Antibiotics inhibiting bacterial protein synthesis (12&13&15&16&/17/) Flashcards
Mechanism of action of inhibitors of of protein synthesis
Most of the antibiotics are acting at the ribosomal level
- binding sites for these antibiotics are on the 50S ribosomal subunit
- Tetracyclines and aminoglycosides bind to the 30S ribosomal subunit
Inhibition of transpeptidation
Selective toxicity may be explained by target differences
-Eukaryotic ribosomes have two unequal subunits, designated small subunit (40S) and large subunit(60S)
30S subunit action
Aminoglycosides
tetracyclins
Glycylcyclines
TAG
50S subunit
Amphenicols - chloramphenicol macrolides Ketolides Lincosamide Streptogramins Oxazolidinones
MAK LOS
Aminoglycosides
effect : bactericidal, irreversible inhibition of protein synthesis, 30 S subunit
Agents :
older:
Streptomycin (1944), Neomycin,
Kanamycin,
(Paromomycin, Spectinomycin)
newer: Gentamicin, Tobramycin, Amikacin, Netilmicin (Sisomicin)
Aminoglycosides include:
TANGS Tobramycin Amikacin Neomycin Gentamycin Streptomycin
Mechanism of action:
- AGs penetrate through the outer membrane via porin channels and also direct diffusion through the lipid membrane (b-lactams only via porin channels)
- In the periplasmic space they become protonated (NH3+-form), and then transported across the inner membrane by an oxygen-dependent process - by anaerobic bacteria AGs have no effect!
- In the cytoplasma they bind to the 30S subunit
misreading, nonfunctional or toxic proteins
interference with the initiation complex
inhibition of translocation
- concentration-dependent bactericidal effect
- longer postantibiotic effect, 3-6 h
- a single large dose is less toxic, than multiple smaller doses
once daily dosing
AMINO Against Aerobic gram negative Mainly bactericidal Inhibit protein synthesis at 30S subunit Nephrotoxic Ototoxic
Spectrum :
Gram (-) AEROBIC rods
(E. coli, klebsiella, proteus, enterobacter, acinetobacter, Haemophilus inf., pseudomonas, brucella)
some Gram (+) bacteria (S. aureus, coagulase-negative staphylococci, Streptococcus pyogenes, enterococci)
+ mycobacteria
(anaerobes and intracellular pathogens are resistant!)
Synergism with b-lactams, glycopeptides and antifolate drugs
Mechanisms of resistance:
1) enzymatic inactivation in the periplasmic space
(phosphorylation, adenylation, acetylation
by transferase enzymes, plasmid-mediated)
2) impaired penetration
3) impaired binding to 30S
Pharmacokinetics:
- no absorption (hydrophilic substances) i.v./ i.m. (whole daily dose in a slow /30-60 min/ infusion)
- bad penetration and distribution (Ø penetration into the cells, eye, CNS)
- Ø metabolism
- renal elimination (glomerular filtration), half-life 1,5 - 2 h
renal insufficiency → increased toxicity
~ 90 % eliminated within one day,
~ 10 % is taken up by the proximal tubular cells (half-life ~ 1 week)
good effect by urinary infections
risk of nephrotoxicity
Adverse effects:
- nephrotoxicity
- usually reversible damage of the proximal tubular cells
- ototoxicity
- irreversible damage of the hair cells in the inner ear
- auditory damage (tinnitus, high-frequency hearing loss)
+ vestibular damage (ataxia, vertigo)
- neuromuscular blockade (by rapid i.v. injection of high doses)
- displacing Ca from neuromuscular junction
- inhibiting Ach release from motor nerve
-may provoke myastenic crisis
- allergy (rare)
Clinical uses:
older drugs – local use or special indications (to avoid toxicity)
streptomycin -
oldest, pronounced ototoxicity, i.v./i.m. by tuberculosis
i.m. by plague, tularemia, brucellosis (in comb. with an oral tetracycline)
neomycin - too toxic for parenteral use, only local (eye drops, ointment - infected skin lesions) or oral use (to reduce aerobic bowel flora – bowel surgery, hepatic coma) – THEY ARE NOT ABSORBED
(paromomycin - oral use by intestinal amoebiasis or i.m. by visceral leishmaniasis) Paromomycin (taken orally) is a luminal-active agent; used against intestinal parasites (Entamoeba histolytica
kanamycin - topical use (eye drops, ointment)
tobramycin – more active against pseudomonas or local use in eyedrops
netilmicin – more resistant against transferases
amikacin – most resistant against transferases → broadest spectrum (reserve-AB)
newer drugs – parenteral use by acute, severe infections (e.g. gentamicin)
- endocarditis, peritonitis, sepsis, patients with neutropenia (in combination with b-lactams, but not in the same infusion bottle - staphylococcus, enterococcus)
- pseudomonas infections (with b-lactams) – complicated urinary tract infection
- urinary infections
- osteomyelitis (gentamicin-loaded bone-cement in surgery)
- pelvic or abdominal infections (in combination with clindamycin or metronidazole – anaerobes!)
