Bacterial resistance to antimicrobials: From the Golden Age to the Bronze Age of antibiotic use

It used to be that physicians could select almost any one of several antibiotics to use empirically in treating an infection in a patient-even in a critically ill patient-and stand a great chance of having selected an effective therapy. But that Golden Age of antibiotic use is over. The bugs are winning.

Bacteria have existed for billions of years, and they have evolved excellent defense mechanisms against each other. These mechanisms are employed by bacteria against antibiotics, even against our new semisynthetic and custom-designed antibiotics. So antibiotic pressure applied to the environment helps select for bacteria with genes that provide antibiotic resistance by one of several mechanisms. Furthermore, these resistance mechanisms are highly mobile among and between bacterial species.

We have entered something akin to the Bronze Age of antibiotic use. Now it is not uncommon, particularly in intensive care units, for patients to have infections caused by bacteria that are resistant to all or nearly all the safe and efficacious antibiotics that physicians are comfortable using.

Widespread administration of antibiotics in people or in animals can result in the selection of resistant bacterial populations. Even as antibiotic innovations have occurred, it does not take long-years at most-for resistant bacteria to appear in the targeted population. And these resistance patterns can spread rapidly around the world. However, controlled antibiotic use-sensible, restrained antibiotic use-can result, even in the short term, in reduced antibiotic resistance. For example, antibiotics that we once used widely and commonly, then used less frequently because we started using newer antibiotics, can show resurgence in efficacy. That is, at least, until they are used widely again. So it is an ongoing battle between the bugs and us.

BACTERIAL TRANSMISSION BETWEEN ANIMALS AND PEOPLE

Many organisms derived from animals, particularly food animals, can infect people directly. The key reservoir animals are chickens, turkeys, cattle, and pigs. In addition, aquaculture is an expanding field, as more of the fish that people consume are cultivated in pens close to shore. Salmonella and Campylobacter species in poultry and Escherichia coli in beef are problems. Enterococcus species are omnipresent as well. These four bacteria can be transmitted from animals to people in many ways, such as from:

• Direct contact with animals on the farm. Farmers tend to carry more resistant bacteria that are derived from animals than nonfarmers carry.1

• Food-animal processing plants, which are a source of bacterial contamination for the workers

• Wastewater runoff from farms, processing plants, and aquaculture

• Fecal waste disposal-both animal waste and, if the people have become infected, human waste

• Ingestion by people of poultry, beef, pork, and fish food products.

This bacterial transmission can result either directly in disease because the pathogens are invasive or, if the bacteria bear antibiotic resistance, their resistance elements can be transmitted to the endogenous human bacterial flora.2

ANTIBIOTIC USE IN ANIMALS AND PEOPLE

Obviously the most appropriate use of antibiotics in animals is targeted, therapeutic use-just as we hope that most antibiotic use in people is targeted, well-selected, as narrow as possible, and discontinued as soon as possible. However, in the animal husbandry industry, antimicrobials are widely used for growth promotion. And in aquaculture, prophylactic antibiotic therapy is common as well. Keep in mind that more tonnage of antimicrobials is used in food animal husbandry than is used in the medical industry.

With companion animals, antibiotics are typically used therapeutically-one infected animal is treated, and treated specifically. With food animals, it is difficult to treat an individual in a flock or herd, so generally the antibiotic is used in widespread distribution for a finite period.

ANTIBIOTIC RESISTANCE MECHANISMS

Bacteria develop resistance through many genetic mechanisms. Many of these are mobile elements-plasmids, transposons, integrons, genomic islands-and the genes can move between these different mobile elements. Point mutations can also occur (a common problem with tuberculosis).

Antibiotic resistance in gram-positive bacteria

Two gram-positive organisms, Staphylococcus and Enterococcus species, are widely problematic resistant bacteria.

Staphylococcus aureus. Bacterial penicillin-binding proteins function as transpeptidases that create the cross-linkage that generates the stable latticework outside the cell membrane. Beta-lactam antibiotics act on bacterial penicillin-binding proteins to interrupt the peptidoglycan cross-linking and activate the natural autolysis system that cleaves the cell during cell division.

