Are there limits to drug resistance?

Are there limits to drug resistance?

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It's well-known that indiscriminate use of a drug leads to resistance. My question is what the limits on resistance are. It seems obvious that there must be limits: for example I can hardly imagine a tiger evolving "resistance to bullets", and similarly I can hardly imagine a microorganism evolving resistance to heat treatment @ 1000 degrees celsius (surely its proteins must long denature before then).

Are there methods of killing microbes that cannot be resisted? If so, can we make similar cannot-be-resisted drugs?

There are physical limits to the existance of life forms, wether temperature, pressure, osmolarity, etc. But these are usually physicochemical fields acting over a wide spatial structure. In the case of drugs, they are physically localized molecular entities. They are usually very tiny, even compared to the smallest microbes. Even though the genome of any microbe is finite and they could not, in theory, recognize the infinitely many drugs we can synthesize (assuming the simple case they need one gene per drug resisted), they can just evolve very generic mechanisms like preventing these molecules to get into the microbe, pumping them out of the cell, or other generic mechanism; with the same overall effect: preventing the drug from acting in the desired way.

The question you ask is very interesting, and it is the focus of some recent efforts and discussions among academics. Here you can find a recent article discussing the possibility of "evolution-proof" drugs. As you can see, the subject is not trivial.



Drug Resistance

Drug Resistance in Tumors

Drug resistance is the main cause of the failure of malignant tumor chemotherapy. In

50% cases, drug resistance exists even before chemotherapy is initiated. A variety of anticancer drug resistance mechanisms have been reported, including increased protein expression resulting in drug removal, mutation to drug-binding sites, restoration of tumor protein production, and preexistence of genetically heterogeneous tumor cell populations. For example, secondary mutations restoring the functionality of BRCA1/2 proteins have been identified as a key mechanism for conferring resistance in tumors. This restoration is often a by-product of cisplatin or poly(ADP-ribose) polymerase (PARP) inhibitor treatment treatment with either drug can not only cause resistance to its own use but also cause resistance to the other treatment method.

Mapping drug-resistant tuberculosis in a single patient

The study team took advantage of nine serial bacterial isolates collected from a single patient, from the time of first diagnosis of drug-susceptible TB through to the development of XDR-TB. The infection ultimately resolved following the addition of linezolid to the treatment regimen - linezolid is known to be a moderately effective treatment for drug-resistant TB when other options have failed [2]. Illumina sequencing was applied to the isolates, which were collected over a period of 42 months, achieving a high depth of coverage. By relaxing the stringency of filters applied to detect single-nucleotide polymorphisms (SNPs), the authors observed unexpected levels of heterogeneity within individual samples. It is worth mentioning that DNA was not extracted from single colonies - instead `loopfuls’ of bacterial cells were harvested for DNA. This approach allowed the group to detect SNPs present at a frequency of approximately 25% at sites with a minimum read-depth of 50. Of the 35 SNPs identified in this way, 20 were transient and 15 eventually became fixed. Twelve of the observed mutations were associated with drug resistance, and phenotypic resistance was observed at the same time that genotypic resistance emerged.

Although the patient was infected with only one Mtb strain, multiple resistance alleles were observed for antitubercular drugs throughout the course of infection, with the exception of rifampicin and kanamycin [2]. The levels of micro-heterogeneity reported are consistent with those of previous studies [3], [4].

These observations suggest that, at any given time, there might be significant Mtb diversity within a single patient. High levels of diversity could affect the accurate interpretation of WGS data that are used to infer transmission. Current WGS of Mtb requires subculture of the bacilli from patient samples to ensure that sufficient DNA is available for analysis, and bacterial subpopulations that are not culturable are not captured during downstream sequencing [5]. Moreover, one cannot be certain that a single sputum sample represents all regions of the lung indeed significant intra-lesional heterogeneity has been observed in humans [6]. Therefore, intra-patient variability could be even higher than reported by the aforementioned studies and might not be detectable by current WGS approaches.

How does HIVDR affect treatment options?