A complicated UTI is an infection associated with a condition, such as structural or functional abnormalities of the genitourinary tract or the presence of an underlying disease, which increases the risks of acquiring an infection or of failing therapy. Two criteria are mandatory to define a complicated UTI: a positive urine culture and one or more of the factors listed inTable: Vesicoureteric reflux or other functional abnormalities, Urinary tract modifications, such as an ileal loop or pouch, Peri- and post-operative ÚTI, Renal insufficiency and transplantation…
Contraindications : pregnancy, allergy, auditory damage
(Spectinomycin)
- aminocyclitol structure (closely related to aminoglycosides)
- binds to the 30S subunit, but Ø misreading, acts only bacteriostatic
- only indication: gonorrhea (if allergy or resistance against b-lactams)
(single dose - 2 g i.m.) - side effects: local pain, fever, nausea
Which aminoglycoside has antituberculotic action
streptomycin
Kanamycin
Amikacin
eye drop aminoglycoside
Tobramycin
also nebulized for pseudomonas aerigunosa in cystic fibrosis patients
neomycin
kanamycin
Oxazolidinones
Linezolid
Tedizolid
Linezolid
Oxazolidinones
synthetic antibiotic
Effect :
bacteriostatic, inhibition of protein synthesis
Mechanism of action :
- binding to the 50 S subunit
inhibit the formation of the initiation complex
- Binds to the 50S ribosomal subunit; inhibits the formation of initiation complex in bacterial translation system
- Bacteriostatic effect
resistance:
- Altered affinity to binding site (currently resistant strains are rare)
- mutation of the binding site
- few organisms have resistant due to special structure, reserved for bacteria which have developed resistsance against other ABiotics. MRSA VRE
Spectrum :
Gram (+) multiresistant pathogens (including MRSA, GRSA (glycopeptide resistant), VRSA, VRE ) staphylococci, streptococci, enterococci (against streptococci- baktericidal) corynebacteria, Listeria monocytogenes
- Effective against multidrug resistant gram-positive cocci (MRSA, PRSP, VRE)
Indications :
reserve antibiotic,
against MRSA, glycopeptide-resistant strains (endocarditis, peritonitis)
- nosocomial or community-acquired pneumonia
- severe skin and soft tissue infections
Kinetics :
- good absorption and central penetration
- half-life ~ 6 h
- metabolism ~ 30 % (inactive metabolites)
- elimination by the kidneys (~ 40 %) and with the feces (~ 60 %)
- Oral/parenteral
- Hepatic metabolism
- T1/2 4-6 h’
- Inhibitor of MAO-A and MAO-B
Side effects :
- myelosuppression (anemia, leukopenia, thrombocytopenia / ~3 % /)
- blood control weekly !
- inhibition of monoamine oxidase (MAO)!!!
- interaction with adrenergic / serotonergic drugs (e.g. risk of serotonin syndrome)
- gastrointestinal (nausea, diarrhea)
- neuropathy, headache, elevation of transaminases, allergy
- Thrombocytopenia
- Neutropenia
- Optic neuropathy
- Serotonin syndrome (in combination with SSRI’s), due to partial MAO inhibition
inhibition of MAO-> no breakdown of serotonin -> risk for serotonin syndrome (also careful with tyramine containing food?)
Tetracyclines
(Tetracycline)
(Oxytetracycline)
Doxycycline
(Minocycline)
absorption: 80 %
T1/2 12-18 h
- oral / i.v./ local use
- moderate / good absorption after oral administration
- tetracyclines chelate divalent metal ions (e.g. Ca2+, Mg2+) → antacids, milk reduce the absorption!
- wide distribution (placenta, fetus, milk, gall bladder, skin), except for CNS (10-20 %)
- tetracycline and oxytetracycline excreted mainly by the kidneys (dose reduction in renal insufficiency)
- DOXYCYCLINE and minocycline excreted mainly in the bile
Effect :
bacteriostatic, inhibition of protein synthesis
Mechanism of action :
binding to the acceptor site of the 30S subunit
Spectrum : originally broad (many Gram (+) and Gram (-) bacteria, aerobic and anaerobic), but several strains became resistant (efflux, ribosomal protection, impaired influx or enzymatic inactivation)
- Gram (-) rods (H. influenzae, Brucella spp., P. multocida, yersinia, vibrios, Francisella tularensis + E. coli and klebsiella with ~ 30 % resistance)
- atypical bacteria!!!!!!!!!
