Pharm: Antimicrobial Therapy

microorganisms

• broad classification scheme based on microscopic appearance and morphology

  • Bacillus vs. coccus vs. coccbacillus

  • Gram-positive vs. gram negative

gram positive bacteria

have cell walls composed of thick layers of peptidoglycan

• stain purple when subjected to gram stain procedure

• bacteria includes all staph, all strep, and some listeria

• NO outer lipid-membrane

• NO O-specific side chains present (not as important)

• YES teichoic and lipoteichoic acids present (not as important)

gram negative bacteria

have cell walls with a thin layer of peptidoglycan

• pale reddish color after gram staining

• bacteria includes enterobacter species, salmonella species, and pseudomonas species

• YES outer lipid membrane

• YES O-specific side chains (not as important)

• NO teichoic and lipoteichoic acids (not as important)

gram positive

staphylococcus sp

• coagulase +: S. aureus

  • methicillin/oxacillin sensitive s. aureas = MSSA

  • methicillin/oxacillin resistant s. aureus = MRSA

• coagulase - staph:

  • methicillin sensitive s. epidermidis = MSSE

  • methicillin resistant s. epidermidis = MRSE

gram positive

streptococcus sp

• a hemolytic: streptococcus pneumoniae

• b hemolytic: group A streptococcus sp = S. pyogenes

gram positive

enterococcus sp

• enterococcus faecalis/enterococcus faecium

• vancomycin-resistance enterococcus = VRE

gram negative

enterobacteriaciae: e coli, klebsiella sp, proteus sp

respiratory: h. influenza, m catarrhalis

pseudomona aeruginosa

anaerobes

bacteroides sp

atypical

mycoplasma pneumoniae, chlamydia pneumoniae, Legionella penumonphila

enterobacteriaciae: enteric bacilli

• e coli: GI flora of humans and animals

• klebsiella sp: nasopharynx and GI flora

• proteus sp: GI flora, soil, water, sewage

• pantoea agglomerans

• enterobacter sp

• citrobacter sp

• serratia sp

• salmonella sp

• shigella sp

• morganella

• morganii providencia sp

  • yersinia sp

mouth flora

1. viridans streptococcus

   1. oral anaerobes

upper resp tract flora

1. oral anaerobes

2. streptococcus sp

3. staphylococcus sp

4. neisseria sp

5. diphtheroids

   1. haemophilus sp

intestine flora

1. lactobaccillus

2. streptococcus

3. enterococcus

4. enterobacteriaceae

5. diphtheroids

6. anaerobes (bacteroids/clostridium)

skin flora

1. staphylococcus

2. corynebacteria

3. streptococcus

4. micrococcus

sterile sites

1. CSF

2. blood

3. urine

4. peritoneal fluid

(no bacteria here!)

know these for antimicrobial agents

1. organism’s identity

2. organism’s susceptibility to an agent

3. site of infection

4. patient factors

   1. has the patient tried this before?

5. safety profile or agent

   1. if you have something that’s renal toxic and they’re diabetic/old, can their kidney excrete that medication?

6. cost

minimum inhibitory concentration

the lowest antimicrobial conc that prevents visible growth of an organism after 24 hours of incubation

the least amount of meds needed to prevent growth of organism (24 hrs of incubation)

minimum bactericidal concentration (MBC)

The lowest concentration of an antimicrobial that reduces the number of bacteria by 99% after overnight incubation in a broth dilution test.

bacteriostatis

• inhibits growth reversibly

  • macrolides

  • sulfonamides

  • tetracycline

  • trimethoprim

bactericidal

kills microbe rapidly

• rifampin

• fluoroquinolones

• beta-lactams (kill bacteria but the bacteria has the be multiplying, not just existing)

• aminoglycosides

site of infection

CNS

• blood brain barrier

• lipid solubility (inc lipophilic = increased penetration)

• molecular weight of drug (low molecule weight = increased penetration)

• protein binding of drug (inc protein binding = decreases penetration)

capillaries

• varying degrees of permeability carry drugs to body tissues

patient factors

• immune factors

• renal function

  • if they have poor renal function, they can’t excrete → more likely to experience adverse effects

• hepatic function

  • metabolism, how is that med metabolized and deliver

• poor perfusion

  • their blood doesn’t reach all the periphery or poor circulation → can’t get to target site

• age

  • perfusion, if it’s topical antibiotic the skin integrity will be an issue, renal function

• pregnancy and lactation

• multidrug-resistant organisms

time-dependent drug

• Some antibiotics kill bacteria at a constant rate, no matter how high the drug concentration is.