The aim of ART is to limit HIV replication in the body, and different drug classes target different parts of this process – the HIV lifecycle – to stop HIV replicating and infecting all cells.

A viral mutation can occur at any stage of this process. For example, it may present along the reverse transcriptase enzyme, meaning the efficacy of certain drugs or drug classes can be undermined – in this example, nucleoside/nucleotide reverse transcriptase inhibitors (NRTI/NtRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) drug classes.

The impact on treatment options for the patient depends on which viral mutations they have. For some drugs, such as the NRTI lamivudine and all NNRTIs, just one mutation – notably the M184V or K103N mutations – can result in high-level drug resistance.9 This is clinically relevant, as NNRTIs including efavirenz and nevirapine have for many years made up the backbone of first-line treatment in low-resource settings.10

As such, the global burden of HIVDR is largely the result of NNRTI resistance. For other NRTIs and most protease inhibitors (PI), high-level drug resistance requires multiple mutations to occur simultaneously. Newer ARVs and drug classes, such as the integrase inhibitor, dolutegravir, have much higher genetic barriers to resistance.

Resistance to integrase inhibitors is very rare and has only been reported in treatment-experienced individuals. No clinical trial has so far reported resistance to bictegravir or dolutegravir when these drugs are used as part of someone’s initial triple therapy.11

Dolutegravir had previously been expensive and out of reach in low-resource contexts, but this is no longer true. Generic fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) is now available at prices comparable to current regimes in most low- and middle-income countries.12

New 2018 interim WHO guidelines now also call for countries to move to TLD as the preferred first-line regime for all people starting treatment.13

There are hundreds of viral mutations associated with antiretroviral resistance. The Stanford HIV Drug Resistance Database keeps an up-to-date record that helps clinicians and programmers to interpret results from drug resistance tests.

Testing for HIV drug resistance

There are three main tests used to detect HIVDR in an individual – these are genotypic, phenotypic and viral load tests. Individual-level HIVDR testing is not widely available in low- and middle-income countries.

Genotypic and phenotypic tests are expensive, require significant laboratory infrastructure, take several weeks to process, and produce results which are complex to interpret. They are therefore not generally recommended by WHO for use for first- or second-line treatment selection in LMICs – except in countries where pre-treatment drug resistance has exceeded 10%. Yet still, only a handful of countries in sub-Saharan Africa have WHO-accredited HIV genotyping laboratories.14

But these tests are standard in high-income countries for people just starting ART, and for those experiencing virological failure (when ART fails to suppress viral load), as a means to select the optimum combination of drugs for treatment success.

Genotypic resistance testing

Genotype tests look at the specific genetic sequence within the viral DNA to assess whether there has been any change in structure compared to a ‘wild type’ virus (a viral sample with no genetic mutations or drug resistance). This type of test will detect specific mutations within the genetic structure of the virus.

In high-income countries, all treatment-naïve people receive this test before starting treatment to give clinicians a better idea of what treatment regime to use.15 In lower income countries, where national levels of HIVDR are greater than 10%, and non-NNRTI regimens are not first-line, then genotypic testing can be used to guide ART selection.16

Phenotypic resistance testing

Phenotype tests look at the impact of mutations on resistance in practice. They test the dose of antiretroviral drugs needed in order for viral replication to stop (testing each drug separately).17 These tests are generally conducted on treatment-experienced patients who have failed a drug regime in high-income countries.

Viral load testing

Viral load testing is another tool which the WHO supports to monitor viral load and identify potential drug resistance, particularly where genotypic and phenotypic testing are not routinely available.18

Viral load tests look at the amount of virus in the body and are a major indicator of HIV treatment success or failure. Regular viral load testing can detect failing treatment early and before too many viral mutations occur, meaning changes in therapy can be minimal and less costly. However, access to even this type of treatment monitoring tool is inadequate in low- and middle-income countries.