- intracellular pathogens (rickettsiae, chlamydiae, francisella tularensis, coxiella Burnetii, Borrelia burgdorferi)
- spirochetes (leptospira, borrelia, treponema)
- some anaerobes (e.g. propionibacteria, but not B. fragilis)
- mycoplasmas, ureaplasmas
- some protozoa (e.g. Plasmodium falciparum, E. hystolytica)
proteus and pseudomonas are resistant against all tetracyclines!
Clinical uses : mainly special indications
- community-acquired pneumonia (Mycoplasmas, Chlamydia psittaci) - non-gonococcal urethritis, STD (Chlamydiae, Mycoplasmas, Ureaplasmas) - pelvic infections, prostatitis - trachoma (Chlamydia trachomatis) - chlamydial salpingitis and pelvic inflammatory disease
cholera, yersiniosis, rickettsiosis
Lyme disease, syphilis, leptospirosis (by penicillin allergy)
- plague, tularemia, brucellosis (in combination with aminoglycosides)
- acne (topical use)
- malaria (by chloroquine-resistance)
- eradication of meningococcal carrier state (minocycline, but rifampin is preferred)
Interactions :
- antacids, iron preparations, laxatives, milk reduce absorption
- effect of oral anticoncipients can be reduced (rarely)
Side effects :
- GI disturbances (most common)
nausea, vomiting, diarrhea, rarely enterocolitis or oral candidiasis
- esp. by agents with poor absorption (e.g. chlortetracycline, oxytetracycline)
- oesophageal ulceration (doxycycline, pills should be taken with liquids)
2. chelation (with di- and trivalent cations, Ca2+, Mg2+, Al3+, Fe3+) → damage of bones, teeth (discoloration, caries, growth inhibition)
3. in pregnants, lactating women and children under 8 years of age, tetracyclines are contraindicated!
- photosensitization (rash, urticaria)
- esp. demeclocycline
- avoid sunbath or solarium during therapy! - local reactions – pain, venous thrombosis (avoid i.m. administration)
- liver toxicity (rarely, at higher doses or in hepatic diseases or pregnants)
- vestibular reactions (vertigo, dizziness, nausea) – more often with minocycline, and at higher dosage
- renal toxicity, hematological problems (rarely)
INTRACELLULAR MICROBES AND TICK BORNES
spirochetes intercellular pathogens protozoa atypical bacterio some anaerobes gram- rods mycoplasma ureaplasma
Glicilcyclines
Tigecycline
Tigecycline
Tetracycline derivative- glycylcyclines
*Tigecycline is classified under the novel antibiotic group Glycylcyclines, derived from tetracycline
Mechanism:
Same as with tetracyclines
- Binding to the 30S ribosomal subunit; inhibit binding of charged tRNA to the acceptor site (event inhibited → amino acid incorporation)
- Bacteriostatic effect
- Tetracyclines act as chelators – bind divalent cations (Ca2+, Mg2+, Fe2+), which decrease their absorption
- Accumulation in bone and teeth (due to the high Ca2+ content)
- Organisms resistant to standard tetracycline
- MRSA strains, VRE strains
- IV only
- Excreted in bile
- T1/2 40 h’
- Pseudomonas and Proteus are resistant
- GI distress (superinfections may lead to severe colitis or candidiasis)
- Enamel dysplasia, bone growth abnormalities
- Hepatotoxicity (high risk during pregnancy and patients with pre- existing liver disease)
- Nephrotoxicity (RTA, Fanconi syndrome)
- Photosensitivity
- Vestibular toxicity (dose-dependent, reversible)
- Teratogenic
bacteriostatic
Spectrum (tetracycline-resistant strains are sensitive to it)
- MRSA, VRSA
- Vancomycin-resistant enterococci or ESBL-producing Gram-
- Penicillin resistant Streptococcus pneumoniae
-No effect on pseudomonas
broad spectrum for doxycycline resistant pathogens!?
