Antibacterials: Cell Wall Synthesis Inhibitors Flashcards
Inhibitors of cell wall synthesis - categories
Beta-lactam antibiotics: penicillins, cephalosporins, carbapenems, monobactams
Vancomycin
Daptomycin
Bacitracin
Fosfomycin
Inhibitors of cell wall synthesis are inactive against what organisms
Organisms without peptidoglycan cells wall: mycoplasma, protozoa, fungi, viruses
Resistance to b-lactams
Beta-lactamases are bacterial enzymes (penicillinases, cephalosporinases) that hydrolyse b-lactam ring
Bacteria with this enzyme can resist effects of penicillins (eg: staph aureus, b-lactamases also found in periplasm of Gm- bacteria)
Beta-lactamase inhibitors
Clavulanic Acid
Sulbactam
Tazobactam
Clavulanic acid, sulbactam, tazobactam MOA and use
b-lacatamase inhibitors –> protect b-lactam antibiotics from inactivation
Contain b-lactame ring but do not have significant antibacterial activity –> bind to and inactivate most b-lactamases
Are available only in fixed combinations with specific penicillins (eg: augmentin = amoxicillin + clavulanic acid)
Beta-lactam antibiotics MOA
Require actively proliferating bacteria (cell wall synthesis must be occurring)
Target: Beta-lactams bind to penicillin-binding proteins (PBP) –> BPB are bacterial enzymes (transpeptidases) involved in cell wall synthesis)
Inhibit last step in peptidoglycan synthesis (cross-linking of peptidoglycan in cell wall) through binding to PBPs –> activated autolytic enzymes to initiate cell death —> bacteria eventually lyse due to activity of autolysis and inhibition of cell wall assembly
Are bactericidal
Penicillin antibacterial spectrum
Ability to reach PBPs determined by: size, charge and hydrophobicity
Gram positive bacteria have cell wall easily crossed by penicillins
Gram negative bacteria have porins (channels) to permit transmembrane entry
Penicillin + aminoglycoside therapy MOA and use
Penicillins facilitate movement of aminoglycosides through the cell wall so that they can reach their target, ribosomes, to inhibit protein synthesis
Should never be placed in the same infusion fluid as they form an inactive complex but can be given at the same time
Effective empiric treatment for infective endocarditis
Mechanisms of resistance to penicillins (4)
- Inactivation by b-lactamases***
- Modification of target PBPs (eg: MRSA does this)
- Impaired penetration of drug to target PBPs (eg: modification of porins by Gm - bacteria)
- Increased efflux
Natural penicillins: antibacterial spectrum and route of administration
Penicillin G
Active against - most Gm+ cocci, Gm+ rods, Gm- cocci and most anaerobes
Cannot be given orally
Penicillin V
Same as penicillin G but less active against Gm - bacteria
More acid stable than G (can be given orally)
Penicillin G clinical applications
Mostly used for Gm + bacteria:
Syphilis: use benzathine penicillin G
Strep infections
Susceptible pneumococci –> most are resistant but few are sensitive rarely used
Repository Penicillins (route of administration, PK, clinical applications)
Developed to prolong duration of penicillin
Penicillin G procaine:
- Given IM (not IV due to risk of procaine toxicity)
- t1/2 = 12-24 hours
- rarely used due to increased resistance
Penicillin G benzathine
- Given IM
- t1/2: 3-4 weeks
- Treatment of syphilis
- Rheumatic fever prophylaxis
Penicillin V clinical applications
Given orally for mild-moderate infections:
- Pharyngitis
- Tonsilitis
- Skin infections (caused by Strep)
Anti-staphylococcal Penicillins
Methicillin
Nafcillin
Oxacillin
Dicloxacillin
Methicillin, nafcillin, oxacillin and dicloxacillin MOA and clinical applications
Anti-staphylococcal penicillins –> bind to PBPs –> inhibit cross-linking of peptidoglycan cell wall –> activate autolytic enzymes –> bactericidal
Very narrow antibacterial spectrum
b-lactamase resistant (only penicillins that are resistant) –> only used to treat b-lactamase producing staphylococci
Inactive against MRSA
Extended-spectrum penicillins
Ampicillin
Amoxicillin
Ampicillin and amoxicillin antibacterial spectrum
Extended-spectrum penicillins –> similar to penicillin G (active against most Gm+ cocci, Gm+ rods, Gm- cocci and most anaerobes) + additional Gm - activity
Susceptible to b-lactamases –> activity is enhanced with b-lactamase inhibitors
Extended-spectrum penicillins PK + main AE
Amoxicillin has higher oral bioavailability that other penicillins: given orally
Ampicillin - given IM
AE:
Pseudomembranous colitis - ampicillin
Maculopapular rash - caused by both
Amoxicillin clinical applications
