The headline that snagged my attention was this: 

‘Thirty-five Thousand Americans Die of Antibiotic-Resistant Infections Each Year”

This was based on the Centers for Disease Control’s Antibiotic Resistance Threats in the United States, 2019, which led off with the statement that more than 2.8 million antibiotic-resistant infections occur in the US every year, and more than 35,000 people die as a result. 

This was a pretty big uptick from the previous figures from the CDC, which Doc Gumshoe had reported in a piece back in March 2017.   At that time, the most recent tally for deaths was 23,000.   The number cited back then for antibiotic-resistant infections was just about 2 million.   The increases were quite a bit larger than one would expect – 40% over two years for infections, and nearly 50% for deaths.   And considering that antibiotic resistance has been getting a great deal of attention, those increases are alarming.   What’s happening, and what are we going to do about it?

Speaking for myself only, I was more troubled by the rise in the number of antibiotic-resistant infections than by the deaths, because “cause of death” is a somewhat fungible bit of data.   For example, if a person recovering from a traumatic injury develops an infection while hospitalized, and the infection turns out to be due to a pathogen that does not respond to any of the drugs used to try to control that infection, and the patient in question then sustains a heart attack and dies, what is the cause of death?   Answer, not the antibiotic-resistant infection.   It was the MI that carried him off.   Similarly, patients with congestive heart failure who are hospitalized may acquire a nosocomial (hospital-acquired) infection resulting in pneumonia that does not respond to whatever is used for treatment.   That patient’s cause of death will likely be reported as congestive heart failure.   This would suggest that the number of deaths related to antibiotic-resistant pathogens was, if anything, larger than the official report.

But the increase in antibiotic-resistant infections in genuinely scary, considering that infections rank fairly low among health-care concerns, at least in the “developed” world.   There are well-publicized and well-funded campaigns to end cancer, HIV, and any number of childhood diseases, but the assumption has been that, antibiotics having been invented, infections can be managed.   Well, not so fast.

It’s not as though resistance is a newly emergent phenomenon.   Microbes have been engaged in a battle against their enemies since those little organisms emerged from the primordial slime.   The process goes like this.   As one generation of microbes gives rise to another generation, there are tiny glitches in the transcription of the genetic material.   Some of those glitches are relatively meaningless.   Some are fatal – creatures with those glitches fail to reproduce and die out.   But some are valuable.   They encode survival characteristics.   Some of those survival characteristics are resistance to their natural enemies – other organisms that would, if they could, attack them and kill them.   The organisms that possess those beneficial glitches survive and multiply.

Precisely the same thing is happening now.   Bacteria, parasites, viruses, and fungi, as they reproduce, do not transcribe their genetic material with complete accuracy.   The offspring are not identical to the parents.   In some cases, the differences in genetic material encode characteristics that enable them to resist their enemies, which in this case may be the antibiotics that have been introduced into their environment specifically to kill them or at least to halt their spread.   The organisms that have those resistance characteristics are the ones that survive and reproduce; the antibiotics eliminate the unprotected remainder.

This process frequently takes place over time.   The patient is dosed with the drug daily, or twice daily, for periods sometimes of a month or even longer.   With each administration of the antibiotic, more of the susceptible pathogens get eliminated, leaving the resistant pathogens to reproduce.   Sometimes, the population of pathogens becomes mostly or entirely resistant to the antibiotic.

Clinicians try to address this problem in several ways.   A regimen of antibiotics may start with an extra heavy dose of the drug, with the intention of effecting a major reduction in the pathogen population right off the bat.   This is then followed by a treatment period which can last a considerable time, depending on the particular infection.   The objective is to reduce to pathogenic population to a level where it can no longer form a colony.   

A major impediment to this process is that a great many patients do not continue the full course of their antibiotic.   In many cases, a patient will feel considerably better after just a few days of treatment with the antibiotic, and say, “I feel just fine.   Why do I have to keep taking that pill?”

It also happens with considerable frequency that physicians prescribe antibiotics when there’s no reason to do so, as in the treatment of viruses.   A new study, published in the British Medical Journal, but conducted in the US, looked at data from more than 28,000 ambulatory clinic visits and found that only about 57% of antibiotic prescriptions were appropriate, that is, for the treatment of bacterial infections.

