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The year is 2045. Antibiotics are now worthless - (3/1/2019)

By Dr. Ron Gasbarro

The year is 2045 
Antibiotics are now worthless. Children and the elderly die of common infections caused by drug-resistant Staphylococcus aureus and Streptococcus pneumoniae. Sexually transmitted diseases (STDs) become complicated because they cannot be eradicated. The human life span plummets from 85 to 48, the same as it was in 1895 before the advent of most vaccines and nearly all antibiotics. Back in 2025, antibiotics became a Schedule 2 class of drugs, not because they were addictive but because it was Earth’s last chance to save that drug class and to possibly save humanity. Yet, the bacteria had become so crafty at sidestepping the antibiotics that nothing tended to work at the expense of human life. 

A 2044 report from the US Centers for Disease Control and Prevention (CDC) described the cases of over 2,000 people with group B streptococcus infections that turned out to be resistant to vancomycin, often considered an antibiotic of last resort. Decades ago in 2015, group B strep infections were relatively easy to subdue because the bacteria were vulnerable to penicillin and other common antibiotics. Yet, every time there is information about one more genus, species, or strain of bacteria that demonstrated resistance to yet another class of antibiotic, that is bad news because it means that yet another antibiotic weapon is about to become useless.

Back to the present
Antibiotic resistance is one of the biggest public health challenges of our time. Each year in the US, at least 2 million people get an antibiotic-resistant infection, and at least 23,000 people die [CDC, 2018].

Almost 50% of all antibiotic scripts in the US are unnecessary or inappropriate, according to the CDC [CDC, 2013]. Studies published in the Journal of the American Medical Association (JAMA) revealed that while only about 10% of adults with a sore throat actually have a bacterial strep infection, they are prescribed antibiotics approximately 60% of the time [Barnett, 2014 “A”]. Although bacteria cause only about 10% of acute bronchitis cases, antibiotics are given to 73% of patients [Barnett, 2014 “B”]. 

The Pew Research Center is a nonpartisan American fact tank based in Washington, DC. The center reports on antibiotic prescribing practices in outpatient settings such as urgent-care and dental clinics. The researchers found that in 2014, outpatient health care providers within the US wrote 266 million antibiotic prescriptions, which amounted to roughly 838 antibiotic prescriptions per 1,000 people [CDC, 2015]. Of these outpatient antibiotic prescriptions, 44% were for acute respiratory conditions, and half of these prescriptions were unnecessary because many respiratory conditions are caused by viral infections that are not susceptible to antibiotics. Curtailing the liberal use of antibiotics requires understanding why and where medical providers are prescribing antibiotics.

Impact of antibiotic resistance
According to the World Health Organization (WHO), when first-line antibiotics can no longer treat infections, then more expensive medicines must be used. A longer duration of illness and treatment, often in hospitals, increases health care costs as well as the economic burden on families and societies. 

In addition, antibiotic resistance is putting the achievements of modern medicine at risk. Organ transplantations, chemotherapy, and surgeries such as cesarean sections become much more dangerous without effective antibiotics for the prevention and treatment of infections.

Resistance started with the very first antibiotics

We only have to go back 70 years, before the “golden era” of antibiotic discoveries of the 1940s to 1960s, to experience infectious disease as the predominant cause of human death. These diseases are still around and some are more virulent – complicated by multiple antibiotic resistances, which evolved through many factors but mostly driven by our overuse. [See Visual 1]  

In 1928, Alexander Fleming discovered penicillin, the first commercialized antibiotic. Ever since there has been discovery and acknowledgment of resistance alongside the discovery of new antibiotics. In fact, germs will always look for ways to survive and resist new drugs. More and more, germs are sharing their resistance with one another, making it harder for us to keep up.

According to the CDC, antibiotic resistance occurs when bacteria and fungi develop the ability to defeat the drugs designed to kill them. That means the antibiotic does not kill the germs, allowing them to continue growing and spreading. Infections caused by antibiotic-resistant germs are difficult and sometimes impossible to treat. In most cases, antibiotic-resistant infections require extended hospital stays, additional follow-up doctor visits, and costly and toxic alternatives. Antibiotic resistance does not mean the body is becoming resistant to antibiotics; it is that bacteria have become resistant to the antibiotics designed to kill them.

