Antimicrobial Stewardship: A competency-based approach

Transcription: MODULE D {timestamp}

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[Slide #1] Antimicrobial resistance for clinicians.

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[Slide #4] Antimicrobial resistance or AMR affects all nations in all areas of healthcare.

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[Slide #5] AMR is the ability of microorganisms to evade effects of drugs that could otherwise inhibit their
growth or kill them. The emergence of AMR is inevitable and is not a new phenomenon.

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[Slide #6] Resistance is a consequence of the microbial genetic variability that is essential for microorganism
survival in an ever-changing environment but this genetic mutability also allows for the development of
multi drug-resistant human pathogens.

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[Slide #7] As microorganisms develop resistance, the number of effective antimicrobials to treat the
infections they cause decreases. Infections due to resistant microorganisms are challenging to manage.

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[Slide #8] As is outlined in the 2015 WHO Global Action Plan on AMR, infections due to resistant
microorganisms can lead to longer illnesses, increased mortality, prolonged hospital stays and increased
costs. The economic impact of AMR is also staggering due to the loss of productivity of infected individuals
and the increased cost of managing them with second- or third-, or even fourth-line drugs that may be less
effective and more toxic.

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[Slide #9] The emergence of a drug-resistant organism in one nation or one unit of a hospital jeopardizes all
patients - current and future. Many drug-resistant organisms become endemic to a particular unit of a
hospital, demonstrating the ability of these organisms to persist in the environment and infect future
patients.
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[Slide #10] Microbes develop resistance readily and quickly via a variety of mechanisms. In this module, we
will review the basic concepts of the development of antimicrobial resistance and microbes using one
common multi drug-resistant pathogen, Neisseria gonorrhea, as an example.

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[Slide #11] Frontline clinicians must then translate these key concepts into a powerful message to their
patient. Each inappropriate use of an antimicrobial can have dire consequences.

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[Slide #13] Genetic variability resides within every population of bacteria. Some bacteria in the population
carry genes that make them resistant to certain antimicrobials.

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[Slide #14] Upon exposure to an antimicrobial, resistance emerges via selective pressure meaning that
susceptible bacteria are inhibited or killed while pre-existing clones resistant to the antimicrobial survive
and replicate, passing their resistance gene on to their progeny.

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[Slide #15] This vertical transmission of resistance allows for the emergence of drug-resistant clones as the
dominant bacterial cells within the population.

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[Slide #16] Microorganisms can also acquire segments of foreign DNA from other microorganisms of the
same or different species via horizontal transmission. This foreign DNA can come packaged in different
forms, including plasmids, bacteriophages and other mobile genetic elements. Horizontal transmission of
resistance genes is an efficient mechanism that is responsible for the emergence for example of
carbapenemase-producing Enterobacteriaceae. Microorganisms can acquire multiple genes encoding
different mechanisms of resistance and become multi drug-resistant, such as in the case of multi drug-
resistant Pseudomonas aeruginosa and multi drug-resistant Acinetobacter.

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[Slide #17] There are 4 major mechanisms by which microorganisms acquire resistance. These broad
categories are:

 decreased entry of the drug into the bacterial cell or decreased uptake,
  alteration or interference with the antimicrobials’ target molecule or target modification,
 inactivation of the antimicrobial,
 increased export of the drug from the bacterial cell or increased efflux.

Many organisms accumulate several mechanisms of resistance over time. Neisseria gonorrhea is one such
example.

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[Slide #18] The WHO estimated that in 2012 there were 78 million new cases of Neisseria gonorrhea
infections worldwide in people aged 19 to 49. Gonorrhea is an ancient disease but one that remains a major
global public health challenge, in large part because of the ability of this organism to develop multi-drug
resistance. Over the course of the antibiotic era, this organism has acquired nearly every known mechanism
of antimicrobial resistance and resistant strains have spread globally. Moreover, most of these acquisitions
have not adversely affected the organism’s biological fitness or, in other words, its ability to survive and
reproduce. In some strains antimicrobial resistance has actually enhanced the microorganisms’ fitness
leading to the persistence and eventual dominance of drug-resistant strains. Strains of extensively drug-
resistant Neisseria gonorrhoeae have been reported. For these reasons, gonorrheal infections must be
managed in concordance with the best available evidence as reflected in guidelines.

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[Slide #19] In 1943 penicillin was first used to treat gonococcal infections. However, resistance was noticed
almost immediately. Over the subsequent decades, the minimal inhibitory concentration or MIC of penicillin
against Gonococcus steadily increased and higher doses, sometimes augmented with probenecid, were
required to achieve cure.