- Only parenteral (iv)
- Elimination via biliary tract
Tigecycline complicated skin infections or intraabdominal infections
Macrolides
(Erythromycin)
oral bioav.: 25%
T1/2 - 2h
Clarithromycin
50%
5h
- azithromycin has better effect against G (–) bacteria (esp. haemophilus), but weaker against pneumococci
- clarithromycin acts better against G (+) bacteria
Roxithromycin
60%
11h
Azithromycin
40%
20-40h
Long PAE for azithromycin (able to reach high concentrations in macrophages)
Effect :
bacteriostatic, inhibition of protein synthesis
Mechanism of action :
binding to the 50 S subunit, inhibition of translocation
same binding site with clindamycin (inhibition + cross-resistance)
- Good oral absorption (except for erythromycin)
- good distribution (also in placenta, breast milk), accumulation in phagocytic cells (especially azithromycin), but poor CNS penetration
biliary elimination
inhibition of cytochrom-P450 CYP3A4
anticoagulants, carbamazepine, cisapride, digoxin, and theophylline
(erythromycin=clarithromycin > roxithromycin)
Spectrum similar to penicillins, USE IN CASE OF PENICILLIN ALLERGIES:
- G (+) bacteria (staphylococci, streptococci, corynebacteria)
- G (-) bacteria (neisseria, Bordetella pertussis, legionella, brucella, haemophilus, moraxella, H pylory)
- atypical pathogens
- bacteria without cell wall / intracellular pathogens (mycoplasma, rickettsia, chlamydia)
- spirochetes (treponema, borrelia, campylobacter)
- some anaerobes (e.g. propionibacteria)
Resistance: mainly plasmid-encoded
Plasmid-mediated:resist plasmidis a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; however,plasmidsare sometimes present in archaea and eukaryotic organisms. anceis the transfer of antibioticresistancegenes which are carried onplasmids.
Indications :
- respiratory infections
- otitis, sinusitis, tracheobronchitis (in case of penicillin allergy)
- community-acquired pneumonia (pneumococcus, mycoplasma, chlamydia, legionella)
(against legionella azitromycin or clarithromycin, in severe cases with rifampicin)
- scarlet fever, tonsillitis, erysipelas (streptococci)
- diphtheria, listeriosis
- campylobacter jejuni enteritis
- STDs (syphilis, gonorrhea, chlamydia)
- other chlamydial infections (trachoma, pelveoperitonitis)
- acne (topically)
- eradication of H. pylori (clarithromycin)
- toxoplasmosis during pregnancy (spiramycin)
safe during pregnancy - toxoplasmosis
Adverse effects: rare, well tolerated
- gastrointestinal disturbances
- vomiting, diarrhea, rarely reversible cholestatic jaundice - especially with erythromycin - allergy (rarely)
- neurotoxicity (rarely, headache, dizziness)
- teratogenicity in animal experiments (clarithromycin)
- phlebitis, prolonged QT (rapid infusion)
(Fidaxomicin)
pregnancy patient with upper respiratory tract infection and penicillin allergy
use macrolides
Ketolides
semisynthetic macrolide-derivatives
Telithromycin (Cethromycin, Narbomycin - under clinical trials)
Effect :
bactericidal, inhibition of protein synthesis
- inhibition of CYP3A4 and CYP2D6
Mechanism of action :
binding to the 50 S subunit (23S ribosomal RNA)
translocation and formation of the initiation complex ↓
Antibacterial activity :
- same as with macrolides, but also acts against macrolide-resistant strains (MLSB (Macrolide-lincosamide-streptogramin B resitant Pneumococci)
- stronger action against G (+) bacteria and H. influenzae
Indications :
- respiratory infections
- sinusitis, otitis, tonsillopharyngitis
- acute exacerbations of chronic bronchitis
- community-acquired pneumonia
Side effects :
- GI (diarrhea ~ 13 %, nausea)
- hepatotoxicity
- CNS (headache), blurred vision, disturbances in taste, allergy, QT-prolong.
Pharmacokinetics :
- ~ 60 % bioavailability,
T1/2 ~ 10 - 14 h,
metabolites eliminated in the feces
Chloramphenicol
has a simple and distinctive structure
Effect :
bacteriostatic, inhibition of protein synthesis
Mechanism of action :
binding to the 50 S subunit - peptidyl transferase ↓
- Binds reversibly to the 50S subunit of bacterial ribosome, inhibits peptide bond formation (catalysed by peptidyl transferase)
- Bacteriostatic effect
- Some strains of H. influenza, N. meningitidis, and Bacteroides are highly-susceptible – for these organisms, chloramphenicol may be bactericidal
bactericides and h. influenza are mostly resistant?