• What really matters is how long the drug level in the blood stays above the MIC (Minimum Inhibitory Concentration).

• To work well, the drug needs to stay above the MIC for at least 40% of the dosing interval (time between doses).

  If it stays above MIC longer, it works even better and for longer.

• These drugs are often given as continuous or extended (prolonged) infusions to keep blood levels steady and above MIC.

concentration-dependent drug

• The higher the drug concentration, the faster and more effective it kills bacteria.

• When you give a bolus (a quick, large dose), the drug level in the blood spikes high for a while before it drops.

• That high peak helps kill bacteria more quickly and strongly.

• The rate of bacterial killing increases as the drug concentration goes higher than the MIC.

narrow-spectrum antibiotics

acts on single or limited group of microorganisms

• ex. isoniazid

extended-spectrum antibiotics

acts on mostly gram-pos but some gram-neg

• ex. ampicillin

broad-spectrum antibiotics

acts on a variety of microorganisms

• typically used when C&S (Culture and sensitivity) has not been done

• ex. tetracycline

empiric therapy

Giving antibiotics right away, before knowing exactly which bacteria is causing the infection or which drugs it responds to

it uses BROAD-spectrum bacteria

dr’s choose based on:

The patient’s symptoms

The doctor’s experience

The most common germs in the area

antibiogram

• An antibiogram shows how well different antibiotics work against certain bacteria.

• It gives a resistance and sensitivity profile — tells you which drugs the bacteria can or can’t fight off

important bc

• Made by a lab using real test results

• Summarizes data from many bacteria samples

• Shows percentages of bacteria that were killed (sensitive) or not killed (resistant) by each antibiotic

colonization

presence of microorganisms that grows and multiples, but is ABSENT of tissue invasion or damage (no clinical significance)

• can become an infection if changes in hosts occurs

infection

existence and development of an infectious agent (ie microorganism)

• may or may not develop into a disease

infectious disease

condition caused by invasion and multiplication of harmful microorganisms, known as pathogens, in body

cell wall synthesis

• vancomycin

• bacitracin

• penicillins

• cephalosporins

• monobactams

• carbapenems

dna gyrase

quinolones

dna-directed rna polymerase

rifampin

protein synthesis (50s inhibitors)

erythromycin

chloramphenicol

clindamycin

streptogramins

protein synthesis (30s inhibitors)

tetracycline

streptomycin

gentamicin

tobramycin

amikacin

protein synthesis (tRNA)

mupirocin

linezolid

cell membrane

polymyxins

daptomycin

folic acid metabolism

trimethoprim

sulfonamides

blocks cell wall synthesis (by inhibition of peptidoglycan cross-linking)

penicillin, ampicillin, ticarcillin, piperacillin, imipenam, aztreonam, cephalosporins

blocks peptidoglycan synthesis

bacitracin, vancomycin

disrupts bacteria cell membrane

polymyxins

block nucleotide synthesis

sulfonamides, trimethoprim

block dna topoisomerase

fluoroquinolones

block mRNA synthesis

rifampin

block protein synthesis (50S ribosomal)

chloramphenicol, macrolides, clindamycin, linezolid, streptogamins

block protein synthesis (30S ribosomal)

aminoglycosides, tetracyclines

bacteriostatic

erythromycin clindamycin, sulfamethoxazole, trimethroprim, tetracyclines, chloramphenicol

(ECSTaTiC bacteriostatics)

bactericidal

vancomycin, fluoroquinolones, penicillin, aminoglycosides, cephalosporins, metronidazole

(Very Finely Proficient At Cell Murder)

beta lactams

cell wall synthesis inhibitors

• penicillin

• monobactams

• carbapenems

• cephalosporins

mimics the substrate the beta lactams are bound to be PBPs → competitively inhibiting enzymatic activity → disruption in CW synthesis

inhibitors of cell wall synthesis

• glycopeptides

• fosfomycin

• daptomycin

  • ____

hydrolysis of the beta-lactam ring

• Beta-lactam antibiotics have a special ring structure called a beta-lactam ring.

• In this ring, a nitrogen atom is attached next to the carbonyl carbon—which is why they’re called beta-lactams.

