antibiotics and antimicrobial stewardship

antibiotic

a naturally occurring agent produced by a microbe that inhibits or kills another.

Now - any antibacterial agent. Either synthetic, semi-synthetic or naturally occurring drug

anti-virals

target viruses

anti-fungals

treat fungal infections

antimicrobial

any drug that inhibits or kills a bacterium, virus, fungus etc.

selective toxicity

agent being used should inhibit or kill the intended pathogen without seriously harming the host

selectively attack targets that are in bacteria cells but not in human cells

example: cell wall or protein building/DNA copying machinery

antibiotic therapy treat of infection

smart smart: Empiric therapy: Treatment of an infection before specific culture information has been reported or obtained

then focus: targeted therapy: treatment focused to known pathogen and susceptibility

antibiotic therapy prevention of infection

prophylactic therapy: administration of antibiotics to prevent an infection

classification of antibiotics

• antibiotic family

• bacterial or bacteriostatic

• narrow or broad-spectrum

• mechanism of action i.e. cell-wall agents, inhibitors of protein synthesis

antibiotic family

bacteriostatic - antimicrobial activity

inhibit growth of susceptible, rather than killing them immediately

will eventually lead to bacterial death

immune defenses important for clearing pathogen

bactericidal - antimicrobial activity

kills susceptible bacteria

important to use if immunodeficient or for certain difficult infections e.g. meningitis, endocarditis and infection

narrow antibiotic spectrum

active against specific organisms or types of organism e.g. penicillin G active against GPC only

minimal disruption of normal flora

not suitable for blind therapy

broad antibiotic spectrum

active against many bacteria e.g. piperacillin-tazobactam, effective against some GPC, some GNB including pseudomonas and anaerobic bacteria

polymicrobial/unknown aetiology

superinfection e.g. clostridium difficile

importance of the spectrum of activity

incorrect method may not kill the bacteria - infection may progress, may increase development of resistance, may kill non-pathogenic bacteria causing change in normal flora and risk of superinfection

C. difficile infection

clostridioides difficile infection

spore forming bacterium that lives in the bowel

infection of the colon

symptoms: watery diarrhea, fever, nausea, abdominal pain

in severe cases: can lead to toxic megacolon or sepsis and be life threatening

10 times more likely to get it after antibiotic use

can occur as antibiotic started up to three months after it is completed

healthy microbiome protects from D. difficile - disrupted by antibiotic use.

groups of bacteria in terms of antibiotic treatment

1. Gram positive

2. gram negative

3. anaerobes

4. atypical

Gram + VE

• staphylococci

• streptococci

• enterococci

• clostridia

• corynebacterial

• listeria

• bacillus

Gram - VE

• E coli, klebsiella

• proteus, salmonella, shigella

• pseudomonas

• haemophilus

• helicobacter, campylobacter

• legionella

• Neisseria meningitidis

• Neisseria gonorrhoea

• Moraxella catarrhalis

• Acinetobacter

• Bacteroides

atypical bacteria and mycobacteria

atypical bacteria

• chlamydia - intracellular pathogen

• mycoplasma and ureaplasma - small bacteria that lack a cell wall

mycobacteria

• M. tuberculosis, M. avium complex, M. leprae

Gram + VE agents

narrow spectrum

• penicillin V/G, flucloxacillin

• Fusidic acid, Rifampicin

• clindamycin

• daptomycin

• vancomycin, teicoplanin

• linezolid

Broad spectrum

• cefalexin, co-amoxiclav, cefuroxime, ceftriaxone

• minocycline, doxycycline, tetracycline, tigecycline

• erythromycin. clarithromycin, azithromycin

• trimethoprim

gram -VE agents

narrow spectrum

• colistin

broad spectrum

• gentamicin, tobramycin, amikacin (aminoglycosides)

• ciprofloxacin, moxifloxacin (quinolones)

• minocycline, doxycycline, tetracycline (tetracyclines)

• cefalexin, cefuroxime, co-amoxiclav (beta-lactams)

• trimethoprim, nitrofurantoin

anti anaerobe agents

metronidazole

clindamycin

co-amoxiclav

piperacillin-tazobactam

meropenem

anti-atypical agents

tetracyclines: tetracycline, minocycline, doxycycline, oxytetracycline, tigecycline

macrolides: erythromycin, clarithromycin, azithromycin

quinolones: ciprofloxacin, moxifloxacin, levofloxacin

modes of action

breach their walls - cidal

• cell wall active agents e.g. beta lactams, glycopeptides

hack into their information center

• antimetabolites (trimethoprim)

