Antimicrobials and Resistance Quiz

Antimicrobial Therapy - History

• Quinine used for malaria in the 1600s
• Emetine used for amebiasis (Entamoeba histolytica) in the 1600s
• Arsphenamines used for syphilis between 1900 and 1910
• A red dye discovered in 1935 with antibacterial properties; sulfonamides were broadly active.
• Initial marketing in the US did not go well
• A chemical analogue of antifreeze
• Penicillin discovered in 1929 by Alexander Fleming (Scottish)
• Nobel Prize for Penicillin in 1945
• Penicillin was knighted in 1944
• Penicillin produced by the fungus Penicillium chrysogenum
• In 1941, penicillin was tested on humans with life-threatening Staphlylococcus aureus infections; treatment was initially effective.
• Supply of penicillin ran out before the infection could be controlled

Antimicrobial Drugs - History and Development

• Alexander Fleming discovered penicillin while working with Staphylococcus.
• He noticed no Staph colonies grew near a mold contaminant.
• The colonies appeared to be melting.
• The mold was identified as Penicillium.
• It produced a bactericidal substance effective against a wide range of microbes.
• In 1943, Selman Waksman (Nobel prize winner) isolated streptomycin from a soil bacterium (Streptomyces griseus).

Antimicrobial Drugs

• Chemicals used to treat microbial infections
• Before antimicrobials, many people died from common illnesses.
• Now many illnesses are easily treated with antimicrobials
• Antimicrobial drugs are now becoming less useful
• Different types of antimicrobial drugs include antibacterial, antifungal, antiprotozoan, and antihelminthic.

Terms Related to Antimicrobial Medications

• Acquired resistance: Resistance that develops through mutation or acquisition of new genes.
• Antibacterial drug: An antimicrobial drug specifically used to treat diseases caused by bacteria.
• Antibiotic: A compound naturally produced by certain molds and bacteria that inhibits the growth of or kills other microorganisms.
• Antimicrobial drug/antimicrobial: A chemical that inhibits the growth of or kills microorganisms, encompassing antibiotics and chemically synthesized drugs.
• Antiviral drug: A drug that interferes with viral replication, all chemically synthesized, none are antibiotics.
• Bactericidal drug: An antimicrobial drug that kills bacteria.
• Bacteriostatic drug: An antimicrobial drug that inhibits bacterial growth.
• Broad-spectrum antimicrobial: An antimicrobial effective against a wide range of microorganisms (Gram-positive and Gram-negative).
• Chemotherapeutic agent: A chemical used to treat a disease.
• Intrinsic resistance: Resistance due to an inherent characteristic of the microorganism.
• Narrow-spectrum antimicrobial: An antimicrobial effective against a limited range of microorganisms
• R plasmid: A plasmid that encodes resistance to one or more antimicrobial drugs.
• Therapeutic index: The ratio of the lowest dose of a drug that is toxic to the patient, divided by the dose typically used for therapy. Indicates whether a drug is less or more toxic to the patient.

Features of Antimicrobial Drugs

• Most modern antibiotics originate from soil microorganisms.
• Steps for commercial antibiotic production.

1. Select a specific strain of mold.
2. Grow the mold in a nutrient solution.
3. Separate and purify the antibiotic from the mold.
4. Alter the chemical structure of the antibiotic to make it more stable.

• Selective toxicity - antibiotics harm microorganisms more than human hosts.
• Usually achieved by interfering with biological structures or biochemical processes common in bacteria but not in humans.
• Drug toxicity is measured by the therapeutic index, which is the ratio of the lowest toxicity dose to the dose used for therapy.
• A higher therapeutic index results in a less toxic drug
• Antimicrobial action - drugs may kill or inhibit microbial growth.
  • Inhibit = bacteriostatic
  • Kill = bacteriocidal
  • Bacteriostatic drugs rely on host immunity to eliminate the pathogen.
  • Bacteriocidal drugs are helpful when host immunity cannot control the pathogen.

Resistance to Antimicrobials

• Some microorganisms are inherently resistant to the effects of a particular drug.

• Other microorganisms that were previously sensitive to an antimicrobial can develop resistance through genetic mutations or acquiring new genes.