Our Approach

We take a problem-driven, multi-disciplinary and multi-technique approach to decipher the molecular underpinnings and mechanisms leading to drug resistance. We strive to apply a synergistic combination of various experimental and computational methods, and establish key collaborations with experts in other fields. We heavily rely on:

Structural biology –having solved hundreds of crystal structures
Parallel molecular dynamics simulations
Structure based drug design
Organic synthesis
Enzyme inhibition and activity assays
Deep sequencing data

Our unique integrative approach also aims to combine data from complementary techniques to effectively elucidate interdependency of molecular recognition.

This is an official Page of the University of Massachusetts Medical School

Schiffer Lab &bull 364 Plantation Street LRB828, Worcester, Massachusetts 01605

Are there limits to drug resistance? - Biology

CRISPR/Cas9 and other site-specific gene-editing techniques enable rapid and efficient generation of knockouts, targeted integrants, and allelic replacements of genes associated with malaria pathogenesis and drug resistance.

Regulatable genetic systems that quantitatively and temporally modulate expression levels facilitate mechanistic studies, especially those involving essential genes, and help distinguish on-target from off-target effects.

New or refined whole-genome-based strategies, such as functional genomic screens and genetic crosses in humanized mice, now accompany traditional techniques, including genome-wide association studies (GWAS) and gene editing to identify and characterize genetic determinants of resistance.

Recent progress in genomics and molecular genetics has empowered novel approaches to study gene functions in disease-causing pathogens. In the human malaria parasite Plasmodium falciparum, the application of genome-based analyses, site-directed genome editing, and genetic systems that allow for temporal and quantitative regulation of gene and protein expression have been invaluable in defining the genetic basis of antimalarial resistance and elucidating candidate targets to accelerate drug discovery efforts. Using examples from recent studies, we review applications of some of these approaches in advancing our understanding of Plasmodium biology and illustrate their contributions and limitations in characterizing parasite genomic loci associated with antimalarial drug responses.

Are there limits to drug resistance? - Biology


An antibiotic is an agent that either kills or inhibits the growth of a microorganism. The term antibiotic was first used in 1942 by Selman Waksman and his collaborators in journal articles to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. This definition excluded substances that kill bacteria but that are not produced by microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic antibacterial compounds such as the sulfonamides. Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 atomic mass units.

With advances in medicinal chemistry, most modern antibacterial are semi synthetic modifications of various natural compounds. These include, for example, the beta-lactam antibiotics, which include the penicillin (produced by fungi in the genus Penicillium), the cephalosporin, and the carbapenems. Compounds that are still isolated from living organisms are the amino glycosides, whereas other antibacterial&mdashfor example, the sulfonamides, the quinolones, and the oxazolidinones&mdashare produced solely by chemical synthesis.

In accordance with this, many antibacterial compounds are classified on the basis of chemical/biosynthetic origin into natural, semi synthetic, and synthetic. Another classification system is based on biological activity in this classification, antibacterial are divided into two broad groups according to their biological effect on microorganisms: Bactericidal agents kill bacteria, and bacteriostatic agents slow down or stall bacterial growth.

What is Antibiotic Resistance?

Antibiotic resistance is a form of drug resistance whereby some (or, less commonly, all) sub-populations of a microorganism, usually a bacterial species, are able to survive after exposure to one or more antibiotics pathogens resistant to multiple antibiotics are considered multidrug resistant(MDR) or, more colloquially, superbugs.

Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as one of the pre-eminent public health concerns of the 21st century, in particular as it pertains to pathogenic organisms (the term is especially relevant to organisms that cause disease in humans). A World Health Organization report released April 30, 2014 states, "this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance&ndashwhen bacteria change so antibiotics no longer work in people who need them to treat infections&ndashis now a major threat to public health."

In the simplest cases, drug-resistant organisms may have acquired resistance to first-line antibiotics, thereby necessitating the use of second-line agents. Typically, a first-line agent is selected on the basis of several factors including safety, availability, and cost a second-line agent is usually broader in spectrum, has a less favorable risk-benefit profile, and is more expensive or, in dire circumstances, may be locally unavailable. In the case of some MDR pathogens, resistance to second- and even third-line antibiotics is, thus, sequentially acquired, a case quintessentially illustrated by Staphylococcus aureus in some nosocomial settings. Some pathogens, such as Pseudomonas aeruginosa, also possess a high level of intrinsic resistance.