Visual 1 – A timeline of antibiotic resistance compared to antibiotic development [CDC, 2018]

 

It’s not just physicians who are quick with the Rx pad
Most research assessing outpatient antibiotic prescribing has focused on physicians [Shapiro, 2014]. Less is known about the prescribing practices of nurse practitioners (NPs) and physician assistants (PAs), who collectively represent more than one-quarter of the US primary care workforce [Primary, 2012].

A study funded by the CDC examined US nurse practitioner (NP) and physician assistant (PA) outpatient antibiotic prescribing [Sanchez, 2016]. Antibiotics were more frequently prescribed during visits involving NP/PA visits compared with physician-only visits, including overall visits (17% vs. 12%, P<.0001) and acute respiratory infection (ARIs) visits (61% vs. 54%, P<.001). As the proportion of outpatient visits involving NPs and PAs continues to increase, interventions to reduce inappropriate antibiotic use in ambulatory care should target these providers.

Regardless of provider type, antibiotic prescribing for ARIs and use of broad-spectrum antibiotics in the study was much higher than desired and necessary, mandating ongoing evaluation and intervention to minimize antibiotic resistance, adverse drug events, and poor clinical outcomes that result from inappropriate antibiotic prescribing.

Visual 2 – Proportion of outpatient visits involving a nurse practitioner (NP) or physician assistant (PA), 1998 to 2011.

Growing resistance threats identified by WHO 

URGENT THREATS

Clostridioides difficile

      

Bacteria
Also known as C. difficile or C. diff, previously Clostridium difficile
About: C. difficile causes life-threatening diarrhea and colitis, mostly in people who have had both recent medical care and antibiotics
Infections per year: 500,000
Deaths per year: 15,000

Drug-resistant Neisseria gonorrhoeae

       

Bacteria
About: N. gonorrhoeae causes the sexually transmitted disease gonorrhea, and has progressively developed resistance to the antibiotic drugs prescribed to treat 
Infections per year: 246,000

 

Carbapenem-resistant Enterobacteriaceae 

     

Also known as Nightmare bacteria, CRE
About: Some Enterobacteriaceae are resistant to nearly all antibiotics, including carbapenems, which are often considered the antibiotics of last resort
Drug-resistant infections per year: 9,000
Deaths per year: 600

 

SERIOUS THREATS

Multidrug-resistant Acinetobacter

     
Bacteria
About:
People with weakened immune systems, including hospitalized patients, are more at risk of getting an Acinetobacter infection, which is resistant to many commonly prescribed antibiotics
Multidrug-resistant infections per year: 7,300
Deaths per year:
500

 

Drug-resistant Campylobacter

     
Bacteria
Also known as 
Campy
About: Campylobacter usually causes diarrhea, fever, and abdominal cramps, and can spread from animals to people through contaminated food, especially raw or undercooked chicken
Drug-resistance infections per year: 310,000

 

Fluconazole-resistant Candida

    
Fungus
About
: Candida yeasts normally live on the skin and mucous membranes without causing infection; however, overgrowth of these microorganisms can cause symptoms to develop
Fluconazole-resistant Candida infections per year: 3,400
Deaths per year: 220

 

Extended-spectrum Beta-lactamase-producing Enterobacteriaceae

        
Bacteria
Also known as
ESBL, or extended-spectrum β-lactamase 
About: ESBL-producing Enterobacteriaceae are resistant to strong antibiotics, including extended-spectrum cephalosporins
(ESBL is an enzyme that allows bacteria to become resistant to a wide variety of penicillin and cephalosporin drugs. Bacteria that contain this enzyme are known as ESBLs or ESBL-producing.) 
Drug-resistant infections per year: 26,000 
Deaths per year: 1,700

 

Vancomycin-resistant Enterococcus 

    
Bacteria
Also known as 
VRE
About: Enterococci cause a range of illnesses, mostly among patients receiving healthcare
Drug-resistant infections per year: 20,000 
Deaths per year: 1,300

 

Multidrug-resistant Pseudomonas aeruginosa     

     
Bacteria
Also known as
P. aeruginosa
About: Severe Pseudomonas infections usually occur in people with weakened immune systems, making it a common cause of healthcare-associated infections 
Multidrug-resistant  infections per year: 6,700 
Deaths per year: 440