• Mechanisms of Resistance:

  • Drug inactivating enzymes - some organisms produce enzymes that chemically alter or modify a drug, making it inactive.
  • Alteration of target molecule - minor structural changes in the target molecule of the drug can prevent binding. Example: penicillinase breaks down the beta-lactam ring, making penicillin ineffective.

• Acquisition of resistance can occur by spontaneous mutation of existing genes (vertical evolution) or via transfer of new genes (horizontal transfer)

• Drug resistance limits use of all known antimicrobials, leading to more resistant bacteria.

Resistance - Staphylococcus Aureus

• A common cause of nosocomial infections.
• Increasingly resistant to penicillin over the past 50 years.
• Development of penicillinase genes.
• Many strains are resistant to Methicillin (effective against penicillinase resistant organisms)
• MRSA is a methicillin-resistant Staphylococcus aureus.

Resistance - Streptococcus pneumoniae

• Has remained sensitive to penicillin.
• Some strains have acquired resistance, possibly due to modification in genes coding for penicillin-binding proteins.
• Changes may be due to the acquisition of chromosomal DNA from other strains of Streptococcus ( via DNA-mediated transformation).

Factors Contributing to the Spread of Antibiotic Resistance

• Transmission of resistant organisms between patients in hospitals or healthcare settings
• Use of antibiotics in animals raised for commercial food
• Incorrect antibiotic prescriptions
  • Antibiotics given for conditions unlikely to be bacterial.
  • Antibiotics given for self-limiting conditions.
  • Narrow spectrum antibiotics instead of broad spectrum ones, when possible
  • Using unnecessary high doses or prolonged treatment periods.
  • Incorrect dosing or treatment duration (non-compliance).

Slowing the Emergence and Spread of Antimicrobial Resistance

• Responsibilities of Providers: identify the microbe, prescribe the appropriate antimicrobial, educate patients.
• Responsibilities of Patients: follow prescribed instructions.
• Educate the Public: understand the appropriateness and limitations of antibiotics; antibiotics are not effective against viruses.
• Global Impacts: organisms can quickly travel to different countries, and in some places, are available without prescription. Antibiotics fed to animals select for drug resistant organisms.

Current Major Antibiotic Resistance Problems: Community Infections

• Respiratory Tract: Penicillin resistance in pneumococci increasing.
• Gastrointestinal: Quinolone resistance in Campylobacter.
• Sexually transmitted: Penicillin and quinolone resistance in gonococci.
• Urinary tract: Beta-lactam resistance in E. coli.
• MRSA and MDR-TB.
• Tropical: Multi-drug resistance in Salmonella typhi, Shigella spp, malaria

So, The Criteria of the Ideal Antibiotic

• Selectively toxic to the microbe, but non-toxic to the host.
• Soluble in body tissue (blood-brain barrier).
• Remains in the body long enough to be effective, resisting excretion and breakdown.
• Shelf life.
• Does not lead to resistance.
• Cost is not excessive.
• Hypoallergenic.
• Microbiocidal, rather than microbiostatic (kills rather than inhibits).
• Doesn't suppress normal flora (does not trigger antibiotic-associated colitis with Clostridium difficile and/or Candida albicans).

Mechanisms of Action of Antibacterial Drugs

• Inhibit cell wall synthesis (e.g., penicillins).
• Inhibit protein synthesis (e.g., tetracyclines).
• Inhibit nucleic acid synthesis (e.g., sulfonamides, quinolones).

Cellular Targets of Antimicrobial Drugs

• Describes specific cellular targets for various antimicrobial drugs.

Mechanisms of Antibiotics

• Cell Wall Inhibitors: Inhibit cell wall synthesis (e.g., penicillins, cephalosporins, vancomycin).
• Protein Synthesis Inhibitors: Prevent protein synthesis in bacteria (e.g., aminoglycosides, tetracyclines, macrolides).
• Inhibit Nucleic Acid Synthesis: Inhibit nucleic acid synthesis (e.g., quinolones, rifampin).

Cell Wall Inhibitors

• Bacteria cell walls are made from peptidoglycan
• Antimicrobials that interfere with cell wall do not interfere with eukaryotic cells
• These drugs have a very high therapeutic index, meaning they are less toxic to humans

Protein Synthesis Inhibitors

• Most interfere with bacteria ribosomes
• Inhibit protein synthesis.
• Compounds which inhibit protein synthesis include aminoglycosides (e.g., streptomycin), tetracyclines, macrolides, chloramphenicol, lincosamides and oxazolidinones.