It may take the form of a spontaneous or induced genetic mutation, or the acquisition of resistance genes from other bacterial species by horizontal gene transfer via conjugation, transduction, or transformation. Many antibiotic resistance genes reside on transmissible plasmids, facilitating their transfer. Exposure to an antibiotic naturally selects for the survival of the organisms with the genes for resistance. In this way, a gene for antibiotic resistance may readily spread through an ecosystem of bacteria. Antibiotic-resistance plasmids frequently contain genes conferring resistance to several different antibiotics. This is not the case for Mycobacterium tuberculosis, the bacteria that causes Tuberculosis, since evidence is lacking for whether these bacteria have plasmids. Also M. tuberculosis lack the opportunity to interact with other bacteria in order to share plasmids.

Genes for resistance to antibiotics, like the antibiotics themselves, are ancient. However, the increasing prevalence of antibiotic-resistant bacterial infections seen in clinical practice stems from antibiotic use both within human medicine and veterinary medicine. Any use of antibiotics can increase selective pressure in a population of bacteria to allow the resistant bacteria to thrive and the susceptible bacteria to die off. As resistance towards antibiotics becomes more common, a greater need for alternative treatments arises. However, despite a push for new antibiotic therapies, there has been a continued decline in the number of newly approved drugs. Antibiotic resistance therefore poses a significant problem.

The growing prevalence and incidence of infections due to MDR pathogens is epitomized by the increasing number of familiar acronyms used to describe the causative agent and sometimes the infection of these, MRSA is probably the most well-known, but others including VISA (vancomycin-intermediate S. aureus), VRSA (vancomycin-resistant S. aureus), ESBL (Extended spectrum beta-lactamase), VRE (Vancomycin-resistant Enterococcus) and MRAB (Multidrug-resistant A. baumannii) are prominent examples. Nosocomial infections overwhelmingly dominate cases where MDR pathogens are implicated, but multidrug-resistant infections are also becoming increasingly common in the community.

Although there were low levels of preexisting antibiotic-resistant bacteria before the widespread use of antibiotics, evolutionary pressure from their use has played a role in the development of multidrug-resistant varieties and the spread of resistance between bacterial species. In medicine, the major problem of the emergence of resistant bacteria is due to misuse and overuse of antibiotics. In some countries, antibiotics are sold over the counter without a prescription, which also leads to the creation of resistant strains. Other practices contributing to resistance include antibiotic use in livestock feed to promote faster growth.] Household use of antibacterial in soaps and other products, although not clearly contributing to resistance, is also discouraged (as not being effective at infection control). Unsound practices in the pharmaceutical manufacturing industry can also contribute towards the likelihood of creating antibiotic-resistant strains. The procedures and clinical practice during the period of drug treatment are frequently flawed &mdash usually no steps are taken to isolate the patient to prevent re-infection or infection by a new pathogen, negating the goal of complete destruction by the end of the course(see Healthcare-associated infections and Infection control).

Certain antibiotic classes are highly associated with colonization with "superbugs" compared to other antibiotic classes. A superbug, also called multiresistant, is a bacterium that carries several resistance genes. The risk for colonization increases if there is a lack of susceptibility (resistance) of the superbugs to the antibiotic used and high tissue penetration, as well as broad-spectrum activity against "good bacteria". In the case of MRSA, increased rates of MRSA infections are seen with glycopeptides, cephalosporins, and especially quinolones.In the case of colonization with Clostridium difficile, the high-risk antibiotics include cephalosporins and in particular quinolones and clindamycin.

Of antibiotics used in the United States in 1997, half were used in humans and half in animals in 2013, 80% were used in animals.