Treatment of many infections
- acute otitis media
- streptococcal pharyngitis
- pneumonia
- skin infections
- UTIs
- widely used to treat upper respiratory infections
** Common antibiotic prescribed in children and in pregnancy
Can be used for prophylaxis of susceptibly infections
Amoxicillin + clavulanic acid: preferred prophylactic treatment for dog, cat and human bites
Ampicillin clinical applications
Treatment of many infections
- acute otitis media
- streptococcal pharyngitis
- pneumonia
- skin infections
- UTIs
Ampicillin + sulbactam: preferred prophylactic treatment for dog, cat and human bites
Antipseudomonal penicillins
Carbenicillin
Ticarcillin
Pipercillin
“CTP - can touch pseudomonas”
Carbenicillin, ticarcillin, pipercillin antibacterial spectrum and clinical applications
Antipseudomonal penicillins: effective against many Gm- and Gm+ bacilli +active against P.aeruginosa (broad spectrum)
Commonly used to treat Pseudomonas aeruginosa
Main clinical use: as an injectable treatment of gram negatives
Treatment of moderate-severe infections of susceptible organisms: uncomplicated and complicated skin, gynecologic and intra-abdominal infections, febrile neutropenia
Penicillins PK: absorption
Very short half-lives: 30-60 minutes (except repository penicillins)
Oral absorption impaired by food (except amoxicillin which has high oral bioavailability).
Nafcillin = erratic, not given orally
Penicillins ineffective against infections located in which body part
Low levels of distribution in prostate and eye –> insufficient to treat infections in these areas
Poor CSF penetration (except in meningitis)
Penicillins PK: distribution
- All achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids and urine
- Nafcillin, ampicillin and piperacillin –> high levels in bile
- Low levels in prostate and eye***
- Poor CSF penetration (except in meningitis)
Penicillins PK: excretion
Mainly by kidneys (need to be careful to adjust dose in patients with renal failure)
Nafcillin –> mainly in bile (can give to someone with renal failure)
Oxacillin and dicloxacillin = renal + biliary excretion
Main AE of penicillins
Hypersensitivity - penicillin acid (degradation product) is a major antigenic determinant. 5% patients claim to have some reaction (maculopapular rash –> anaphylaxis)
GI disturbance –> diarrhea
Pseudomembranous colitis (ampicillin)
Maculopapular rash (ampillicin, amoxicillin)
Neurotoxicity - epileptic patients at risk
Interstitial nephritis (particularly methicillin)
Cephalosporins MOA
Beta-lactam antibiotics –> inhibit cell wall synthesis by inhibiting cross-linking of peptidoglycans –> bactericidal
Less susceptible to beta-lactamases than penicillins
Antibacterial spectrum of cephalosporins
From 1st to 3rd generation: gram positive activity decreases and gram negative activity increases
4th generation: broad spectrum. Similar activity to 1st generation against gram positive cocci + active against most gram-negative bacilli
5th generation: similar to 3rd but can act against MRSA
All inactive against: "LAME" Listeria Acinetobacter Atypicals: mycoplasma (no cell wall), chlamydia and legionella (intracellular) Enterococci
Cephalosporins inactive against
1st - 4th generation: inactive against MRSA
All inactive against: "LAME" Listeria Acinetobacter Atypicals: mycoplasma (no cell wall), chlamydia and legionella (intracellular) Enterococci
Cephalosporins mechanism of resistance
Modification of target PBPs
1st generation cephalosporins spectrum of activity
Cefazolin
Cephalexin
Penicillin G substitues: given if patient has a mild allergy
Resistant to staphylococcal penicillinase (a beta-lactamase)
Activity against: gram + cocci, P.mirabilis, E.coli and K.pneumoniae
1st generation cephalosporins clinical applications
Cefazolin
Cephalexin (given orally)
Rarely DOC for any infections
Cefazolin - DOC for surgical prophylaxis = given pre-op to avoid skin wound infections
2nd generation cephalosporins spectrum of activity
Cefaclor (given orally)
Cefoxitin
Cefotetan
Cefamandole
Extended gram negative coverage –> H.influenzae, Enterobacter aerogenes and some Neisseria
Weaker against gram positive
2nd generation cephalosporins clinical applications
Mainly used to treat sinusitis, otitis, lower respiratory tract infections
Cefotetan and cefoxitin –> prophylaxis and treatment of abdominal and pelvic cavity infections (as there is an increased risk of gm - bacteria being present)
3rd generation cephalosporins spectrum of activity