Nucleic Acid Synthesis Inhibitors

• DNA/RNA polymerase inhibitors, quinolones, sulfonamides, and other similar compounds.

Determining Susceptibility of Bacteria to Antimicrobial Drug - Conventional Disc Diffusion

• Kirby-Bauer disc diffusion method is commonly used to qualitatively determine susceptibility of a bacterial strain to specific antibiotic.
• Standard concentration of the bacterial strain is spread uniformly across a plate.
• Discs containing specific concentrations of antibiotics are placed on the plates.
• The plates are incubated and observed for zones of inhibition around the discs.

Determining Susceptibility of Bacteria to Antimicrobial Drug - Minimum Inhibitory Concentration (MIC)

• MIC is the smallest quantity of antibiotic required to inhibit the growth of a bacterial organism.
• Determined by measuring how bacteria grow in broth containing various concentrations of test drugs
• The lowest concentration of an antibiotic that stops bacterial growth is the MIC.

Susceptibility Determination

• Provides examples of specific susceptibility data.
• Includes a table which shows the MIC results for several antimicrobials.

Antibiotic Choice

• Factors besides susceptibility and resistance include: infection location (e.g., lipid-soluble vs. water-soluble drugs) and excretion properties (e.g., drug excreted by kidneys reaching higher bladder levels than serum levels).
• Gram-positive vs gram-negative organisms considerations.

Remember

• Selective toxicity
• Spectrum of activity
• Antimicrobial action
• Adverse effects
• Resistance

Antimicrobial Classes

• Lists various classes of antimicrobial drugs, e.g., sulfonamides, penicillins, cephalosporins, tetracyclines, macrolides, glycopeptides, aminoglycosides, fluoroquinolones, nitroimidazoles, and other drugs.

Sulfonamides

• First group of antibiotics.
• Bacteriostatic effect by inhibiting folic acid synthesis.
• Broad spectrum.

Penicillins

• Part of a large group of chemically related antibiotics.
• Derived from fungus or mold.
• Inhibits the synthesis of the bacterial cell wall, most effective on newly forming and actively growing cell walls.

Cephalosporins

• Chemically and pharmacologically related to penicillins.
• Action: prevents bacterial cell wall synthesis, but binds to different proteins.
• All are bactericidal.
• Include several generations
  • First: good gram-positive coverage
  • Second: good gram-positive coverage; some gram-negative coverage
  • Third: less gram-positive coverage, more gram-negative coverage
  • Fourth: good gram-negative coverage, pseudomonas
  • Fifth: MRSA
• Has no activity against LAME; Listeria, atypicals (including mycoplasma & chlamydia), MRSA (except 5th generation), enterococci.

Tetracyclines

• Action: inhibits protein synthesis in bacterial cells; bacteriostatic.
• Broad spectrum (gram+ and gram-).
• Effective against several types of bacteria, including protozoa, Mycoplasma, Rickettsia, Chlamydia, syphilis, and Lyme disease infections.
• Tetracyclines (TCNs) bind to calcium in growing bones and teeth and can discolor teeth.
• Should be avoided in children below 8 years old.

Macrolides and Ketolides

• Structural analogues of erythromycin.
• Include erythromycin, azithromycin, clarithromycin.
• Bacteriostatic; inhibit protein synthesis in bacterial cells.
• Very effective against organisms that typically cause CAP (community-acquired pneumonia), including atypical infections like mycoplasma and chlamydia.
• Can be used as an alternative in patients who are sensitive to penicillin.
• Treat both Gram+ (some Gram -) bacteria.

Ketolides

• Only ketolide on market - telithromycin.
• Can be used for respiratory infections, those resistant to macrolides.
• Initial safety concerns were ignored, fraudulent research indicated safety; later significant liver injury and hepatotoxicity has occurred.

Vancomycin - Glycopeptides

• Bactericidal
• Poorly absorbed orally.
• Inhibits peptidoglycan formation.
• Active against most Gram+ organisms.
• IV administration used in severe infections (e.g. septicemia, or endocarditis).
• Oral vancomycin administered commonly for Clostridium difficile infections.
• Inhibits cell wall synthesis.
• Other glycopeptides include oritavancin and dalabavancin

Aminoglycosides

• Effective against many Gram- and some Gram+ organisms.
• Bactericidal, inhibiting cell wall protein synthesis.
• Narrow therapeutic index - potentially very toxic
• VIIIth cranial nerve (ototoxicity) and kidney damage are significant adverse side effects.