Need of this Experiment

Antibiotic resistance is becoming more and more common. Antibiotics and antimicrobial agents are drugs or chemicals that are used to kill or hinder the growth of bacteria, viruses, and other microbes. Due to the prevalent use of antibiotics, resistant strains of bacteria are becoming much more difficult to treat. These "super bugs" represent a threat to public health since they are resistant to most commonly used antibiotics. Current antibiotics work by disrupting so-called cell viability processes. Disruption of cell membrane assembly or DNA translation are common modes of operation for current generation antibiotics. Bacteria are adapting to these antibiotics making them ineffective means for treating these types of infection. For example, Staphylococcus aureus have developed a single DNA mutation that alters the organism's cell wall. This gives them the ability to withstand antibiotic cell disruption processes. Antibiotic resistant Streptococcus pneumoniae produce a protein called MurM, which counteracts the effects of antibiotics by helping to rebuild the bacterial cell wall.

Fighting Antibiotic Resistance

Researchers are attempting to develop new types of antibiotics that will be effective against resistant strains. These new antibiotics would target the bacteria's ability to become virulent and infect the host cell. Researchers at Brandeis University have discovered that bacteria have protein "switches" that when activated, turn "ordinary" bacteria into pathogenic organisms. These switches are unique in bacteria and are not present in humans. Since the switch is a short-lived protein, elucidating its structure and function was particularly difficult. Using nuclear magnetic resonance (NMR) spectroscopy, the researchers were able to regenerate the protein for one and one half days. By extending the time frame that the protein was in its "active state," the researchers were able to map out its structure. The discovery of these "switches" has provided a new target for the development of antibiotics which focus on disrupting the activation of the protein switches.

Monash University researchers have demonstrated that bacteria contain a protein complex called Translocation and Assembly Module (TAM). TAM is responsible for exporting disease causing molecules from the inside of the bacterial cell to the outer cell membrane surface. TAM has been discovered in several antibiotic resistant bacteria. The development of new drugs to target the protein would inhibit infection without killing the bacteria. The researchers contend that keeping the bacteria alive, but harmless, would prevent the development of antibiotic resistance to the new drugs.

Researchers from the NYU School of Medicine are seeking to combat antibiotic resistance by making resistant bacteria more vulnerable to current antibiotics. They discovered that bacteria produce hydrogen sulfide as a means to counter the effects of antibiotics. Antibiotics cause bacteria to undergo oxidative stress, which has toxic effects on the microbes. The study revealed that bacteria produce hydrogen sulfide as a way to protect themselves against oxidative stress and antibiotics. The development of new drugs to target bacterial gas defenses could lead to the reversal of antibiotic resistance in pathogens such asStaphylococcus and E.coli.

These studies indicate how highly adaptable bacteria are in relation to the application of antimicrobial treatments. Antibiotic-resistant bacteria have become a problem not only in hospitals, but in the food industry as well. Drug-resistant microbes in medical facilities lead to patient infections that are more costly and difficult to treat. Resistant bacteria in turkey and other meat products have caused serious public health safety issues. Some bacteria may develop resistance to a single antibiotic agent or even multiple antibiotic agents. Some have even become so resistant that they are immune to all current antibiotics. Understanding how bacteria gain this resistance is key to the development of improved methods for treating antibiotic resistance.


Increased awareness of the cardiovascular toxic effects of chemotherapy has led to the emergence of cardio-oncology (or onco-cardiology), which focuses on screening, monitoring and treatment of patients with cardiovascular dysfunctions resulting from chemotherapy. Anthracyclines, such as doxorubicin, and HER2 inhibitors, such as trastuzumab, both have cardiotoxic effects. The biological rationale, mechanisms of action and cardiotoxicity profiles of these two classes of drugs, however, are completely different, suggesting that cardiotoxic effects can occur in a range of different ways. Advances in genomics and proteomics have implicated several genomic variants and biological pathways that can influence the susceptibility to cardiotoxicity from these, and other drugs. Established pathways include multidrug resistance proteins, energy utilization pathways, oxidative stress, cytoskeletal regulation and apoptosis. Gene-expression profiles that have revealed perturbed pathways have vastly increased our knowledge of the complex processes involved in crosstalk between tumours and cardiac function. Utilization of mathematical and computational modelling can complement pharmacogenomics and improve individual patient outcomes. Such endeavours should enable identification of variations in cardiotoxicity, particularly in those patients who are at risk of not recovering, even with the institution of cardioprotective therapy. The application of systems biology holds substantial potential to advance our understanding of chemotherapy-induced cardiotoxicity.