only use for intracellular pathogens, in some 3rd world countries for meningitis and cephalosporin allergy
Spectrum :
- Wide spectrum
- Clinical use as systemic drug is limited due to toxicity
- Topical antimicrobial agent
- Empiric treatment of bacterial meningitis
(in developing countries)
- Backup drug against Rickettsia, B. fragilis,
Salmonella
originally broad spectrum, but many strains became resistant
(enzymatic modification or impaired penetration)
- G (+)- and G (-) bacteria (but e.g. staphylococci, S. pneumoniae, H. influenzae, salmonella, shigella are resistant)
- intracellular pathogens (rickettsia) -> rocky mountain spotted fever
- anaerobes (but not B. fragilis)
Indications :
very limited, only rarely used (resistance + toxicity)
- abscesses (brain, stomach - good penetration and activity against anaerobes, usually after metronidazole + cephalosporins (in case of unsuccessful treatmen))
- rickettsial infections in children (tetracyclines are contraindicated)
- meningitis (in case of cephalosporin-allergy)
- eye infections (locally, but no effect against chlamydia)
Pharmacokinetics :
- Oral/parenteral
- Freely crosses placenta and
blood-brain barrier - Enterohepatic cycling
- Hepatic metabolism; dose-reduction required in hepatic impairment
- Inhibitor of CYP450 enzymes
- rapid and complete absorption
- wide distribution (CNS, placenta, abscesses, eye, intracellular space)
- hepatic metabolism (70 – 90 %, conjugation with glucuronic acid), inactive metabolites excreted renally (tubular secretion)
- ~ 10 % eliminated unchanged in the urine
also used in solutions, ointments
very severe side effects - not used much
Side effects: !!!!!!!!!
- hematotoxicity
- dose-dependent, reversible anemia
- idiosyncratic (not dose-dependent) aplastic anemia (1:20000) (potentially lethal)
„gray baby syndrome”!!!!!!!!!
in newborns and premature infants (decreased conjugation)
- ‘Grey baby syndrome’:
decreased RBC’s, cyanosis, cardiovascular collapse in infants
‘Grey baby syndrome’ → pathomechanism involves decreased activity of glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol
vomiting, gray skin (pallor and cyanosis), acidosis, hypothermia (can be fatal)
neurotoxicity (after prolonged use, dizziness, headache)
gastrointestinal disturbances (nausea, vomiting) risk of candida superinfection
inhibition of CYP450 CYP → drug interactions
resistance:
- Bacteria may express plasmid-encoded acetyltransferase enzymes, that inactivate the drug
- Alteration of drug binding site
Streptogramins
Quinapristin (Streptogramin B) + Dalfopristin (Streptogramin A) (30:70, synergistic activity)
used together
Quinapristin (Streptogramin B) + Dalfopristin (Streptogramin A)
used together
Effect :
rapid bactericidal, inhibition of protein synthesis
Mechanism of action :
binding to the 50 S subunit - peptidyl transferase ↓
- Bind to the 50S ribosomal subunit; blocking the exit channel on the ribosome through which nascent polypeptides are extruded
- Bactericidal effect
resistance: mutation of the binding site, enzymatic inactivation or efflux) - Efflux pump - E. faecalis is resistant
Spectrum :
- G (+) cocci (including multiresistant strains, like MRSA, penicillin-resistant S. pneumoniae and glycopeptide- resistant E. faecium) – no effect against E. faecalis
- some G (–) bact. (neisseria, H. influenzae, moraxella, legionella) /but no effect against enterobacteria or Pseudomonas/
- some atypical bacteria (mycoplasma, chlamydia)
combination of:
Quinupristin Dalfopristin
- Effective against MRSA, PRSP, VRSA, and resistant strains of E. faecium
- Considered as ‘reserve antibiotics’ for complicated resistant infections
Indications :
- reserve antibiotics in case of severe infections
- nosocomial pneumonia
- severe skin and soft tissue infections
- infections caused by glycopeptide- resistant E. faecium
Side effects :
- GI disturbances (nausea, diarrhea)
- arthralgia, myalgia (dose-dependent)
- local reactions (inflammation, pain, phlebitis) - infusion only via central venous catheter (+ rinsed with glucose solution)
- skin reactions (exanthems, itching)
- hyperbilirubinemia
- Arthralgia-myalgia syndrome
Pharmacokinetics :
- only IV and no brain prenetration
- inhibition of CYP3A4
- i.v. administration (1-h-infusion), strong binding to plasma proteins, no brain penetration
- short T1/2 (quinupristin ~ 3 h, dalfopristin ~ 1 h), but accumulation in the leukocytes
- metabolites are eliminated in the feces
Lincosamide
(Lincomycin (from Streptomycin lincolensis, barely used))
Clindamycin!!!
(semisynthetic, 7-Cl-lincomycin)
Mechanism of action similar to macrolides
Clindamycin
Effect : bacteriostatic
Lincosamide
Mechanism of action :
binding to the 50 S subunit, inhibition of translocation
(similar to macrolides)
+ inhibition of bacterial toxin production!!