Fluoroquinolones

• Bactericidal, altering DNA.
• Effective against Gram- organisms and some Gram+ organisms.
• Well-absorbed orally and intravenously.
• Include levofloxacin, ofloxacin, ciprofloxacin, moxifloxacin, gemifloxacin.
• Used to treat many infections, such as lower respiratory tract infections, bone and joint infections, infectious diarrhea, and urinary tract infections.
• Significant drug-drug interactions, including increased effects of theophylline, warfarin, propranolol, and antacids.
• Prolongs QT intervals; use with steroids increases the risk of tendonitis and rupture, especially in older adults.

5-Nitroimidazoles

• Anti-anaerobic agents.
• Wide-spectrum and bactericidal.
• Metronidazole - useful against anaerobic bacteria and protozoan infections.
• Tinidazole - longer duration of action than metronidazole.
• Inhibits DNA synthesis and/or damages DNA.

Other- Rifampin

• Inhibits DNA-dependent RNA synthesis.
• Active against Gram+ bacteria, some Gram- bacteria, and MRSA.
• Effective against Mycobacterium tuberculosis; often given in combination with other drugs for synergistic effect and to reduce resistance.
• Side effects include headache, nausea and vomiting, and fever; body fluids turn orange.

Other - Nitrofurantoin

• Structurally similar to quinolones.
• Used only to treat and prevent UTIs.
• Serum concentrations are very low; not suitable for complex UTIs and sepsis.
• Renal excretion, contraindicated in renal insufficiency.

Principles of Antibiotic Therapy

• Empiric therapy: Best guess therapy, broad-spectrum, multiple drugs when the infection isn't well defined.
• Directed therapy: A narrow-spectrum, single drug approach when the infection is well-defined. Directed therapy relies on evidence for optimal treatment.

Why So Much Empiric Therapy

• Need for rapid therapy in life-threatening infections with limited time for cultures or definitive diagnosis.
• Difficult to perform cultures for some infections (e.g., pneumonia, sinusitis, cellulitis.)
• Potential provider bias that patients with serious illness need more antibiotics.
• Patients respond to prior, empirically chosen therapies and providers often continue on the same drug.

Therapy for Outpatients

• Define the infection (anatomically, microbiologically, pathophysiologically.)
• Obtain cultures before starting antibiotics.
• Narrow-spectrum antibiotics are often effective for many illnesses with good supporting evidence.
• Medications commonly used in outpatient settings include amoxicillin, penicillin, cephalosporin, trimethoprim/sulfamethoxazole or nitrofurantoin.

Tenet 1: Treat Bacterial Infection, not Colonization

• Many patients are colonized with bacteria (often asymptomatic).
• Treat ONLY confirmed infections to avoid unnecessary use of antibiotics.

Tenet 2: Treat Patient, Not the X-ray

• It's critical to evaluate symptoms over just X-rays.
• Confirm the symptoms indicate an infection.
• Non-infectious issues could be present, such as atelectasis, malignancy, hemorrhage, or pulmonary edema.

Community-Acquired Pneumonia (CAP)

• Not all patients with chest x-rays showing pneumonia actually have an infection.
• Do not treat if no evidence of systemic inflammatory response.

Tenet 3: Do not Treat Viral Infections with Antibiotics

• Antibiotics are ineffective against viruses; treating viral infections with antibiotics provides no benefit.

Tenet 4: Limit Duration of Antibiotic Therapy to the Appropriate Length

Specific treatment durations for infections like community-acquired pneumonia, cystitis, pyelonephritis, intra-abdominal infections, and cellulitis. - Appropriate duration is based on clinical response and not simply on an arbitrary time frame.

Other Tenets of Antibiotic Stewardship

• Re-evaluate, de-escalate, and stop therapy based on diagnosis and microbiologic results.
• Do not give two antibiotics with overlapping activity.
• Use rapid diagnostics.
• Solicit expert advice.
• Strategies to prevent infections.

Sensitivity

• Negative test rules out the issue
• SNOut

Specificity

• Positive test rules in the issue
• SPin