 

Drug-resistant non-typhoidal Salmonella

     

Bacteria
About:
Salmonella spreads from animals to people mostly through food, and usually causes diarrhea, fever, and abdominal cramps 
Non-typhoidal Salmonella includes serotypes other than Typhi, Paratyphi A, Paratyphi B, and Paratyphi C 
Drug-resistant infections per year: 100,000

 

Drug-resistant Salmonella Serotype Typhi 

     
Bacteria
Also known as
Typhoid fever
About: Salmonella Typhi causes a serious disease called typhoid fever, and is spread by contaminated food and water
Drug-resistant infections per year: 3,800 

 

Drug-resistant Shigella

     

Bacteria
About
: Shigella spreads in feces through direct contact or through contaminated surfaces, food, or water, and  most people infected with Shigella develop diarrhea, fever, and stomach cramps
Drug-resistant infections per year: 27,000

 

Methicillin-resistant Staphylococcus aureus

     
Bacteria
Also known as
MRSA, resistant staph (short for Staphylococcus), resistant S. aureus
About: MRSA is S. aureus that has become resistant to certain antibiotics called beta-lactams, including methicillin (Patients in healthcare settings frequently get severe or potentially life-threatening infections, and people can also get MRSA in their community)
Severe infections per year: 80,461
Deaths per year: 11,285 

 

Drug-resistant Streptococcus pneumoniae

     
Bacteria
Also known as
S. pneumonia, pneumococcus
About: S. pneumoniae causes pneumococcal disease, which can range from ear and sinus infections to pneumonia and bloodstream infections 
Drug-resistant infections per year: 1.2 million 
Hospitalizations per year: >19,000 
Deaths per year: 7,000 

 

Drug-resistant Tuberculosis

     
Bacteria
Also known as
TB, multidrug-resistant TB (MDR TB), or extensively drug-resistant TB (XDR TB), Mycobacterium tuberculosis (M. tuberculosis)
About: TB is caused by M. tuberculosis, and is among the most common infectious diseases and a frequent cause of death worldwide 
Drug-resistant cases in 2011: 1,042 

 

CONCERNING THREATS

Vancomycin-resistant Staphylococcus aureus

     
Bacteria
Also known as
VRSA, resistant staph (short for Staphylococcus), resistant S. aureus
About: VRSA is S. aureus that has become resistant to the antibiotic vancomycin, the antibiotic most frequently used to treat serious S. aureus infections 
Cases 2002-2013: 13 in 4 states 

 

Erythromycin-resistant Group A Streptococcus

     
Bacteria
Also known as
resistant group A strep, GAS 
About: Group A strep can cause many different infections that range from minor illnesses to very serious and deadly diseases, including strep throat, scarlet fever, and others 
Drug-resistant infections per year: 1,300 
Deaths per year:
160 

 

Clindamycin-resistant Group B Streptococcus

     
Bacteria
Also known as
resistant group B strep, GBS
About: Group B strep can cause severe illness in people of all ages 
Drug-resistant infections per year: 7,600 
Deaths per year: 440 


Explaining threats to your patients
Urgent Threat: Carbapenem-Resistant Enterobacteriaceae (CRE)
What is it? It is a family of bacteria normally found in the gut. However, many types of CRE are resistant to all antibiotics, including carbapenem, which is usually the last resort. E. coli is an example. 
How does one get it? Healthy people usually do not get this type of infection. Most cases are in people who are in the hospital or a medical care facility, like a nursing home. The bacteria can be hard to remove from medical tools that are placed into the body, such as catheters, breathing tubes, or viewing scopes, even after cleaning. That is what happened in California after doctors unknowingly used contaminated endoscopes on patients.
Why is it a concern? They can cause life-threatening blood infections. No effective treatments exist. Some research states that up to 50% of patients who are sick from CRE die because of it, according to the CDC.