For example, when children catch colds that are nasty enough to keep them home from school, they are sometimes required to present proof that they were seen by a physician before being allowed back into the classroom.   And when their parents take them to the doctor, the parent wants a prescription for something.   The parent is thinking, “The kid has a cold!   For Lord’s sake, give her something to help her get over it, or at least prevent her from catching something worse.”   But then, after a couple of days, the kid’s cold vanishes, and her mother stops making her take her medicine.   So, even if the child was infected with one of those upper respiratory viruses that are hanging around, the antibiotic did have an effect, but what it did was kill off some of the population of susceptible bacteria that are present in all of our bodies.   It killed off the susceptible germs, but left unharmed the ones that had some kind of resistant mechanism.   Those remained, and reproduced.   

The child is now the carrier of a potentially dangerous source of infection, which she might pass on to a debilitated elderly relative or to another child whose immune system is temporarily compromised, or, in fact, to anyone at all.

What mechanisms do pathogens use to defend themselves against antibiotics?

For example, let’s look at Acinetobacter baumanii.   This little bug didn’t get a lot of attention until military personnel in Iraq and Afghanistan began to be infected with this particular pathogen, which got nicknamed “the Iraquibacter.”   A. baumanii  infected many soldiers who had been injured by explosive devices.   Their open wounds came into contact with the pathogen, which can survive for fairly long periods on exposed surfaces.   When the infected soldiers were admitted to hospitals, the pathogens spread, sometimes to other patients.   A. baumanii  has been identified as the cause of nearly 20% of cases of pneumonia in patients who require the assistance of a ventilator in some hospitals.   It happens to be related to Staph aureus, Klebsiella, and Pseudomonas aeruginosa  (a pathogen particularly linked with the development of pneumonia in intubated hospital patients).   All of these bugs are good at developing the mutations that combat antibiotics, and A. baumanii excels at that game, which is to say that it comes on board all ready and able to do battle against the antibiotics that may be deployed.

A particularly menacing characteristic of this bacterium is that is possesses not just one, but several distinct mechanisms of antibiotic resistance.   These include:

• Beta-lactamase:   By far the most common antibiotics are the cell-wall antibiotics, which, as the name implies, attack the bacterial wall.   These include all of the penicillin-related antibiotics, known as beta-lactams, including amoxicillin, ampicillin, and methicillin, but also the cephalosporins, which are the largest class of antibiotics, as well as vancomycin and daptomycin.   A. baumannii has been shown to produce at least one beta-lactamase, which is an enzyme responsible for cleaving the four-atom lactam ring typical of beta-lactam antibiotics, thereby destroying the antibiotic. 

• Biofilm formation:   A. baumanii has the ability to form a biofilm, which reduces its sensitivity to antibiotics and permits it to survive on artificial surfaces for an extended period.   Thus, it can survive in the hospital environment unless aggressive cleaning is carried out.

• Efflux pumps:   Some pathogens develop the capacity to pump the antibiotic out of the cell, so that the antibiotic does not attain the concentration necessary to kill the pathogen.   A. baumanii possesses not one but two efflux pumps.   Efflux pumping is the means through which pathogens inactivate several antibiotics that target protein synthesis, such as the tetracyclines and the macrolides, a group of drugs including erythromycin and its relatives.   

A. baumanii was initially treated with carbapenems, but when resistance to carbapenems began to emerge, colistin was the next – and last! – drug in line.   Thus, when resistance to colistin began to emerge, shock waves went through the infectious disease community.   What was left?   The answers were not encouraging.

Before we leave the subject, let’s look at some other mechanisms of resistance.

• Inhibiting bacterial synthesis of folic acid:    The sulfonamides (“sulfa drugs”) target bacterial synthesis of folic acid, which the bacteria require to survive – except that some bacteria develop a form of resistance which entails not needing to synthesize their own folic acid, but scavenging it from other sources.   

