Antimicrobial treatment I.Tereza Kopecká

What are antimicrobials?

• Medications that kill microbes.• Antibiotics kill or inhibit the spread of bacteria.

• Antimycotics kill or inhibit the spread of fungi.

• Antivirotics inhibit the spread of viruses.

• Antiparasitic drugs kill parasites.

• We try not to kill patients at the same time.

• If you are not careful, you might kill them all. Or damage the patient.

Topical or systemic ATBs?

• Not every infection deserves systemic treatment• If superficial and mild, you may start with topical antimicrobials

• If deep or severe, start with systemic

• In high-risk patients, systemic treatment is unavoidable

• The indication for topical antimicrobials might be also colonization• Colonization is a bare presence of microbes on body surfaces

• Principally harmless – interaction with the organism missing

• Dangerous due to potential infection

• Systemic antimicrobials usually don‘t penetrate much to the superficialstructures - skin and mucous membranes

When do we use them?• Antibiotics: in proven or highly probable bacterial infections

• In life-threatening conditions (meningitis, pneumonia)• In conditions with a significant risk of severe complications (otitis, UTI)• If a significant benefit is expected (bronchitis)• NOT JUST BECAUSE BACTERIA ARE PRESENT OR BECAUSE YOU DON‘T KNOW WHAT ELSE

TO DO!

• Antivirotics: in high-risk patients• They are all only virostatic, toxic, and their action is limited

• Antimycotics: in proven or probable symptomatic infections• In otherwise healthy patients, topical treatment should be preferred in superficial infects

• Antiparasitic drugs: in proven symptomatic infections• Many parasites are commensals – they just don‘t bite

How long have we had them?

• The antibiotic effect was first observed in 1928 by Alexander Fleming in a culture of bacteria contaminated by Penicillium chrysogenum.

• Due to trouble with isolation of the effective substances, they werelaunched only during the WW2

• In Czech lands, shortly after the war

• During the following years, new classes were discovered

• During the past 20 years, only a few new antibiotics have been discovered

• Old or basic does not mean BAD. Penicillin is still super-effective.

• Antivirotics and antiparasitic drugs were invented in the 2nd half of the20th century.

What is the future of ATBs?

• It depends.• On the bacteria a bit.

• On our attitude to antibiotics a lot.

• To predict and influence the future, we monitor the resistance rates.

• How can we improve it?• Proper diagnostic process – look for the microbes, identify, assess the

susceptibility and the relationship between the microbe and the symptoms

• Careful indication - avoid using them without a good reason

• Prefer basic antibiotics to the special ones

• Prefer weaker inductors of resistance – some ATBs induce resistence in a flash

• Discover new antibiotics and handle them carefully (secret from bacteria)

What are you expected to know aboutantimicrobials?• Classes of antibiotics – categorize every antibiotic

• Mechanism of action

• Utilization frame – hospital or community

• Administration – oral, intravenous, intramuscular, topical…• Not a SUPERlist. If they are only intravenous, say IV. If also oral, say oral. If even

topical, add it. They are few.

• Bactericidal or bacteriostatic (in some medications, it depends on the dose)

• Target microbes

• Target organ / diagnosis, if mentioned

• Excretion

• Main side effects and ways how to avoid them

Classification

• The main class must be mentioned in every antibiotic• (during the final exam)

• In some antibiotics, subclasses are necessary• Beta-lactams – several subclasses

• Cephalosporins (five generations)

• The classification might be interpreted in a different way• Azithromycin like one of the macrolides or extra azalides

• Carbapenems are sometimes excluded from beta-lactams

• We know these gaps and accept all the possibilities

Mechanism of action

• Inhibition of cell wall formation

• Disruption of cell membrane

• Inhibition of proteosynthesis in ribosomes

• Interference with DNA/RNA synthesis• Directly or through folic acid

• In some classes, we don‘t know the mechanism exactly• Or at least some book say that

Bactericidal or bacteriostatic

• Bactericidal means „killing bacteria“

• Bacteriostatic means „inhibiting the growth and splitting of bacteria“• Furthermore, some bacteriostatic ATBs inhibit the synthesis of toxins

• In some antibiotics, the effect is (always) cidal or always static

• In others, it typically depends on concentration• Co-trimoxazole – static, in high doses bactericidal

