Pharm Antibiotics Flashcards
To understand the pharmacology as well as the viability of tetracycline, clindamycin, and chloramphenicol in treating listed diseases
Clinically important tetracyclins
Chlortetracycline Oxytetracycline tetracycline demaclocycline methacycline doxycycline minocycline
Properties of tetracyclins
Poorly water soluble and are formulated as hydrochlorides
GI absorption is by the presence of food in the GI
MOA of tetracycline
Reversibly blocks the 30s ribosome to prevent protein synthesis
by binding, it prevents charged tRNA from binding to the loading A site and stops translation
Tetracyclins
chemical backbone = 4 rings
different members arise from different substituents on the ring
new member: Tigecycline
Tigecycline
Broad-spectrum
Long half life
Improved resistance profile
Can be given with proton pump inhibitors (to tx helicobacter induced ulcers)
Low resistance hospital-aquired (nosocomial) infections
doxycycline
minocycline
not affected by food
No decrease in absorption even in the presence of food
100% bioavailability via IV
High pH effect
Decrease tetracycline’s effect?
mycoplasmas
cause pneumonia
Rikettsiae
Rocky mountain spotted fever Purple rashes (pectechaie)=> bleeding underneath the skin
What drugs are not substrates for efflux pumps (produced by resistant strains)?
Doxycycline
minocycline
tigecycline
Most effective types of bacterial resistance
Efflux pumps
Proteins that protect the ribosomes
Three mechanisms that convey bacterial resistance to tetracycline
1) Impaired influx or enhanced efflux(of tetracycline) by an active transport protein pump, 2) Ribosome protection and 3) Enzymatic inactivation of the drugs
In simple terms…..
Bacteria will have a mutation that will produce efflux pumps that are selective for antibiotics
The drug is pumped out by active transport
Bacteria produce proteins that bind to the antibiotics
Bacterial enzymes can completely degrade the drugs
Contraindications of tetracyclines
Not good for children:
The drug crosses the placenta, breast milk
bind to calcium and damage bones
bind to teeth
Enterohepatic circulation
drugs absorbed from the liver => secreted into the bile
a fatty meal => drugs are re-secreted to the GI tract via bile, so it can get reabsorbed again => increases the long half life of the tetracyclines
Advantages of tetracyclines
Improve patient compliance
Clinical Uses : Chlymadiae
Sclera of the eye is irritated, red, yellow pus,
Chlortetracycline tx. Chlymadiae conjunctivitis
What is the problem with the combination therapy of tetracycline + proton pump inhibitor to treat helicobacter pylori-induced ulcers?
change the pH = high pH which will make tetracycline ineffective
need acid to absorb tetracycline
Change the order of how you give the two drug
-wait 8 to 12 hours
give tetracycline first
Demeclocycline
prevent the action of ADH
Tx tumors that secrete ADH
central diabetes insipidus?
Tetracyclins used in combination with aminoglycosides
Tx plague, tularemia and brucellosis
Adverse effects of tetracyclines
MOST IMPORTANT : effect on BONE
Tetracyclines are deposited in bone and teeth and are contraindicated in children less than 8yrs old and pregnant women
How can you reduce the adverse effect on kidneys
adjust dose
Adverse effect of Demaclocycline
Photosensitivity
MOA of Clindamycin
Binds exclusively to the 50S ribosome �
block the whole protein synthesis
1st mechanism of resistance to clindamycin
Mutation of the ribosomal receptor site
Drug will not have high affinity for the target site
need high conc. of drug but can’t be achieved physiologically
Mechanism of Clindamycin
Binds to 50S ribosome and inhibits protein synthesis
Clindamycin binding to plasma protein
90% except in CNS
Combination clindamycin and cephalosporin or aminoglycosides �
used for prophylaxis
Tx penetrating wounds of the abdomen and the gut
Clindamycin combination with pyrimethamine
inhibit tetrahydrolate synthase
inhibit synthesis of folate from PABA
used for AIDS-related toxoplamosis of the brain�
Gray baby syndrome
Toxicity in newborn infants: gray baby syndrome (vomiting, flaccidity, hypothermia, gray color shock and collapse)
Must be used with caution in infants
Unique to chloramphenicol!!!!!