• The antibacterial effect of these drugs can be destroyed either by:

  • Enzymes called beta-lactamases, which cut the beta-lactam ring, or

  • Acid (like stomach acid), which also breaks the ring.

cell wall synthesis inhibitors

• penicillins

• monobactams

• carbapenems

• cephalosporins

penicillins

• natural

• aminopenicillins

• penicillinase-resistant penicillins

• anti-pseudomonal penicillins

natural penicillin

• oral: penicillin VK

• IV: penicillin G Sodium

  • penicillin G Potassium

• IM:

  • penicillin G Procaine

  • Penicillin G Benzathine

  (in the butt)

natural penicillin

blocks the last step of building the bacterial cell wall, which makes the wall weak and causes the bacteria to burst (lyse).

• It kills bacteria (bactericidal).

• It works by attaching to penicillin-binding proteins and inhibiting an enzyme called transpeptidase.

• This stops the bacteria from linking the peptidoglycan side chains (PEP side chains), which is the final step in making the cell wall.

• It also triggers the bacteria to produce autolysins, enzymes that break down their own cell wall.

activity of natural penicillin

gram pos

• steptococcus (Drug of choice)

  • pneumoniae (resistance is increasing)

  • pyrogenes

  • viridans

• enterococcus

gram neg

• not very effective of gram negative

• neisseria

  • gonorrhoae

  • meningitidis

• additional

  • treponema pallidum (syphilis)

NOT EFFECTIVE FOR

• mycobacteria

• protozoa

• fungi

• viruses

gonorrhea

• Silver nitrate eye drops are used to stop newborn babies from getting eye infections caused by gonorrhea.

• Strains of gonorrhea that make penicillinase (an enzyme that breaks down penicillin) are treated with ceftriaxone, and azithromycin is used as a backup medicine

syphilis

• contagious venereal disease that progressively affects many tissues

• single treatment with penicillin is good for primary and second syphillis

  • no antibiotic resistance has been reported

natural penicillin adverse reactions

hypersensitivity

• 5-10% of pop reports allergy

GI***

• Nausea/vomiting, abdominal pain, diarrhea

interstitial nephritis

neurotoxicity

• seizures in high dosage

hematologic toxicity

• neutropenia at high doses

aminopenicillins (extended spectrum penicillin)

Ampicillin and Amoxicillin: What They Do

• Work against most gram-positive bacteria and some gram-negative bacteria.

• Forms:

  • Ampicillin: given by IV (injection) or by mouth (PO)

  • Amoxicillin: given by mouth (PO)

What They Fight Against (Spectrum of Activity):

• Gram-positive bacteria:

  • Streptococci

  • Enterococcus (these drugs are the first choice for enterococcus infections)

• Gram-negative bacteria: (only if they don’t produce beta-lactamase)

  • E. coli

  • Proteus species

  • Haemophilus influenzae

Side Effects (Adverse Reactions):

• Similar to natural penicillins

• Up to 10% of patients can get a rash that is not itchy and not hives (non-pruritic, non-urticarial rash)

penicillinase-resistant penicillin

PO: dicloxacillin

IV: nafcillin and oxacillin

spectrum of activity

WORKS AGAINST gram +: staphylococcus sp (MSSA/MSSE, drug of choice) and strepticoccus sp

(not effective on anaerobes and gram neg)

penicillinase-resistant penicillin adverse reactions

• allergic reactions

• renal (interstitial nephritis)

• hepatic (oxacillin can inc LFTs and hepatitis)

• hematologic: neuropenia and nafcillin (thrombophlebitis)

• drug-drug interaction: warfarin (anticoagulant)

anti-pseudomonal penicillin activity

IV: piperacillin (more potent) and ticarcillin

gram +: streptococcal sp, enterococcus

gram -: e. coli, klebsiella sp., proteus sp (beta lactamase negative), h. influenza/m. catarrhalis (beta-lactamase negative), pseudomonas

anti-pseudomonal penicillin adverse reactions

• allergic reaction

• electrolyte abnormalities (hypernatremia, hypokalemia)

• renal (interstitial nephritis)

• hematologic (neutropenia, thrombocytopenia)

• CNS (seizures at high doses, psychosis, delirium)

Monobactams and activity

IV: azetreonam (Azactam)

Inhalation: Aztreonam (Cayston)

activity: NOT EFFECTIVE FOR gram + and anaerobes

works ONLY on gram -: e. coli, klebsiella sp, proteus sp, h. influenza, M. catarrhalis, pseudomonas sp

note: beta-lactam ring is NOT fused to another ring

monobactams

• azetreonam can be used with pts with penicillin allergy/IgE reactions but NOT allergies to ceftazidime (bc of possible sensitivity to azetreonam)

adverse

• watch renal function

• phlebitis

• skin rash

• abnormal liver function (occasionally)