• Attacking DNA gyrase:   The fluoroquinolones (ciprofloxacin and others) attack DNA gyrase, which twists the single DNA strands into the familiar double helix.   However, some bacteria develop mutations in their DNA gyrase, rendering them resistant to fluoroquinolones.   

The global perspective: what does the World Health Organization have to say?

Here’s what WHO said on the topic in their release about global threats to health:

“The development of antibiotics, antivirals and antimalarials are some of modern medicine’s greatest successes.   Now, time with these drugs is running out. Antimicrobial resistance – the ability of bacteria, parasites, viruses and fungi to resist these medicines – threatens to send us back to a time when we were unable to easily treat infections such as pneumonia, tuberculosis, gonorrhoea, and salmonellosis.   The inability to prevent infections could seriously compromise surgery and procedures such as chemotherapy.

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Resistance to tuberculosis drugs is a formidable obstacle to fighting a disease that causes around 10 million people to fall ill, and 1.6 million to die, every year.   In 2017, around 600,000 cases of tuberculosis were resistant to rifampicin – the most effective first-line drug – and 82% of these people had multidrug-resistant tuberculosis.

Drug resistance is driven by the overuse of antimicrobials in people, but also in animals, especially those used for food production, as well as in the environment.   WHO is working with these sectors to implement a global action plan to tackle antimicrobial resistance by increasing awareness and knowledge, reducing infection, and encouraging prudent use of antimicrobials.”

How did this situation come to be?

To return to the question immediately before us: why, with huge amounts of money being devoted to pharmaceutical research and development, has there been such a large increase in drug-resistant infections and deaths, particularly in a country with mostly adequate health care?   It cannot be merely because too many doctors are prescribing antibiotics when they are not needed, such as in viral infections.   And most likely it’s not just because little Betsy – and others like her – didn‘t finish her Z-pack.   

No, there’s a larger, and more ominous reality out there.   

Pharmaceutical companies are simply not lavishing large amounts of money, nor yet large amounts of time and energy, on the development of new antibiotics or antimicrobials.   It is not good business to do so.   As by now you are aware, bringing a new drug from the earliest research into the active molecular agent all the way through to regulatory approval and market launch is extremely expensive.   A usually cited price tag is $1.5 billion.   Billion, not million.   

Yes, a billion and a half or so is an okay amount to bet on a drug that addresses a disease form for which most existing treatments are less than adequate – for example, one of the many cancer variants which so far have not responded to existing treatment.   One would think that a new antibiotic, which successfully managed infections that don’t respond to any existing antibiotics, would be a pretty good bet.   

But that’s not how it works.   Let’s say that Company Alpha has developed and brought to market an antibiotic that effectively resolves hospital-acquired pneumonias that have not responded to any other drug in the hospital’s armamentarium.   That drug, which we will call AlphaBeta, has the capacity to save the lives of a certain number of patients that develop similar nosocomial pneumonias, and would otherwise have died in the hospital.   You could call it a “miracle drug.”

However, even though it is a “miracle drug,” chances are that it will not make a whole lot of money for Company Alpha.   The reason for that is that, chances are, AlphaBeta won’t be used much.   Most patients that develop nosocomial pneumonia will be treated successfully with existing drugs, of which there are many.   The physicians in charge of the patient’s care have several drugs at their disposal, and they will use those first.   AlphaBeta has to be kept in reserve for those cases that don’t respond to the existing drugs.   The medical establishment wants it that way.   It’s best to hold the big guns in reserve until you need them.   That way, you always have the ultimate weapon available.

Company Alpha doesn’t want it to be that way.   Having spent their billion and a half to get AlphaBeta to market, they want it to be employed so they can recover some of their money.   So they press hard to expand their indication beyond resistant nosocomial pneumonia caused by Pseudomonas aeruginosa.   They might be successful, or not.

In the meantime, something else is happening, half-way around the world.   A laboratory, let’s say in India, has copied the AlphaBeta molecule, and is selling pills based on that same molecule in India and other countries in defiance of Company Alpha’s patent.   A lawsuit is brought against the company that is selling this AlphaBeta copy, but the court decides in favor of the Indian company on the basis that giving the AlphaBeta copy to newborns in the hospital will reduce the number of respiratory fatalities.