Natural (Biological) Causes

Selective Pressure

In the presence of an antimicrobial, microbes are either killed or, if they carry resistance genes, survive. These survivors will replicate, and their progeny will quickly become the dominant type throughout the microbial population.

Diagram showing the difference between non-resistant bacteria and drug resistant bacteria. Non-resistant bacteria multiply, and upon drug treatment, the bacteria die. Drug resistant bacteria multiply as well, but upon drug treatment, the bacteria continue to spread.


Most microbes reproduce by dividing every few hours, allowing them to evolve rapidly and adapt quickly to new environmental conditions. During replication, mutations arise and some of these mutations may help an individual microbe survive exposure to an antimicrobial.

Diagram showing that when bacteria mulitply some will mutate. Some of those mutations can make the bacteria resistance to drug treatment. In the presence of the drugs, only the resistant bacteria survive and then multiply and thrive.

Gene Transfer

Microbes also may get genes from each other, including genes that make the microbe drug resistant. Bacteria multiply by the billions. Bacteria that have drug-resistant DNA may transfer a copy of these genes to other bacteria. Non-resistant bacteria receive the new DNA and become resistant to drugs. In the presence of drugs, only drug-resistant bacteria survive. The drug-resistant bacteria multiply and thrive.

Diagram showing how gene transfer facilitates the spread of drug resistance. Bacteria multiply by the billions. Bacteria that have drug resistant DNA may transfer a copy of these genes to other bacteria. Non-resistant bacteria recieve the new DNA and become resistant to drugs. In the presence of drugs, only drug-resistant bacteria survive. The drug resistant bacteria multiply and thrive.

Societal Pressures

The use of antimicrobials, even when used appropriately, creates a selective pressure for resistant organisms. However, there are additional societal pressures that act to accelerate the increase of antimicrobial resistance.

Inappropriate Use

Selection of resistant microorganisms is exacerbated by inappropriate use of antimicrobials. Sometimes healthcare providers will prescribe antimicrobials inappropriately, wishing to placate an insistent patient who has a viral infection or an as-yet undiagnosed condition.

Inadequate Diagnostics

More often, healthcare providers must use incomplete or imperfect information to diagnose an infection and thus prescribe an antimicrobial just-in-case or prescribe a broad-spectrum antimicrobial when a specific antibiotic might be better. These situations contribute to selective pressure and accelerate antimicrobial resistance.

Hospital Use

Critically ill patients are more susceptible to infections and, thus, often require the aid of antimicrobials. However, the heavier use of antimicrobials in these patients can worsen the problem by selecting for antimicrobial-resistant microorganisms. The extensive use of antimicrobials and close contact among sick patients creates a fertile environment for the spread of antimicrobial-resistant germs.

Agricultural Use

Scientists also believe that the practice of adding antibiotics to agricultural feed promotes drug resistance. More than half of the antibiotics produced in the United States are used for agricultural purposes. 1, 2 However, there is still much debate about whether drug-resistant microbes in animals pose a significant public health burden.

Multidrug-Resistant Mycobacterium tuberculosis

The emergence of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) is also of significant global concern. MDR-TB strains are resistant to both rifampin and isoniazid, the drug combination typically prescribed for treatment of tuberculosis. XDR-TB strains are additionally resistant to any fluoroquinolone and at least one of three other drugs (amikacin, kanamycin, or capreomycin) used as a second line of treatment, leaving these patients very few treatment options. Both types of pathogens are particularly problematic in immunocompromised persons, including those suffering from HIV infection. The development of resistance in these strains often results from the incorrect use of antimicrobials for tuberculosis treatment, selecting for resistance.

Think about It

Factory Farming and Drug Resistance

Although animal husbandry has long been a major part of agriculture in America, the rise of concentrated animal feeding operations (CAFOs) since the 1950s has brought about some new environmental issues, including the contamination of water and air with biological waste, and ethical issues regarding animal rights also are associated with growing animals in this way. Additionally, the increase in CAFOs involves the extensive use of antimicrobial drugs in raising livestock. Antimicrobials are used to prevent the development of infectious disease in the close quarters of CAFOs however, the majority of antimicrobials used in factory farming are for the promotion of growth—in other words, to grow larger animals.