• Some antibiotics show significant post-antibiotic effect• E.g. Aminoglycosides in gram-negative rods

Target organisms

• Not every ATB is suitable for every bacterium• (this is twice more valid in viruses or fungi, parasites are rather non-specific)

• Glycopeptides are suitable for gram-positives

• Colistin works with gram-negatives

• In most other ATBs, you must know the genera (at least examples)

• Terms like broad-spectrum and narrow-spectrum are principallyunclear and outdated, although still used• It‘s better to know which antibiotic is suitable for which genera,

• and whether it is basic or reserved

Target organs

• The target organ is given by:1. Penetration to tissues

2. excretion organs

• Aminoglycosides poorly penetrate to tissues and are excreted by kidneys =

i.v. treatment of the bloodstream and urinary tract

• Tetracyclines are excreted by the liver = not suitable for the treatment ofurinary tract infections

• Ceftriaxon has an excellent penetration through the BBB = No. 1 treatment forbacterial neuroinfections

Target diagnosis

• Before you decide about the treatment, you must start with thepatient and her symptoms!

• Not only location and agents tell you what to give.

• E.g. In toxigenic soft-tissue infections, you need to:• Kill the bacteria by a bactericidal drug

• Stop the production of toxins through the blockade of ribosomes

• If you don‘t add the ribosomal ATB, you might worsen the condition!

Administration of systemic ATBs• Oral

• It‘s not easy to find a digestible antibiotic• If oral administration is possible, you find the picture of pills in this

presentation

• Intravenous• The „basic“ option in terms of development of new ATBs• Enables us to give high doses of medications or to give indigestible ATBs

• Intramuscular• Prolonged absorption of antibiotics, e.g. Penicillin

• Intrathecal• Is sometimes possible but usually not primary

Utilization frame

• Some antibiotics can be given broadly – in community. What are theylike? Mostly:• Basic antibiotics

• Oral way

• Good accessibility on the market

• Affordable

• Some other ATBs are used in hospital settings. They are rather:• Higher classes for resistant strains or hospital bacteria

• Parenteral way

• Distribution only to hospital pharmacies

• Sometimes costly

Side effects + prevention

• The most frequent (and almost matter-of-course effect) is disruptionof the normal microbiome• Antibiotic-associated diarrhea – disposition for C. diff infection• In other regions: colonization / infection by resistant organisms

• Nephrotoxic drugs• Aminoglycosides• Glycopeptides• Membrane-affecting drugs – Polymyxins, Polyenes

• Hepatotoxic drugs - tetracyclines

• Tendon disruption, wrong ossification – quinolones

Correct indication, correct doses, level measurement, hydration(nephrotox.), symptom observing, organ function assessment

Contraindications

• Is the antimicrobial drug suitable for this disease and type of agent?

Still can be refused.

Obstacles for antibiotic treatment:

• Patient side• Proven allergy

• Inability to eliminate the antibiotic from the bloodstream

• Microbe side• Proven resistance of the microbes

• Factors of pathogenicity enhanced by ATB treatment in a serotype (EHEC)

Patient aspects

• The treatment should be individual, especially for patientswith „special needs“• Babies and children

• Pregnant women

• Immunocompromised

• Chronic illnesses

• You must always consider what• You can give

• They can take

Let‘s start with the classification ofantibiotics!• The most important point of this topic!

• If you know well the classification

and the mechanism of action,

everything else can be deduced (easily).

Beta-lactams

• Beta-lactam ring• The principle is always the same: by irreversible bond to the PBP (penicillin-

binding protein), they prevent the final crosslinking (transpeptidation) of the nascent peptidoglycan layer

• Bactericidal• The least toxic, safe for everyone

• especially penicillins – they target exclusively the structures we don‘t have

• Should be preferred, if possible• Main adverse effect: possible allergic reaction, Hoigné sy., JH reaction• Excreted usually by the kidneys

Natural penicillins

• Penicillin G• intravenous, can be administered in mega-doses

• Penicillin V• oral, the shortest interval – 6 hours

• Benzathin Penicillin, Procain Penicillin• intramuscular• need for depot medication• Hoigné syndrome – anxiety, hallucination...

• Streptococci (pyogenes, agalactiae, pneumoniae...), Corynebacteriumsp., Bacillus sp., Clostridium sp...