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[Slide #20 - 22] The primary mechanism of this resistance was the accumulation of chromosomal mutations
that modified the target protein of penicillin and other beta-lactam antimicrobials - a transpeptidase called
penicillin binding protein 2 encoded by the penA gene. Penicillin resistance was potentiated by several
other chromosomal mutations at different sites, including mutations that led to lower concentrations of
penicillin within the cell via decreased uptake and increased efflux or export of the drug from the cell via
overexpression of efflux pumps.

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[Slide #23] In 1976, gonococcal strains with beta-lactamase producing plasmids emerged that conferred
high-level penicillin resistance. Beta-lactamases hydrolyze the beta-lactam ring, a core structural
component of all beta-lactam antimicrobials, inactivating the antimicrobial. Gonococcal strains are thought
to have acquired these plasmids from Haemophilus parainfluenzae via horizontal transmission. These beta-
lactamase producing strains spread globally rapidly. Ultimately however, the emergence of chromosomally
mediated resistance led to the removal of penicillin as the first-line drug for the treatment of gonococcal
infections.
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[Slide #24] Tetracyclines were commonly used to treat gonococcal infections and penicillin allergic patients.
These antimicrobials inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit. The
mechanisms of tetracycline resistance are similar to that of penicillin. Soon after tetracyclines were
introduced, chromosomal mutations emerged that conferred target modification, decreased uptake and
increased efflux of these drugs. Gonococcal strains also acquired high-level plasmid mediated tetracycline
resistance via the tetM gene which, by blocking the target site, prevented tetracycline binding to bacterial
ribosomes. In 1986, tetracyclines were no longer recommended to treat gonococcal infections.

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[Slide #25] Fluoroquinolones and azithromycin have followed a similar fate as penicillin and tetracycline
with gonococcal strains rapidly developing resistance conferring target modification and increase efflux of
the drug. These drugs were no longer recommended as sole agents to treat gonococcal disease in 2007.

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[Slide #26] Now let's switch gears somewhat and discuss the management of gonococcal disease with the
case.

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[Slide #27] Imagine you are evaluating a 28-year-old male who presents to your clinic with a one-week
history of dysuria and urethral discharge. He reports learning today that a recent sexual partner was
diagnosed with gonococcal cervicitis. You suspect gonococcal urethritis. He denies any history of allergies to
antimicrobials.

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[Slide #28] There are several key steps in the management of this patient that are critical in preventing and
limiting the emergence of multi drug-resistant gonococcal strains.

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[Slide #29] The first step is accurate diagnosis and your diagnostic workup will depend upon your available
resources.

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[Slide #30] In many places, Gram stains - with or without culture - performed on urethral swabs from
symptomatic men like this patient are the first-line diagnostic tests. In other places, nucleic acid
amplification test from first stream urine samples are recommended. Importantly, Gram stains performed
without culture or nucleic acid amplification tests do not provide antimicrobial susceptibility data. Only
organisms grown in culture can be tested for antimicrobial susceptibility. It's also important to screen this
patient for other sexually transmitted infections such as HIV and Chlamydia trachomatis.

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[Slide #31] If local susceptibility data is not available international guidelines are available to assist you in
making this decision.

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[Slide #32] The 2016 WHO guidelines recommend that in the absence of local resistance data, clinicians
prescribe dual therapy with either of the following single-dose combinations: ceftriaxone plus azithromycin
or cefixime plus azithromycin.

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[Slide #33] Given the high rate of asymptomatic gonococcal infection in both women and men, it is
paramount that your patients' sexual partners are tested and treated to limit transmission. Patient
education is critical in reaching these at-risk individuals. In addition, safe sex practices should be discussed
to prevent reinfection and the consequences of delaying care should be emphasized. It's also important to
inform the patient that he must return to clinic if his symptoms persist to be evaluated for treatment failure.
Re-presenting to clinic is a critical step in the early detection and containment of drug-resistant gonococcal
strains.

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[Slide #34] In this module, we reviewed the basic concepts of antimicrobial resistance and microbes, using
one common multi drug-resistant pathogen, Gonococcus, as an example. We also highlighted tools
clinicians can use to optimize their use of antimicrobials to curb the emergence of antimicrobial resistance.

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[Slide #35 - 37] These principles include:

 Prescribing antimicrobial therapy according to guidelines,

 Paying attention to prevention to help contain the spread of drug-resistant organisms in the
community,
 Patient education is a critical element of the fight against antimicrobial resistance.

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[Slide #38] Routinely following these principles will improve the quality of care you provide to your patients
and help to ensure that antimicrobial prescribing is appropriate.