• inhibit RNA synthesis (rifampicin) or DNA replication (ciprofloxacin)

disrupt their factories

• inhibitors of protein synthesis e.g. gentamicin

susceptibility testing oorgansim

determine antibiotic susceptibility profile of an infecting organism

minimum inhibitory concentration (MIC)

susceptibility profile can aid bacterial identification and epidemiology

susceptibility testing patient

predicts patient response

empiric therapy often begins before this result is available so epidemiological data supports empiric therapy

results are important

• if patient fails to respond to therapy allow to change to more appropriate agent e.g. with respect to cost, sensitivity, effectiveness or side effects

susceptibility testing methods

disk diffusion - result is that organism is susceptible or resistant

minimum inhibitory concentration (MIC) - result is a value that indicates how susceptible/resistant the organism is e.g. broth microdilution or E-test

disk diffusion

1. inoculate surface of agar plate with test organism

2. apply cellulose discs with standard amount of antibiotic on an agar plate

3. antibiotic diffuses into agar and zone sizes reflect susceptibility or resistance

4. easy to do, cheap, test 4-6 agents at one time

5. not quantitative, only semi quantitative at best

6. many different standard methods e.g. BSAC, Stokes, CLSI

minimum inhibitory concentration

the lowest concentration of an antibiotic required to inhibit growth of a bacterium

determined by testing the ability of the test organism to grow in the presence of the drug in a series of concentrations in either broth or on agar

selective organisms e.g. strep pneumoniae and penicillin

can detect changes in susceptibility

broth microdilution

fixed concentration of bacteria added to tubes/microwell plates

grow in the presence of increasing concentration of antibiotic

examine growth after 24h

at what concentration does it inhibit growth

MIC is the lowest concentration that inhibits growth

E test

an agar based quantitative susceptibility test

diffusion method that enables MIC values to be estimated directly

an extended series of two fold dilutions of an initially high standard concentration of antibiotic

antibiotic concentrations are distributed linearly along a special carrier strip

MIC is the concentration corresponding to the point of intersection of the eclipse zone as shown

ideals in antibiotics

1. selective toxicity - toxic to the target pathogen but not the host

2. bactericidal vs. bacteriostatic (host defenses)

3. favorable pharmacokinetics - reaches target site in the body with effective concentration (good bioavailability)

4. spectrum of activity - broad vs. narrow

5. lack of side effects - effective to toxic dose ratio

6. little resistance development - can withstand bacterial resistance

antimicrobial stewardship

key strategy to overcome resistance

involves the careful and responsible management of antimicrobial use

improves patient outcomes - improve infection cure rates, reduce surgical infection rates, reduce morbidity and mortality

improve patient safety - reduce antimicrobial consumption without increasing mortality or infection related re admissions

reduce resistance - restricting relevant agents can reduce colonization or infection with resistant bacteria

reduce healthcare costs without compromising patient care

factors affecting antibiotic choice

concentrations of antibiotics achievable may differ at different sites

bacteria vs. viruses

gram positive or negative

accompanying treatment

how effectively or fast the drug are absorbed, distributed and metabolized

antibiotics and their most likely infection

anaerobes - mouth, teeth, throat, sinuses and lower bowel → abscesses, dental infection, peritonitis, appendicitis

atypical - chest and Genito-urinary → pneumonia, urethritis, PID

gram+ - skin and mucous membrane → pneumonia, sinusitis, cellulitis, osteomyelitis, wound infection, line infection

gram- - GI tract → peritonitis, biliary infection, pancreatitis, UTI, PID

adverse effects of antibiotics

hypersensitivity (allergy) e.g. penicillin

altered normal flora - bacterial overgrowth

drug interactions

specific organ toxicity

antibiotic resistance

allergy types

anaphylaxis - rare but life threatening systemic reaction, develops rapidly and is antibody (IgE) mediated

urticaria - itchy, raised skin and angioedema (local, rapid swelling). also IgE-mediated, more common reactions but less severe

maculopapular rashes - most common allergic reaction but are not life threatening

GI upset cause by penicillin is NOT an allergy

altered normal flora

often occurs when using broad spectrum antibiotics]opportunistic infections may arise

superinfection

• candida albicans - oral/vaginal thrush

• clostridium difficile diarrhea

drug interactions

tetracyclines or rifampicin and oral contraceptives - reduces effectiveness

ciprofloxacin and aminophylline: this can cause nausea, vomiting, diarrhea, headache, insomnia, seizures or heart palpitations

tissue/organ toxicities

rifampicin and isoniazid long term → liver hepatitis

aminoglycosides e.g. gentamicin → nephro- (kidney) and/or ototoxicity

chloramphenicol → bone marrow depression

antibiotic resistance

commonly used antibiotics are becoming less effective

resistant pathogens threaten our ability to treat common infections and to perform life saving procedures e.g. chemo

antimicrobial stewardship is key in reducing antibiotic misuse to preserve these precious resources for the future