The UDP-glucuronyl transferase enzyme system of infants, especially premature infants, is immature and incapable of metabolizing the excessive drug load.
Insufficient renal excretion of the unconjugated drug.
Broad spectrum activity of tetracyclines
antimicrobial activity against gram + and gram - bacteria including anaerobes, chlamydiae, myocoplasma, rikettsiae, ameobas
How does tetracycline enter susceptible bacteria?
simple diffusion and through active transport
What if the antibiotic does not have high affinity for the efflux pump?
Resistance is avoided
What is the drug that is effect even against the Tet(A) efflux-expressing gram - strains having resistance to the older tetracycline like doxycycline and minocycline
Tegecycline
Which tetracycline resistance protein confers resistance to tetracycline, doxycycline, and minocycline but not to tigecycline?
Tet (M)
Which agent has Tet (K) that confers resistance to tetracycline but not to doxycycline, minocycline, or tigecycline
Staphylococcus
Tigecycline is effective in the presence of which Tet proteins
Tet A, Tet M
Tet K
Tet M
Which gram strains express Tet M
gram positive
Gram + strains that express Tet M have what kind of protection
Ribosomal
Which species have intrinsic resistance to all tetracyclines?
proteus and psudomonas aeroginosa
Tet (A)
Gives gram negative strains efflux pumps for doxycycline and minocycline.
NOT EFFECTED: Tigecycline
Tet (K)
Confers resistance to tetracyclines in staphylococcus.
NOT EFFECTED: Tigecycline, Doxycycline, Minocycline
Tet (M)
Ribosomal protection expressed by gram + strains. Resistance to Doxy, Mino, Tetra.
NOT EFFECTED: Tigecycline
What does food in the GI do to the absorption of tetracyclines?
Impairs it
except in the case of doxycycline and minocycline
Which drugs have 95-100% bioavailability?
doxycycline and minocycline
What other products can impair absorption of tetracyclines in the GI tract?
Ingestion of dairy products, antacids or the presence of alkaline pH, cations like Ca2+, Mg2+, Fe2+ or Al3+ can cause tetracycline to become more insoluble
The site where tetracycline are not distributed to
CNS
only a small fraction of the administered dose is found
otherwise, tetracyclines are widely distributed
Which tetracycline attain high concentration in saliva and tears making it useful for tx of meningococal carrier state?
minocycline
*remmber they can’t get to the CNS)
What are two main routes of excretion of tetracyclines?
Urine
Enterohepatic circulation
Which drugs are not eliminated by renal mechanisms and adjustments of these drugs are not required in renal failure?
doxycycline and tigecycline
Which tetracycline has a half life of 36 hrs?
tigecycline
Which tetracyclines have half lives of 16-18 hrs (long lasting)?
doxycycline
minocycline
Clinical uses of tetracyclines
Mycoplasma pneumoniae Ricketssiae (Rocky Mountain Spotted Fever) Chlamydial conjunctivitis Helicobacter pylori-induced ulcers Vibrio infections (cholera) Protozoa/entamoeba ADH secreting tumors Cholera (Vibrio) Malaria Parrot Fever (Chlamydia) Lyme Disease (Borrelia) Q Fever (Coxiella) Anthrax Trachoma
Tx of vibro infections
tetracyclines have rapid actions against cholera (stop shedding of vibro). However resistance may be emerging
What is the drug of choice for chlamydial conjunctivitis
Chlortetracycline
eye drops
What can treat ADH secreting tumors?
Demeclocycline
Which protozoal infections are tx with tetracyclines
Entamoeba histolytica
plasmodium falciparum
Miscellaneous uses of tetracyclines
acne, exercitation of bronchitis, community acquired pneumonia, Lyme disease, relapsing fever, leptospirosis and Mycobacterium marinum
How is tigecycline administered?