As it happens, in India, because of the poor prevailing sanitary conditions, expectant mothers are strongly encouraged to give birth in hospital.   And hospitals routinely dose newborns with antibiotics for one or two days, to reduce the frequency of hospital-acquired infections.

In the context of extremely bad sanitary conditions, both in the streets and in hospitals, and in many countries around the world in addition to India, dosing babies with antibiotic right off the bat may be an okay idea.   But it’s an idea that’s likely to result very quickly in rising bacterial resistance against that particular antibiotic.   So if the antibiotic given to millions of newborns is AlphaBeta, it won’t be long before AlphaBeta loses its standing as the ultimate weapon.   It becomes just another antibiotic to which some bugs are resistant.  And Company Alpha stands to lose a big chunk of their billion and a half.  

The results of the reluctance of clinicians in the US and other developed nations to use AlphaBeta in all but the most demanding situations, coupled with indiscriminate overuse of the generic copy in other parts of the world, have had clearly depressing effects on drug development.   Some examples:

• FDA approvals of new antibiotics have declined by 90% since the 1990s.

• Pfizer terminated research into new antibiotics in 2011.   This doesn’t mean that Pfizer is out of the antibiotics business.   Late last year Pfizer plunked down $1.5 billion for AstraZeneca’s antibiotics portfolio, which includes a couple of advanced cephalosporins – ceftaroline fosamil, marketed as Zinforo by AZ and as Teflaro by Allergan, which treats some resistant Staph aureus infections, and another beta-lactamase inhibitor, a drug combination of avibactam and ceftazidine marketed as Avycaz.   

• Several Big Pharmas have conducted no antibiotic research at all in the 21^st century.   These include Bristol-Myers Squibb, Eli Lilly, and Sanofi.

• The London School of Economics conducted a study that concluded that a pharmaceutical company that launched a new antibiotic would suffer a net loss of about $50 million.

All of this indicates a major slowing of antibiotic research, but not quite a grinding halt.   Many pharmaceutical companies have had antibiotics in the pipeline for several years and have already invested huge sums in their development up to now, so they aren’t unwilling to throw some more money into the hopper in an effort to recoup at least some of their investment.   And several of the newly-launched antibiotics have scored sales in the two to three hundred million dollar range in their first year on the market – not enough to offset their R & D costs in one fell swoop, but a promising start.    

Some specific resistant pathogens

The Centers for Disease Control’s Antibiotic Resistance Threats in the United States, 2019 categorizes and lists 22 threats from bacteria and fungi.   The categories are: Urgent, Serious, Concerning, and Watch List.

Urgent Threats

• Acinetobacter resistant to carbapenem causes pneumonia and wound, bloodstream, and urinary tract infections. Nearly all these infections happen in patients who recently received care in a healthcare facility   This pathogen was responsible for an estimated 8,500 cases in hospitalized patients, and 700 deaths in 2017.

• Candida auris (C. auris) is an emerging multidrug-resistant yeast, classified as a fungus.   It can cause severe infections and spreads easily between hospitalized patients and nursing home residents.   It was responsible for 323 cases of resistant yeast infections in 2017.

• Clostridioides difficile (C. difficile),   This bacterium was previously named Clostridium difficile, or C. diff;  and is a member of the pseudostreptococci family; however, the renaming makes no difference at all to the severity of the threat.   C. difficile  causes life-threatening diarrhea and colitis (an inflammation of the colon), mostly in people who have had both recent medical care and antibiotics.   It is the cause of 223,900 infections per year and 12,800 deaths.   The population of C. diff in a patient can grow rapidly in patients who have been on extended courses of antibiotic treatment.   When the bacterial populations – including both pathogenic and non-pathogenic microbes – have been decimated by antibiotic treatment, the C. diff  population zooms.

• Carbapenem-resistant Enterobacteriaceae (CRE), which are also known as Nightmare Bacteria.   These pathogens are a major concern for patients in healthcare facilities. Some Enterobacteriaceae (a family of germs) are resistant to nearly all antibiotics, leaving more toxic or less effective agents as the only treatment options.   Nightmare Bacteria have infected 13,100 hospitalized patients in the US in 2017, and are considered responsible for the deaths of 1,100.