The mechanism underlying this enhanced growth remains unclear. These antibiotics may not necessarily be the same as those used clinically for humans, but they are structurally related to drugs used for humans. As a result, use of antimicrobial drugs in animals can select for antimicrobial resistance, with these resistant bacteria becoming cross-resistant to drugs typically used in humans. For example, tylosin use in animals appears to select for bacteria also cross-resistant to other macrolides, including erythromycin, commonly used in humans.

Concentrations of the drug-resistant bacterial strains generated by CAFOs become increased in water and soil surrounding these farms. If not directly pathogenic in humans, these resistant bacteria may serve as a reservoir of mobile genetic elements that can then pass resistance genes to human pathogens. Fortunately, the cooking process typically inactivates any antimicrobials remaining in meat, so humans typically are not directly ingesting these drugs. Nevertheless, many people are calling for more judicious use of these drugs, perhaps charging farmers user fees to reduce indiscriminate use. In fact, in 2012, the FDA published guidelines for farmers who voluntarily phase out the use of antimicrobial drugs except under veterinary supervision and when necessary to ensure animal health. Although following the guidelines is voluntary at this time, the FDA does recommend what it calls “judicious” use of antimicrobial drugs in food-producing animals in an effort to decrease antimicrobial resistance.

Clinical Focus: Nakry, Part 3

Unfortunately, Nakry’s urinary tract infection did not resolve with ciprofloxacin treatment. Laboratory testing showed that her infection was caused by a strain of Klebsiella pneumoniae with significant antimicrobial resistance. The resistance profile of this K. pneumoniae included resistance to the carbapenem class of antibacterials, a group of β-lactams that is typically reserved for the treatment of highly resistant bacteria. K. pneumoniae is an opportunistic, capsulated, gram-negative rod that may be a member of the normal microbiota of the intestinal tract, but may also cause a number of diseases, including pneumonia and UTIs.

Specific laboratory tests looking for carbapenemase production were performed on Nakry’s samples and came back positive. Based upon this result, in combination with her health history, production of a carbapenemase known as the New Delhi Metallo-β-lactamase (NDM) was suspected. Although the origin of the NDM carbapenemase is not completely known, many patients infected with NDM-containing strains have travel histories involving hospitalizations in India or surrounding countries.

We’ll return to Nakry’s example in later pages.

Key Concepts and Summary

  • Antimicrobial resistance is on the rise and is the result of selection of drug-resistant strains in clinical environments, the overuse and misuse of antibacterials, the use of subtherapeutic doses of antibacterial drugs, and poor patient compliance with antibacterial drug therapies.
  • Drug resistance genes are often carried on plasmids or in transposons that can undergo vertical transfer easily and between microbes through horizontal gene transfer.
  • Common modes of antimicrobial drug resistance include drug modification or inactivation, prevention of cellular uptake or efflux, target modification, target overproduction or enzymatic bypass, and target mimicry.
  • Problematic microbial strains showing extensive antimicrobial resistance are emerging many of these strains can reside as members of the normal microbiota in individuals but also can cause opportunistic infection. The transmission of many of these highly resistant microbial strains often occurs in clinical settings, but can also be community-acquired.

Multiple Choice

Which of the following resistance mechanisms describes the function of β-lactamase?

Which of the following resistance mechanisms is commonly effective against a wide range of antimicrobials in multiple classes?

  1. efflux pump
  2. target mimicry
  3. target modification
  4. target overproduction

Which of the following resistance mechanisms is the most nonspecific to a particular class of antimicrobials?

Which of the following types of drug-resistant bacteria do not typically persist in individuals as a member of their intestinal microbiota?

Fill in the Blank

Staphylococcus aureus, including MRSA strains, may commonly be carried as a normal member of the ________ microbiota in some people.


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  2. Mezijin

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  3. Delbert

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