IV
Tigecycline is effective against what types of species
many tetracycline resistance strains
Tigecycline has activity against the following strains
Has activity against Coagulase negative staphylococci and Staphylococci aureus and methicillin-resistant strains
Streptococci, penicillin susceptible and resistant, enterococci, vancomycin-resistant strains and gram –ve rods
Clinical uses of tigecycline
Enterobacteriacae, multiple resistant strains of Acenitobacter species, Rickettsiae, chlamydia and legionella
Tetracyclines disrupt normal flora. What are some of the effects?
overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia and candida may give rise to anal pruritus, vaginal or oral candidiasis (yeast infection) or enterocolitis with shock and death
Hepatic necrosis�
an adverse effect seen in pregnancy if pt his given IV tetracycline
Renal insufficiency
tetracycline can accumulate
nitrogen retention
exceptions: doxycycline and tigecycline
Vestibular reaction → dizziness, vertigo
Doxycycline
Agents susceptible to clindamycin
Streptococci, staphylococci and pneumococci �ANaerobic Bacteriodes species �
Agents resistant to clindamycin
enterococci and gram-ve aerobic �
Bacterial resistance to Clindamycin
• Change in one AA can result of loss of affinity for the drug to the bacterial binding site
o Need a larger concentration of drug to achieve the same effect
• Constitutive expression of methylase will result in modification of the drug’s receptors
• Gram (—) are intrinsically resistant due to lack of permeability of cell wall
Enzymatic inactivation of clindamycin
What sites do clindamycin penetrate well?
abscesses … treat pelvic abscesses
Where does clindamycin concentrate?
phagocytic cells via active transport
Where does clindamycin metabolize?
liver
Where does clindamycin get excreted?
urine and bile
Clindamycin and clinical use for the heart
prohpylaxis against endocardiatis in patients with vavular heart diseas�
Clindamycin combined with primaquine
Forms an effective alternative to trimethoprim-sulfamethozazole against moderate to severe pneumocystis jirovei (result of AIDS or corticosteriods) in AIDS patients�
Adverse effects of Clindamycin
impaired liver function - jaundice
neutropenia
severe diarrhea
pseudo membranous colitis - due to clostridium difficile
***Can create a super bug by killing off normal flora → bacteria that remain grow uninhibited and have resistance
Chloramphenicol drug MOA
inhibits bacterial 50S ribosomes and prevent protein synthesis VIA INHIBITING TRANSPEPTIDATION
Which agent is Chloramphenicol active against but not against Chlamydia
Rickettsia
Which other agents are highly susceptible to chloramphenicol?
Haemophilus influenza, N meningitis and bacteriodes
What enzyme is produced to confer resistance to chloramphenicol?
a plasmid encoded enzyme
CHLORAMPHENICOL ACYL TRANSFERASE
Unlike tetracyclines and clindamycin, how is chloramphenicol distributed?
widely distributed throughout the body including the CNS and body fluids
How is chloramphenicol metabolized/eliminated?
Conjugated in the liver (glucuronic acid) and eliminated in urine
Which drug’s dose must be reduced in newborns and premature infants?
Chloramphenicol
because it can cause grey baby syndrome
which two drugs’ doses do not need to be reduced in renal insufficiency?
clindamycin and chloramphenicol
What is the second line drug for cholera?
Chloramphenicol
Tx of serious rickettsial infection such as typhus and rocky mountain spotted fever
chloramphenicol
Alternative to beta-lactam against meningococcal meningitis
chloramphenicol given in its wwho are either hypersensitive to penicillin or if the infection is penicillin-resistant
Tx brain abscess (staph brain abscess)
chloramphenicol
Topical tx of eye infection
chloramphenicol has good penetration into ocular tissues and aqueous humor
why is chloramphenicol rarely used?
toxic
increased resistance
Adverse effect
GI tract: Adults (but not children) commonly develop nausea, vomiting and diarrhea
�
Bone marrow disturbances: decreased production of red blood cells
Aplastic anemia (idiosyncratic) may be reversible but could be fatal
Important Chloramphenicol effect in women
Risk of oral or vaginal candidiasis may occur (due to alteration of normal flora)
What does chloramphenicol inhibit that reduces the rate of metabolism of phenytoin, tolbutamide, chlorpropamide, and warfarin
a CYP inhibitor
increase their half life
Need to adjust the doses of those drugs to avoid toxicity
On which drugs does chloramphenicol have antagonistic effect?
penicillin (cell wall synthesis inhibitors) and aminoglycosides �(protein synthesis inhibitors)