• Neisseria gonorrhoeae (N. gonorrhoeae)
  This bacterium causes gonorrhea , a sexually transmitted disease, which can result in infertility  and life-threatening ectopic pregnancy, and can increase the risk of getting and transmitting HIV.   Drug-resistant N. gonorrhoeae are considered responsible for 550,000 infections per year. 

Serious threats

• Campylobacter
  Drug-resistant Campylobacter , also called “Campy,” usually causes diarrhea (often bloody), fever, and abdominal cramps, and can spread from animals to people through contaminated food, especially raw or undercooked chicken.   This pathogen causes an estimated 448,400 infections per year, and 70 deaths.

• Candida Species
  Dozens of Candida species—a group of fungi—cause infections, ranging from mild oral and vaginal yeast infections to severe invasive infections. Many are resistant to the antifungals used to treat them.   Resistant Candida species caused an estimated 34,800 cases in hospitalized patients in the US in 2017, as well as 1,700 deaths. 

• Enterobacteriaceae-producing ESBL
  Enterobacteriaceae that produce extended-spectrum beta-lactamase (ESBL) are a concern in healthcare settings and the community. They can spread rapidly and cause or complicate infections in healthy people.   Beta-lactamases, discussed earlier, are enzymes that break down commonly used antibiotics, such as penicillins and cephalosporins, making them ineffective.    This group of pathogens caused an estimated 197,400 infections and 9,100 deaths in hospitalized patients in 2017.

• Vancomycin-resistant Enterococcus (VRE)
  Enterococci can cause serious infections for patients in healthcare settings, including bloodstream, surgical site, and urinary tract infections.   VRE caused an estimated 54,500 infections and 5,400 deaths in hospitalized patients in 2017.

• Multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa)
  P. aeruginosa infections usually occur in people with weakened immune systems, and can be particularly dangerous for hospitalized patients with chronic lung diseases.    This pathogen caused an estimated 32,600 infections in hospitalized patients, as well as 2,700 deaths. 

• Drug-resistant nontyphoidal Salmonella
  Nontyphoidal Salmonella can spread from animals to people through food, and usually causes diarrhea, fever, and abdominal cramps. Some infections spread to the blood and can have life-threatening complications.   It is thought to be the cause of 212,500 drug-resistant infections per year, and 70 deaths. 

• Drug-resistant Salmonella serotype Typhi
  Salmonella Typhi causes typhoid fever, which can be life-threatening.   Most people in the US become infected while traveling to countries where the disease is common.   Drug-resistant Salmonella Typhi causes an estimated 4,100 cases of typhoid fever in the US per year, but fewer than 5 deaths.

• Drug-resistant Shigella
  Shigella spreads in feces through direct contact or through contaminated surfaces, food, or water.   Most people with Shigella infections develop diarrhea, fever, and stomach cramps.   An estimated 77,000 cases of drug-resistant Shigellosis are seen in the US per year, and fewer than 5 deaths.

• Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA)
  S. aureus are among the most common bacteria that spread in healthcare facilities and the community.   The term “methicillin-resistant” applies to an entire group of related drugs including amoxicillin, ampicillin, and related drugs.   MRSA can cause difficult-to-treat staph infections because of this resistance   An estimated 323,700 cases of MRSA infections have required hospitalization, and MRSA infections have caused 10,600 deaths.

• Drug-resistant Streptococcus pneumoniae (S. pneumoniae)
  S. pneumoniae causes a range of infections, from ear and sinus infections to pneumonia and bloodstream infections.   Resistant strep infections affected 900,000 persons in the US in 2014 and led to 3,600 deaths.

• Drug-resistant Mycobacterium tuberculosis
  Mycobacterium tuberculosis is the cause of tuberculosis.   Two categories of this pathogen are labeled multidrug-resistant TB (MDR TB) or extensively drug-resistant TB (XDR TB).   The bacterium is among the most common infectious diseases and a frequent cause of death worldwide.   In the US in 2011, there were 847 cases if drug-resistant TB and 62 deaths. 