Aminopenicillins

• Amoxicillin - oral

• Ampicillin – intravenous

• Can be administered alone or with inhibitors of beta-lactamases• Typically amoxicillin-clavulanic acid and ampicillin-sulbactam

• Gram-positive and gram-negative bacteria, suitable for empirical treatment

• Listeria meningitis!

• Clavulanic acid is strongly associated with antibiotic diarrhea• Aminopenicillins can be given in high doses but not the inhibitors

Acylureidopenicillins

• Piperacillin

• Usually administered with tazobactam

• First choice for susceptible Pseudomonas aeruginosa

• Effective against many other gram-negatives and gram-positives

Inhibitors of beta-lactamase

• Clavulanic acid

• Sulbactam

• Tazobactam

• Avibactam

• Never administered alone, only with beta-lactams

• Make the spectrum broader, eliminate SOME resistances

Cephalosporins

• The most problematic subclass of drugs• All of them start with CEF – hard to remember

• The generations of cephalosporins have different properties!

• Remember the number spectrum, examples and use• From first to third generation, the spectrum moves from G+ to G-

• Fourth takes both

• Fifth is only against MRSA

• Enterococci and listeriae are primarily resistant!

First generation

• Cefazolin

• Cefalexin

• Cefadroxil

• First choice in penicillin allergy

• Mostly Gram-positives like staphylococci, streptococci

Second generation

• Cefuroxim

• Cefoxitin (MRSA testing, not given to pts.)

• More enterobacteria, still staphylococci, streptococci

Third generation

1. Non-antipseudomonadal1. Cefotaxim – enterobacteria, G+ bacteria; bones!

2. Ceftriaxon – neuroinfections, gonorrhoea

2. Antipseudomonadal1. Ceftazidim – enterobacteria, pseudomonadacae

2. Cefoperazon - enterobacteria, pseudomonadacae

Worse effectivity against gram-positives

Fourth generation

• Cefepime

• Has a very broad spectrum for gram-positives and negatives

• Useful in infections by resistant bacteria

• Broadly used in specialized care

Fifth generation

• Ceftaroline

• Ceftobiprole

• Only for MRSA treatment or decolonization

Carbapenems

•Imipenem

•Meropenem

•Ertapenem (lab testing)

enterobacteria, non-fermenters, resistant strains especially

Administer carefully in epilepsy

Reserved, highly specialized hospital care (ICU)

Excreted by kidneys

Macrolides

• (Erythromycin)

• Clarithromycin - safe for children

• Spiramycin - for pregnant women, other macrolides not suitable

• Protein synthesis, bond to 50s subunit – used for toxin inhibition

• Bacteriostatic

• Gram-positives, intracellular bacteria

• Atypical pneumonia, allergy to penicillin

• Community and hospital, overprescribed, resistance rate rising

• Excreted by the liver

Azalides (sub-macrolides)

• Azithromycin

• Protein synthesis inhibition – 50s bond – used for toxin inhibition

• Bacteriostatic

• Suitable for pregnant women and children of all ages

• Always resistant when macrolides are resistant

• Three doses, long half-time and long post-antibiotic effect

• Gram-positives, intracellular bacteria

• Atypical pneumonia, allergy to penicillin

• Community and hospital

• Overprescribed, resistance rate rising

• Excreted by the liver

Lincosamides

• Lincomycin

• Clindamycin

• Protein synthesis – bond to 50s subunit – used for toxin inhibition

• Bacteriostatic

• MLI – resistance can be induced when macrolides resistant

• Penetration into bone tissue

• Excreted by the liver and kidneys (20%)

• Community and hospital (orthopedics) care

Tetracyclines

• Doxycycline

• Tigecycline

• Protein synthesis through bond to the 30s subunit

• Bacteriostatic, slow effect

• Intracellular bacteria, gram-positives, gram-negatives

• Excreted by the liver

• Mostly community care

• Hepatotoxic

• NOT FOR CHILDREN! tetracycline teeth

Aminoglycosides• Gentamicin, amikacin, tobramycin

• Only intravenous, usually given in a combination

• Target subcellular structure: ribosome• Irreversible bond to the 30S subunit• The only bactericidal ribosomal ATB

• Target organ: bloodstream and urinary tract (poor penetration into tissues

• Bactericidal

• Nephrotoxic, ototoxic• Assess the risk first• Measure blood levels, prehydrate before administration