Urgent Threat: Neisseria gonorrhoeae
What is it? This strain of bacteria causes gonorrhea, a sexually transmitted disease (STD).
How does one get it? Anyone who has sex can get this infection. It commonly spreads during oral, anal, or vaginal contact. If one is pregnant, this infection can be passed to the baby during childbirth.
Why is it a concern? Every year, hundreds of thousands of people get gonorrhea. Some people do not have symptoms. That means it can spread without the carrier knowing. It used to be treatable with antibiotics. But the bacteria are becoming more resistant to current drugs. Untreated, gonorrhea can lead to infertility in men and women. It also increases the risk of HIV and other STDs. Rarely, it can cause life-threatening infections of the blood.

Urgent Threat: Clostridium difficile (C. diff)
What is it? It is a type of bacteria that can live in the intestines. Usually, it does no harm. But some things can cause it to overgrow, triggering serious problems.
How does one get it? Most people who get a C. diff infection are getting medical care. The biggest risk factor is taking antibiotics. While antibiotics may cure the bacteria that are making one sick, the drugs can also knock out the healthy bacteria in your digestive tract. Then C. diff takes over.
Why is it a concern? A C. diff infection can cause life-threatening diarrhea. About 14,000 people a year die from it, mostly older adults. In severe cases, one may need surgery to remove part of the infected intestine.
Particles of the bacteria, called spores, can be left behind in bathrooms, on linens, or on clothing. They can be passed from person to person. In the past, doctors used antibiotics called fluoroquinolones to treat C. diff. But these drugs do not always work. From 2000-2007, deaths spiked 400% when a new drug-resistant strain of C. diff appeared.

Serious Threat: Multidrug-Resistant Acinetobacter 

What is it? It is a bacteria found in soil and water, which can also live on your skin for days. It does not always make one sick. A superbug strain that doctors worry about is Acinetobacter baumannii.
How does one get it? People outside the hospital usually do not get sick from this germ. It is most often seen in people who are already ill and in the hospital for another reason. Having a breathing tube raises one’s risk.
Why is it a concern? Doctors call this a "significant" hospital germ. It can develop antibiotic resistance more rapidly than many other bacteria. It can cause serious illness and can infect the sickest patients. These bacteria cause dangerous lung, brain, and urinary tract infections, among others. About 12,000 people get this infection in hospitals every year. Most are resistant to multiple antibiotics. This bacterium is considered a "survivor" because it forms a protective shield against antibiotics. It is tough to treat because it can easily spread between people.

Serious Threat: MRSA
What is it? MRSA stands for methicillin-resistant Staphylococcus aureus. It is a type of bacteria that cannot be treated with penicillin. Many healthy people have staph on their skin and in their nose and it does not make them sick. But one can spread it to others.
How does one get it? This infection most often happens to people in the hospital, often after surgery. It can infect a wound and spread to surrounding tissues and the blood. However, new strains have emerged outside medical settings. There have been recent concerns about MRSA outbreaks among athletes, including athletes in schools. The bacteria can spread easily with skin-to-skin contact. The risk is higher if you have an open cut.
Why is it a concern? MRSA can cause life-threatening lung and blood infections. Rates of life-threatening MRSA have been declining thanks to improvements in medical procedures.

The critical need for new antibiotics
There are not enough antibiotics in development globally to meet current and anticipated patient needs. Only 42 antibiotics are in clinical development. Any of these can fail to receive FDA approval. Products can fail to receive approval for many reasons, including a lack of effectiveness or safety concerns. Historical data show that, generally, only 1 in 5 infectious disease drugs that enter phase 1 trials will receive FDA approval [Hay, 2014]. 

Possibilities in the pipeline
Antibiotic resistance is the focus of some promising research: 
Researchers from Boston University and Harvard revealed that adding low levels of silver – an ancient antibacterial agent – to some antibiotics, such as vancomycin, ampicillin, ofloxacin, and gentamicin, made them more effective. The silver-coated drugs even worked on bacteria that were previously antibiotic resistant, such as E. coli [Morones-Ramirez, 2013].
Scientists in the United Kingdom have isolated viruses that eat bacteria, called bacteriophages, to destroy Clostridium difficile—a pathogen that causes life-threatening diarrhea and kills thousands every year—without harming beneficial bacteria in the gut [Nale, 2015].
A new antimicrobial-resistance gene, VCC-1, a beta-lactamase gene, has been discovered in benign close relatives of virulent Vibrio  cholerae, which causes cholera. Now, a team of Canadian researchers has found a way to block the VCC-1 enzyme, which disables that resistance gene [Mangat, 2019].
Researchers at Washington University School of Medicine in St. Louis have identified a key step in the transmission of antibiotic resistance from one Acinetobacter bacterium to another, an insight that sheds light on how antibiotic resistance spreads through a hospital or community [Di Venanzio, 2019]. The findings open up a new strategy to safeguard our ability to treat bacterial infections with antibiotics. The research indicates that the effectiveness of current antibiotics may be somewhat preserved by curtailing the spread of antibiotic-resistance genes.