Concerning Threats

• Erythromycin-resistant Group A Streptococcus
  Group A Streptococcus (GAS) can cause many different infections that range from minor illnesses to serious and deadly diseases, including strep throat, pneumonia, flesh-eating infections, and sepsis.   Resistant GAS caused an estimated 5,400 infections in 2017, as well as 450 deaths. 

• Clindamycin-resistant Group B Streptococcus
  Group B Streptococcus (GBS) can cause severe illness in people of all ages.   Drug resistant GBS caused an estimated 13,000 infections in 2016, and 720 deaths. 

Watch List

• Azole-resistant Aspergillus fumigatus 
  Aspergillus is a fungus that can cause life-threatening infections in people with weakened immune systems. These infections are treated with antifungals called azoles. Azoles are also increasingly used in agriculture to prevent and treat fungal diseases in crops. Azole use in human medicine and agriculture can contribute to resistance to antifungal medicines.

• Drug-resistant Mycoplasma genitalium (M. genitalium)
  M. genitalium bacteria are sexually transmitted and can cause inflammation of the urethra in men and may cause inflammation of the cervix in women. Few antibiotics are available to treat M. genitalium infections. Resistance to azithromycin, which has been recommended for treatment, is high across the globe.

• Drug-resistant Bordetella pertussis (B. pertussis)
  Pertussis, a respiratory illness commonly known as whooping cough, is a very contagious disease caused by a type of bacteria called B. pertussis. It can cause serious and sometimes deadly complications, especially in babies.

Is there any encouraging research going on?

Just because the big pharma outfits have turned their attention to more profitable areas than merely fighting infection does not mean that the battle has been abandoned.   However, researchers are picking their engagements carefully.   It would likely be futile to lavish great efforts at developing new drugs in the beta lactams family (penicillins and cephalosporins, for example), since the crafty little microbes are pretty good at summoning up defenses against these.   So researchers are on the alert for new potential mechanisms through which to attack pathogens.

For example, researchers at Nationwide Children’s Hospital have developed a new synthetic peptide that mimics an essential component of bacterial biofilms, which protect bacteria from antibiotics.   This peptide redirects this natural adaptive immune response in bacteria in such a way as to disrupt their biofilms and render those bacteria susceptible to antibiotics.   In animal studies, employing this peptide against a resistant pathogen that had caused inner ear infections permitted antibiotic treatment to clear the pathogen.   Researchers noted that the inner ears of these animals had entirely returned to normal in eight days.   

This research is not directed at creating new antibiotics so much as at overcoming bacterial resistance to existing antibiotics.

Another group of researchers, at McMaster University in Canada, targeted methicillin-resistant Staphylococcus aureus, known as MRSA.   They screened 45,000 small molecules and hit upon one that works by lessening the ability of MRSA to tolerate an immune attack.   The antibiotic uncouples MRSA from glycopeptide resistance-associated protein (GraR).   This protein normally shields MRSA from external threats, which allows the bacterium to become resistant to front-line antibiotics.

Another approach also focuses on disrupting the external membranes of such bacteria as E. coli.   A peptide, called darobactin, binds to a protein that normally resides on the protective external membrane of gram-negative bacteria.   This action prevents the germs from forming an intact external membrane, thus causing those germs to die.   This research was carried out by an international team of scientists, from Justus Liebig University Giessen in Germany, and Northwestern University in the US.

Obviously, these lines of research are a considerable way from culminating in practical treatment alternatives that can be prescribed for us by our family doctor when we get a stubborn infection, but it’s clear that the scientists have not raised the white flag.

Doc Gumshoe’s take-away from all this is that our species is not doomed to extermination by the unrelenting spread of resistant pathogens.   Big pharma may have eyes on the Main Chance, but there appear to be plenty of worthy researchers with more lofty goals.

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If Doc Gumshoe is not back in touch with you before the culmination of the holiday season, let me wish you now the very best of the season.   Enjoy the holidays in excellent health, and may health and happiness attend you in 2020 and the years beyond!   (In the meantime, keep those comments coming – they help keep my brain awake and alert.)   Best to all, Michael Jorrin, aka Doc Gumshoe.