• Target bacteria• G- fermenting and non+fermenting rods• Some staphylococci and some streptococci

• Hospital and community (injections daily) care

Glycopeptides

• Vancomycin

• Teicoplanin

• Interference with the formation of the cell wall

• Bactericidal

• Specialized hospital care (ICU)

• Reserved for resistant strains of gram-positives, takes also anaerobes

• Excreted by kidneys, nephrotoxic

Polypeptides (polymyxins)

• Polymyxin B

• Colistin (intravenous, inhalation)

• Bacitracin (topical)

• Disruption of the cytoplasmatic membrane

• Bactericidal

• The most toxic (we have such membranes as well)• Mainly nephrotoxic!

• The last choice of antibiotic treatment of highly resistant gram-negatives

Quinolones

• (Nalidixic acid) – obsolete treatment of UTI

• Fluoroquinolones• Levofloxacin• Ciprofloxacin• Moxifloxacin – pulmonary quinolone

• Bactericidal

• Strong inductors of resistance

• Infections of soft tissues and bones

• Salmonella, Yersinia, intracellular bacteria

• Ruptures of tendons; NOT FOR CHILDREN! wrong ossification

Oxazolidinones

• Linezolide

• Inhibits the initiation of protein synthesis

• Bacteriostatic

• Reserved antibiotic for infections by resistant G+ bacteria or invasive infections by PVL-positive S. aureus• Inhibits the synthesis of the toxin!

• Excreted by kidneys

• Only specialized hospital care

Amphenicols

• Chloramphenicol

• 50s ribosomal subunit – proteosynthesis inhibition

• Bacteriostatic

• Luxurious penetration to the brain

• Neuroinfections in the hospital

• We try to avoid it, it supresses the bone marrow and in 1:50 000 induces aplastic anemia

• Excreted by kidneys unchanged

• G+, G-, spirochetes, rickettsiae

• Hospital care

Sulfonamides

• Co-trimoxazole = sulfamethoxazol + trimethoprim

• Interference with folic acid metabolism• Bacteria including intracellular• Fungus – pneumocystis• Parasites - prevention of toxoplasmosis

• The effect is typically delayed

• Excretion through kidneys

• Mildly nephrotoxic, risk of leukopenia (lower doses)

• Hospital, community

• Bacteriostatic/bactericidal in higher concentrations

Nitroimidazoles

• Metronidazole

• Damage of the bacterial DNA

• Bactericidal

• Anaerobic non-sporulating bacteria (Bacteroides etc.), protozoa!

• GIT injuries and surgeries, aspiration pneumonia

• Nausea, metallic taste

• Hospital, community

Nitrofurans

• Nitrofurantoin - „Yellow devil“

• Complex mechanism of action – inhibition of ribosomal proteins etc.

• Empirical treatment for urinary tract infections

• Bactericidal

• Effective only within the urinary tract

• Enterobacteria, Staphylococci,

Enterococci, Aerococcus urinae

• Nausea

• Community care

Fosfomycin

• Alone in the class

• Cell wall synthesis

• Bactericidal

• E.coli urinary infections without complications

• Excreted by kidneys

• A re-discovered antibiotic

• Community care

First choices! Revise repeatedly...• Streptococci penicillin, ampicillin

• Enterococci ampicillin, vancomycin

• Staphylococci oxacillin/clindamycin

• Neisseriae ceftriaxone

• Legionella clindamycin

• Brucella, Francisella doxycycline

• Bordetella azitromycin

• Haemophilus influenzae amoxicillin-clavulanate

• Listeria ampicillin

• Corynebacterium diphteriae macrolides

• Escherichia coli amoxicillin-clavulanate

• Shigella co-trimoxazole

• Salmonella fluoroquinolons

• Enterobacteria piperacillin-tazobactam

• Yersinia fluoroquinolons

• Vibrio cholerae doxycycline

• Campylobacter jejuni azithromycin

• Helicobacter pylori amoxicillin

• Pseudomonas aeruginosa piperacillin-tazobactam

• M. tuberculosis antituberculotics

• M. leprae dapson + rifampin

• Non-sporulating anaerobes metronidazole

• Actinomyces penicillin

• Nocardia co-trimoxazole

• Clostridium tetani metronidazole

• Clostridium difficile vancomycin oral

• Clostridium perfringens penicillin

• Bacillus anthracis doxycycline

• Treponema pallidum penicillin

• Borrelia penicillin doxycycline

• Leptospira penicillin

• Rickettsia, Coxiella, Bartonella doxycycline

• Chlamydia macrolides, co-trimoxazole

• Mycoplasma, Ureaplasma macrolides, doxycycline

Susceptibility testing

• Routine susceptibility testing is performed for bacteria and fungi

• 3 methods• Disc diffusion method – ATB discs on MH agar

• Minimal inhibitory concentration – dilution method

• E-test (combination of both – quantitative stripes on MH agar)