Prevention and control
Antibiotic resistance is accelerated by the misuse and overuse of antibiotics, as well as poor infection prevention and control. Steps can be taken at all levels of society to reduce the impact and limit the spread of resistance.

Individuals
To prevent and control the spread of antibiotic resistance, individuals can:
Only use antibiotics when prescribed by a certified healthcare professional.
Never demand antibiotics if your healthcare provider says you do not need them
Always follow your healthcare provider’s advice when using antibiotics.
Never share or use leftover antibiotics.
Prevent infections by regularly washing hands, preparing food hygienically, avoiding close contact with sick people, practicing safer sex, and keeping vaccinations up to date.
Prepare food hygienically, following the WHO Five Keys to Safer Food (keep clean, separate raw and cooked, cook thoroughly, keep food at safe temperatures, use safe water and raw materials) and choose foods that have been produced without the use of antibiotics for growth promotion or disease prevention in healthy animals.

Healthcare professionals
To prevent and control the spread of antibiotic resistance, healthcare professionals can:
Prevent infections by ensuring your hands, instruments, and the countertops are clean.
Only prescribe and dispense antibiotics when they are needed, according to current guidelines.
Report antibiotic-resistant infections to surveillance teams.
Talk to your patients about how to take antibiotics correctly, antibiotic resistance and the dangers of misuse.
Talk to your patients about preventing infections (for example, vaccination, hand washing, safer sex, and covering nose and mouth when sneezing).

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com 

References

Barnett ML, Linder JA. Antibiotic prescribing for adults with acute bronchitis in the United States, 1996-2010. JAMA. 2014;  311:2020-2. “B”

Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. “A”

CDC. Antibiotic resistance threats in the United States, 2013. Available at: http://www.cdc.gov/drugresistance/threat-report-2013. 

CDC. Antibiotic/Antimicrobial Resistance; 2018. Available at: https://www.cdc.gov/drugresistance/index.html 

CDC. Outpatient antibiotic prescriptions—United States, 2015. Accessed at: https://www.cdc.gov/antibiotic-use/community/pdfs/Annual-report-2015.pdf 

Di Venanzio G, Moon KH, Weber BS, et al. Multidrug-resistant plasmids repress chromosomally encoded T6SS to enable their dissemination. Proc Natl Acad Sci U S A. 2019;116:1378-83.

Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51.

Hicks LA, Bartoces MG, Roberts RM, et al. US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin Infect Dis. 2015;60:1308-16.
JAMA Intern Med. 2014;174:138-40.  “A”

Mangat CS , Vadlamani G, Holicek V, et al. Molecular basis for the potent inhibition of the emerging carbapenemase VCC-1 by avibactam. Antimicrob Agents Chemother 2019; DOI: 10.1128/AAC.02112-18

Morones-Ramirez JR, Winkler JA, Spina CS, Collins JJ. Silver enhances antibiotic activity against gram-negative bacteria. Sci Transl Med. 2013;9;5:190ra81.

Nale JY, Spencer J, Hargreaves KR, et al. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2015;60:968-81. 

Primary Care Workforce Facts and Stats: Overview. Agency for Healthcare Research and Quality. Rockville, MD: U.S. Department of Health & Human Services, 2012.

Sanchez GV, Hersh AL, Shapiro DJ, Cawley JF, Hicks LA. Outpatient antibiotic prescribing among United States nurse practitioners and physician assistants. Open Forum Infect Dis. 2016;3:ofw168.

Shapiro DJ, Hicks LA, Pavia AT, Hersh AL. Antibiotic prescribing for adults in ambulatory care in the USA, 2007–09. J Antimicrob Chem 2014; 69:234–40. 

 


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