAC.01103-16.full.pdf+html
CDC. Antibiotic resistant threats in the United States, 2013 (2013). Downloaded from http://www.cdc.gov/drugresistance/threat-report-2013/index.html.