Mechanisms of resistance

1. Barriers averting penetration of the antibiotic into the cell

2. Active transport out

3. Change of target structures1. PBP change - MRSA

4. Enzymes destroying the antibiotic1. Penicillinase of Staphylococcus (now all the strains)

2. ESBL in enterobacteria

3. Carbapenemases in enterobacteria

Genetic determinants of resistance

• Chromosome-coded resistance is more stable (MRSA)• Vertical type of resistance

• Resistance coded by mobile elements can be easily shared and thenlost (ESBL)• Horizontal type of resistance

• Antibiotic pressure can induce a short time upregulation ofadaptation processes in bacteria; after stopping the therapy, they are susceptible again

Resistance phenotypes for you to know• MRSA (methicillin-resistant S. aureus)

• Chromosome-coded change of PBP – resistance to beta-lactams• Tested by cefoxitin disc; decolonization attempted by co-trimoxazole (s)• Treatment of serious infections: 5th gentamicin, cephalosporin, vancomycin, linezolide...

• VRE (vancomycin-resistant enterococci)• tested by vancomycin disc, treated with tigecyclin

• ESBL (extended spectrum beta-lactamase)• Enterobacteria – fermenting G- rods, coded on plasmids, resistance to penicillins and

cephalosporins• Tested by three ATB discs – cefotaxim, ceftazidim, amoxicillin-clavulanate• Treatment: carbapenems

• Carbapenemase• Enterobacteria, resistance to carbapenems, coded on plasmids• Tested by ertapenem disc and confirmed by MALDI-TOF• Treatment: amikacin (aminoglycoside)

Topical antibiotics

• Inhalation – Tobramycin, Colistin (+AmphoB – antimycotic)

• Ointment and creams - Neomycin/Bacitracin, Fusidic acid, Mupirocin

• Drops• Eye – Tobramycin, Erythromycin, Ciprofloxacin, Gentamicin, Tobramycin

• Nose - Neomycin/Bacitracin

• Ear - Gentamicin

• Vaginal suppositories - Neomycin/Bacitracin

Antimycotics

• Topical and systemic!

• The mechanism of action is either unknown or disruption of the cell membrane, so this can be mentioned for the whole group and thenneedn‘t be repeated for every class

Topical antimycotics

• Disinfectants• Potassium permanganate, Borax-glycerine, Gentian violet

• Imidazoles• Clotrimazole, econazole

• Polyenes• Nystatin

• Allylamines• Naftifin

Systemic antimycotics

• Triazoles• Fluconazole for C. albicans• Voriconazole for C. non-albicans and Aspergillus sp.• Posaconazole and ISAVUCONAZOLE for Zygomycetes

• Echinocandins• Caspofungin, Anidulafungin for systemic candidosis

• Polyenes• Amphotericin B – molds (reserve for „everything“) - NEPHROTOXIC

• Allylamins• Terbinafin – dermatophytic molds with deep penetration

Antiparasitic drugs

• The mechanism of action is not completely clear

• Protozoa – metronidazole (that anaerobic antibiotic)

• Round helminths – mebendazole

• Tapeworms, tissue helminths, trematodes etc.: praziquantel, albendazole

• In some tissue helminths, beware of starting with medications• Massive release of antigens of the dead parasite might kill the patient

• In others, it is unavoidable – perforation of the focus would lead to massive dissemination of the infection

Antivirotics

• Will be taught by Petr Hubáček during virology weeks

• Remember• The basic principles of action

• Absolute selectivity

• Toxicity

• Static effect only

• Possible resistance

• Examples:• Herpes virus medications

• Flu medications

• Antiretrovirotics – subgroups, names, significance

Don‘t study

•Chemical formulas

•Chemical names

• But you should have a general

overview about everything

Thank you.