Spectrum :
- G (+) and (-) bacteria (staphylo-, streptococci)
- anaerobes (B. fragilis, fusobacteria, Gardnerella vaginalis, clostridia – but not C. difficile)
+ Chlamydia trachomatis,
P. falciparum,
Toxoplasma gondii,
Pneumocystis carinii
Narrow spectrum: - Gram-positive cocci, anaerobic organisms - Skin and soft tissue infection caused by Staph., and Strep. - Community-acquired MRSA - Osteomyelitis (by Staph.) - Endocarditis prophylaxis - Pneumocystis jirovecii, toxoplasmosis - Polymicrobial infections of the abdomen, gut, and female genital tract (usually in combination with aminoglycosides) - B. fragilis infection (lung abscess due to aspiration pneumonia)
Indications :
- infections caused by G (+) bacteria in case of penicillin allergy
- aspiration pneumonia
- dental infections /prophylaxis in case of penicillin allergy)
- toxic shock syndrome - activity against bacterial toxin
- pelvic and abdominal mixed infections (in combination with aminoglycosides)
- chronic osteomyelitis
- acne
- pneumocystis pneumonia (with primaquine) and toxoplasmosis (with pyrimethamine) in AIDS patients
Side effects :
- GI disturbances (diarrhea, pseudomembranous colitis)
- allergy (morbilliform rash, itching)
- hematologic (rarely, leukopenia, thrombocytopenia)
- increases the effect of peripheral muscle relaxants (e.g. succinylcholine)
- Neutropenia
- Hepatotoxicity
- C. difficile superinfection (pseudomembranous colitis
Kinetics:
- oral bioavailability ~ 80 %
- good distribution (joints, bones, intracellular, placenta, breast milk), but poor CNS penetration
- Oral, parenteral
- Hepatic metabolism, excreted in bile and urine both intact and metabolised
Contraindications:
lactation,
newborns
resistance:
- Methylation of ribosomal binding site
- Enzymatic inactivation
- Poor penetration via the outer membrane of gram- negative bacteria (intrinsic resistant)
Fusidic acid
Effect :
bacteriostatic, inhibition of protein synthesis, not entirely known mechanism
- inhibits elongation factor G
Spectrum :
- G (+) bacteria (staphylococci - also MRSA, streptococci, corynebacteria)
Kinetics :
- good absorption and tissue penetration (except CNS)
- hepatic metabolism, half-life ~ 9 h
Indications :
used mainly topically
- Inhibitor of bacterial protein synthesis – inhibits elongation factor G
- Bacteriostatic effect
- Gram-positive
- Aerobes and anaerobes
- Topical → skin infections
(cellulitis, impetigo),
conjunctivitis - Systemic → MRSA infections
- Topical/parenteral
- Hepatotoxicity (with systemic use)
Cellulitis, impetigo
˃ Topical agents -> 1st line
Gram positive cocci (staphylococci, streptococci) -topical application
Mupirocin
Effect :
bacteriostatic, inhibition of protein synthesis
Spectrum :
G (+) cocci (streptococci, staphylococci - also MRSA)
Indications :
- minor skin infections caused by staphylococci
- only local use (fast systemic inactivation)
Side effects :
local reactions,
itching
- Inhibits bacterial protein synthesis by selectively binding to isoleucyl-tRNA synthetase
- Active against gram-positive cocci
- Treatment of impetigo caused by Staphylococci (including MRSA), β-hemolytic streptococci, S. pyogenes
- Intranasal ointment for eliminating nasal carriage of S. aureus (medical workers)
- Topical administration (not absorbed)
- Local itching and burning
- Rash, erythema, contact
dermatitis
Cellulitis, impetigo
˃ Topical agents -> 1st line
Gram positive cocci (staphylococci, streptococci) -topical application
gentamicin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action (independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
- Aerobic gram-negatives
(E. coli, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia) - Commonly used in combination with beta-lactam antibiotics:
Enterococci (with penicillin)
Pseudomonas (with 3rd gen’ cephalosporin) - Parenteral
- T1/2 2-3 h’
- Renal elimination (directly proportional
to creatinine clearance) - Dose reduction in renal impairment
- Requires monitoring of drug plasma
concentrations (due to narrow TI) - Dosing regimens consist of 2-3 times daily (traditionally), or once-daily
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
*Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
tobramycin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action
(independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
tobramycin – more active against pseudomonas or local use in eyedrops
- Aerobic gram-negatives
(E. coli, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia) - Commonly used in combination with beta-lactam antibiotics:
Enterococci (with penicillin)
Pseudomonas (with 3rd gen’
cephalosporin) - Parenteral
- T1/2 2-3 h’
- Renal elimination (directly proportional
to creatinine clearance) - Dose reduction in renal impairment
- Requires monitoring of drug plasma