Staphylococcus aureus that is resistant to beta-lactam antibiotics is called methicillin-resistant S. aureus (MRSA) because when it first appeared, methicillin was the first of the anti-staphylococcus penicillins. Even decades after it dropped from clinical use, methicillin was employed in susceptibility-testing systems used to assess susceptibility of S. aureus to beta-lactam antibiotics. Thus, MRSA should really be called beta-lactam resistant S. aureus because these bacteria are resistant to all beta-lactam antibiotics.

Staphylococcus aureus is resistant not because it cleaves the antibiotic but because it has changed its penicillin-binding protein. This protein, called PBP2A, has low affinity for beta-lactam antibiotics. It is directed by a mobile genetic element. In fact, it is suspected that this resistance mechanism was acquired from a coagulase-negative Staphylococcus species.3

Several antibiotics are available to treat MRSA infections, and the most common is vancomycin. Vancomycin is a complex molecule and has been in use for 40 years. It was not used much in the 1960s and early 1970s because MRSA was not a problem and cephalosporins and penicillins were the preferred antibiotics. Vancomycin resistance is relatively uncommon among S. aureus, but it is common among enterococci. Yet the amount of vancomycin required in a test tube to inhibit or kill S. aureus has crept upward over the last 20 years, and physicians now dose it more aggressively.

Although vancomycin's minimum inhibitory concentrations-how much drug is required to inhibit bacterial growth-are creeping upward, experience suggests that vancomycin remains an excellent drug and there is no reason, in the minds of most infectious disease specialists, to switch to one of the two newer antibiotics-linezolid or daptomycin.

Linezolid is not a new drug. People have been experimenting with oxazolidinones in the laboratory for years, but it was not until vancomycin-resistant Enterococcus species (VRE) appeared that linezolid became commercially available. Bacterial resistance emergence has been documented for linezolid,4,5 which is not surprising with a bacteriostatic antibiotic.

Daptomycin is bactericidal and works by inhibiting bacterial protein synthesis and depolarizing membranes. It should not be given to patients with pneumonia because it binds to surfactant, thus the functional effective concentration in the lungs is reduced.

Enterococcus species. Enterococci are intrinsically resistant to most classes of antimicrobials, and most commonly are susceptible to ampicillin, penicillin G, piperacillin, and vancomycin. These drugs are all bacteriostatic, so in treating enterococcal endocarditis, an aminoglycoside must be added-gentamicin being the most common.

Vancomycin resistance occurs by alteration of the peptidoglycan precursors such that they are not affected by vancomycin. And often resistance occurs to ampicillin and gentamicin as well. If a patient has a VRE infection, physicians have two choices: linezolid and daptomycin. VRE has become a bigger problem in the last 15 years, possibly due to the use of oral vancomycin to treat Clostridium difficile colitis in people.

Antibiotic resistance in gram-negative bacteria

Multidrug resistance is becoming widespread and broadly based in gram-negative organisms. Among the enterobacteriaceae, multidrug-resistant Escherichia coli and Klebsiella pneumoniae exist. Even Proteus mirabilis, which used to be a pansusceptible organism, now may exhibit broad resistance.

These gram-negative organisms are often resistant to all third-generation cephalosporins-some may remain susceptible to cefepime-and they are often resistant to fluoroquinolones and aminoglycosides. These bacteria tend to have complex genetic elements that carry multidrug resistance. The treatment of choice in people with these infections is with a carbapenem such as imipenem. Cefepime is a fourth-generation cephalosporin, and often it will be effective against multidrug-resistant members of the enterobacteriaceae-Klebsiella, Proteus, and Providencia species and E. coli.

Gram-negative organisms become resistant to antibiotics in many ways. These organisms can develop enzymes against beta-lactams and other antibiotics, change their target sites as MRSA and VRE do, change their porins (protein-lined channels through which molecules including antibiotics move) to diminish antibiotic concentration, and change their efflux pumps to increase antibiotic removal.