concentrations (due to narrow TI) - Dosing regimens consist of 2-3 times daily (traditionally), or once-daily
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
- Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
netilmicin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action
(independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
tobramycin – more active against pseudomonas or local use in eyedrops
- Aerobic gram-negatives
(E. coli, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia) - Commonly used in combination with beta-lactam antibiotics:
Enterococci (with penicillin)
Pseudomonas (with 3rd gen’
cephalosporin) - Parenteral
- T1/2 2-3 h’
- Renal elimination (directly proportional
to creatinine clearance) - Dose reduction in renal impairment
- Requires monitoring of drug plasma
concentrations (due to narrow TI) - Dosing regimens consist of 2-3 times daily (traditionally), or once-daily
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
*Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
netilmicin – more resistant against transferases
amikacin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action
(independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
amikacin – most resistant against transferases → broadest spectrum (reserve-AB)
- Aerobic gram-negatives
(E. coli, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia) - Commonly used in combination with beta-lactam antibiotics:
Enterococci (with penicillin)
Pseudomonas (with 3rd gen’
cephalosporin) - Parenteral
- T1/2 2-3 h’
- Renal elimination (directly proportional
to creatinine clearance) - Dose reduction in renal impairment
- Requires monitoring of drug plasma
concentrations (due to narrow TI) - Dosing regimens consist of 2-3 times daily (traditionally), or once-daily
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
- Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
streptomycin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action
(independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
streptomycin -
oldest, pronounced ototoxicity, i.v./i.m. by tuberculosis
i.m. by plague, tularemia, brucellosis (in comb. with an oral tetracycline)
- In combination with penicillin:
Tuberculosis, tularemia, plague
Enterococcal endocarditis - Parenteral
- T1/2 2-3 h’
- Renal elimination (directly proportional
to creatinine clearance) - Dose reduction in renal impairment
- Requires monitoring of drug plasma
concentrations (due to narrow TI) - Dosing regimens consist of 2-3 times daily (traditionally), or once-daily
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
- Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
kanamycin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action
(independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
kanamycin - topical use (eye drops, ointment)
- Used to suppress intestinal flora before bowel surgery
- Topical use (neomycin)
- Oral, topical
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
- Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
neomycin
Mechanism of action:
- Penetration through bacterial cell requires O2-dependent active transport; entry can be enhanced by cell wall synthesis inhibitors (antimicrobial synergism)
- Bind to the 30S ribosomal subunit and interfere with protein synthesis by: (1) blocking formation of the initiation complex; (2) inducing misreading of mRNA, causing
incorporation of incorrect peptides, which yield a non-functional protein; (3) inhibiting translocation
- Bactericidal effect; concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC). In contrast with time-dependent killing action
(independent of concentration, continues as long as blood levels are maintained above the MIC) shared by penicillins and cephalosporins
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
- Toxicity of aminoglycosides is both concentration-dependent and time-dependent
- Once-daily dosing of aminoglycosides → provides post-antibiotic effect, reduces severity of side effects
Toxicity and side effects:
- Ototoxicity → auditory damage (irreversible), vestibular damage (reversible); toxicity proportional to plasma levels
- Nephrotoxicity → proteinuria, acidosis, hypokalemia, acute tubular necrosis (more common in the elderly, usually reversible); risk enhanced by vancomycin,
amphotericin B, cyclosporine, loop diuretics, cisplatin
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
neomycin - too toxic for parenteral use, only local (eye drops, ointment - infected skin lesions) or oral use (to reduce aerobic bowel flora – bowel surgery, hepatic coma) – THEY ARE NOT ABSORBED
- Used to suppress intestinal flora before bowel surgery
- Topical use (neomycin)
- Oral, topical
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
- Netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria
Doxycycline
Tetracyclines
Mechanism of action:
- Binding to the 30S ribosomal subunit; inhibit binding of charged tRNA to the acceptor site (event inhibited → amino acid incorporation)
- Bacteriostatic effect
- Tetracyclines act as chelators – bind divalent cations (Ca2+, Mg2+, Fe2+), which decrease their absorption
- Accumulation in bone and teeth (due to the high Ca2+ content)
- Alternative treatment to macrolides in community- acquired pneumonia
- Gonorrhea, chlamydia
- Tick-borne diseases
- Zoonotic diseases
- Acne treatment (covers Propionibacterium acnes)
- Drug accumulates intracellularly
- Excreted in feces
- Safe to use in renal dysfunction
- Efflux pump expressed by bacteria – lowers effective drug concentration
- Alteration of ribosomal binding site
- Formation of ribosomal- protecting proteins that interfere with drug binding
- Resistance to most tetracyclines is wide-spread nowadays
- GI distress (superinfections may lead to severe colitis or candidiasis)
- Enamel dysplasia, bone growth abnormalities
- Hepatotoxicity
(high risk during pregnancy and patients with pre- existing liver disease) - Nephrotoxicity
(RTA, Fanconi syndrome) - Photosensitivity
- Vestibular toxicity
(dose-dependent, reversible) - Teratogenic
Tetracycline – Contraindications:
- Children < 10 years of age
- Pregnancy
- Pre-existing liver disease (requires cautious)
Clarithromycin
Macrolides
Mechanism of action:
- Bind to the 50S ribosomal subunit; inhibit translocation of peptidyl tRNA from acceptor to donor site
- Bacteriostatic effect
- Non-antimicrobial immunomodulatory properties (neutrophils ↓, inflammatory cytokines ↓)
Clarithromycin
50%
5h
- clarithromycin acts better against G (+) bacteria
- Similar to erythromycin
- Prophylaxis against M. avium
- H. pylori eradication regimen
- Hepatic metabolism or renal elimination of intact drug
- Inhibitor of CYP450 enzymes
- Methylation of ribosomal binding site
- Efflux pump
- Drug-metabolising
esterase enzymes (Enterobacteriaceae) - Cross-resistance with clindamycin, and
streptogramins - GI distress
(motilin receptor stimulation → enhanced peristalsis) - Ototoxicity (at high doses)
- Skin rash
- Eosinophilia
- QT prolongation
- Acute cholestatic hepatitis (generally rare, more common with erythromycin)
Roxithromycin
Macrolides
Mechanism of action:
- Bind to the 50S ribosomal subunit; inhibit translocation of peptidyl tRNA from acceptor to donor site
- Bacteriostatic effect
- Non-antimicrobial immunomodulatory properties (neutrophils ↓, inflammatory cytokines ↓)
Roxithromycin
60%
11h
Broad spectrum: - Gram-positive cocci, gram-negatives, atypicals - Chlamydia, Mycoplasma, Legionella, Campylobacter - Bordetella pertussis (treatment and prophylaxis) - Community-acquired pneumonia - No activity against MRSA and PRSP - Prokinetic agent
- Oral
- Biliary elimination
- Inhibitor of CYP450 enzymes
- Methylation of ribosomal binding site
- Efflux pump
- Drug-metabolising
esterase enzymes (Enterobacteriaceae) - Cross-resistance with clindamycin, and
streptogramins - GI distress
(motilin receptor stimulation → enhanced peristalsis) - Ototoxicity (at high doses)
- Skin rash
- Eosinophilia
- QT prolongation
- Acute cholestatic hepatitis (generally rare, more common with erythromycin)
Azithromycin
Macrolides
Mechanism of action:
- Bind to the 50S ribosomal subunit; inhibit translocation of peptidyl tRNA from acceptor to donor site
- Bacteriostatic effect
- Non-antimicrobial immunomodulatory properties (neutrophils ↓, inflammatory cytokines ↓)
Azithromycin
40%
20-40h
Long PAE for azithromycin (able to reach high concentrations in macrophages)
- azithromycin has better effect against G (–) bacteria (esp. haemophilus), but weaker against pneumococci
Similar to erythromycin - More selective to Neisseria, H. influenza, M. catarrhalis - Urogenital infections caused by Chlamydia (single dose)
- Absorption impeded by food
- Reaches high intracellular
concentrations (ex. Phagocytes) - Renal elimination as intact drug
- T1/2 2-4 days
- Methylation of ribosomal binding site
- Efflux pump
- Drug-metabolising esterase enzymes (Enterobacteriaceae)
- Cross-resistance with clindamycin, and
streptogramins - GI distress
(motilin receptor stimulation → enhanced peristalsis) - Ototoxicity (at high doses)
- Skin rash
- Eosinophilia
- QT prolongation
- Acute cholestatic hepatitis (generally rare, more common with erythromycin)
telithromycin
Ketolide
Structurally related to macrolides; mechanism of action, resistance, and spectrum similar to erythromycin
Telithromycin
- Macrolide-resistant strains (S. pneumoniae)
- Oral; given once daily
- Eliminated in bile and urine
- Inhibitor of CYP450 enzymes
- Hepatotoxicity
- QT prolongation