Enzymes. Carbapenems are potent and broadly active beta-lactam antibiotics. But now several carbapenamases are being described,6 particularly among Enterobacter and Klebsiella species and among Acinetobacter and Pseudomonas species-two of the most common ICU-associated superinfecting organisms. So we now have resistance to imipenem, our ultimate top-shelf antibiotic-its efficacy is diminishing.

The aminoglycosides have been wonderful drugs. Gentamicin became available in 1969, and it is still relatively effective in the general population-except for treating Pseudomonas aeruginosa infections and in the ICU, where infections with multiresistant nonfermenter and multiresistant enteric organisms are prevalent. On the other hand, resistance to gentamicin and tobramycin is becoming common. Bacteria have the most difficulty generating resistance to amikacin because its side chains block the access of inactivating enzymes, and it is generally the last of the aminoglycosides to fail.

Target sites. Aminoglycoside-resistant enterococci exhibit ribosomal resistance. Their ribosomes simply ignore aminoglycosides.

Fluoroquinolone resistance occurs when bacteria change their DNA gyrase, which is a fairly simple one- or two-step mutation.

Porins. Porin changes are most important in nonfermenter organisms. Pseudomonas species can change its porins and become carbapenem resistant, but it may retain susceptibility to other beta-lactams and aminoglycosides. Acinetobacter species is intrinsically resistant to many antibiotics and was resistant even when these antibiotics were introduced. Acinetobacter species is always hard to treat, probably in part because its porin channels do not allow passage of many molecules.

Efflux pumps. Efflux-pump resistance mechanisms are most important in Pseudomonas aeruginosa and Stenotrophomonas maltophilia (formerly Pseudomonas maltophilia), and, again, these often are broad-based antibiotic resistances.

MANAGING THE RESISTANCE PROBLEM

Probably 60% of antibiotic use in the United States occurs in animal husbandry; such use involves broad-based administration to land animals and fish, not cats and dogs. International organizations such as the World Health Organization and the World Organisation for Animal Health have developed criteria for so-called critical antimicrobials, whose use should be restricted in the animal husbandry field. The criteria are antimicrobials that are the sole or an important therapy for infections in people, treatment for diseases acquired from animals (the four species mentioned above in the section "Bacterial transmission between animals and people"), and treatment for infections with organisms that are known to have rapid acquisition of resistance. Unfortunately, for the food-animal industry, the list of antibiotics is almost all-inclusive.

So this is a challenging era. Bacterial resistance to antibiotics is an increasing problem. As an infectious disease consultant, I am seeing more bacterial infections that are barely treatable or are untreatable. Just as when I was an intern telling patients, "You have a bug we cannot treat very well or at all, but we are going to do the best we can,"-a talk I have not had in about 40 years-I am now having that talk with patients when I am on clinical service performing inpatient consultations.

The Golden Age of antibiotic use is past, and we have got to do something. I think part of that something is to be more careful with the use of antibiotics both in people and in animals.

Speaker: Richard Glew, MD

Infectious Diseases and Immunology Medicine

University of Massachusetts Medical School

Worcester, MA 01655

Dr. Glew presented this information at the physician and veterinarian collaborative seminar “Pets, People and Pathogens: Emerging Diseases” on November 18, 2009 in Providence, R.I. Coastal Medical (Providence, R.I.) and the Companion Animal Parasite Council jointly sponsored this seminar. This presentation summary was written by Theresa Entriken, DVM, Advanstar Communications.

REFERENCES

1. Aubry-Damon H, Grenet K, Sall-Ndiaye P, et al. Antimicrobial resistance in commensal flora of pig farmers. Emerg Infect Dis 2004;10:873-879.

2. Oppegaard H, Steinum TM, Wasteson Y. Horizontal transfer of a multi-drug resistance plasmid between coliform bacteria of human and bovine origin in a farm environment. Appl Environ Microbiol 2001;67:3732-3734.

3. Leclercq R. Epidemiological and resistance issues in multi-drug resistant staphylococci and enterococci. Clin Microbiol Infect 2009;15:224-231.

4. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001;358:207-208.

5. Kainer MA, et al. Response to emerging infection leading to outbreak of linezolid-resistant enterococci. Emerg Infect Dis 2007;13:1024-1030.

6. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009;9:228-236.