Ceftriazone Cefoperazone Cefotaxime Ceftazidime Cefixime (given orally)
Enhanced activity against gram negative cocci = enterobacteriacae, Niesseria and H.influenzae
Cefotaxime, Ceftazidime and ceftriazone –> usually active against pneumococci
Ceftriaxone clinical applications
3rd generation cephalosporins
DOC for gonorrhea
DOC for empiric treatment of meningitis
Prophylaxis of meningitis in exposed individuals
Treatment of disseminated Lyme disease (CNS or joint infection)
Cefaperazone and ceftazidime clinical applications
Activity against Pseudomonas aeruginosa
4th generation cephalosporins spectrum of activity and clinical applications
Cefipime
Broad spectrum = eg: enterobacter, Haemophilia, Niesseria, E.coli, pneumococci, P.mirabilis and P. aeruginosa
Parenteral administration only
Treatment of mixed infections with susceptible organisms: complicated UTIs, complicated intra-abdominal infections, febrile neutropenia
Cephalosporins with activity against P.aeruginosa
Cefaperazone and ceftazidime (3rd gen)
Cefipime (4th gen)
*5th gen have no coverage against this
5th generation cephalosporins spectrum of activity and clinical applications
Ceftaroline
Similar spectrum of activity to 3rd gen (enhanced activity against gram negative) + activity against MRSA**
Parenteral administration only
Used to treat skin and soft-tissue infections due to MRSA, especially if gram negative bacteria are co-infecting
Cephalosporins PK (route of administration and elimination)
Most given parenterally
–> except caphalexin (1st gen), Cefaclor (2nd gen) and cefixine (3rd gen) given orally
Only 3rd generation can reach adequate levels in CSF
Mainly eliminated by kidneys
–> except ceftrizone and cefoperazone excreted in bile (both 3rd gen)
Cephalosporins AE
Allergic reactions –> cross-reactivity with penicillins can occur but most patients with minor penicillin allergy can be treated with cephalosporins
Pain at infection site (when given IM)
Thrombophlebitis - inflammation of a vein caused by a blood clot (when given IV)
Superinfection (eg: C.difficile)
Kernicterus (pregnancy)
Cefamandole, cefotetan (2nd gen) and cefoperazone (3rd gen) –> contain methyl-triotetrazole group and can cause:
- Hypoprothrombinemia (vit K1 can prevent this)
- Disulfarim-like reactions (avoid alcohol)
Carbapenems MOA
Doripenem
Ertapenem
Imipenem
Meropenem
Synthetic b-lactam antibiotics –> inhibit cell wall synthesis by inhibiting cross-linking of peptidoglycans –> bactericidal
Resist hydrolysis by most b-lactamases
Carbapenems antibacterial spectrum
Very broad spectrum
Active against b-lacatmase producing gram positive and negative organisms, aerobes and anaerobes, P.aeruginosa
Ertapenem: less broad, not active against P.aeruginosa***
Not active against carbapenemase producing organisms (carbapenem resistant enterobacteriaceae and klebsiella)
Not active against MRSA
Carbapenems clinical application
Use typically restricted to avoid resistance
Used only for life-threatening infections, especially if broad spectrum coverage is needed
Commonly used to treat extended-spectrum b-lactamase producing gram negatives
Carbapenems PK
Given IV
Imipenem: forms potentially nephrotoxic metabolite by enzyme dehydropeptidase I in kidney
—> Give it with cilastatin (dehydropeptidase I inhibitor) to prevent metabolism and toxicity and increase its availability***
Doripenem, ertapenem and meropenem not metabolised by same enzyme
Carbapenems AE
GI distress - nausea, vomiting, diarrhea
High levels of imipenem can cause CNS toxicity (eg: seizures)***
Allergic reactions - partial cross-sensivity with penicillins***
Monobactams MOA and antibacterial spectrum
Aztreonam
Aerobic gram negative rods only (including pseudomonas)***
Resistant to action of b-lactamases***
Aztreonam clinical applications
Monobactam
Useful in treatment of gram negative infections in patients allergic to penicillin (little cross-reactive with other beta-lactams as it is most different structurally)***
Monobactam (aztreonam) PK: route of administration and excretion
Mainly given IV or IM –> can be given by inhalation in CF patients
Penetrates CSF when inflamed
Excreted mainly via urine
Monobactam (aztreonam) AE
Relatively nontoxic
Occasional skin rashes and GI upset
Little cross-hypersensitivity with other b-lactams***
Vancomycin MOA
Bacterial glycoprotein
Binds to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide –> inhibits cell wall synthesis and peptidoglycan formation
Resistant to beta-lactamases
Vancomycin antibacterial spectrum
Active against gram positives only***
Almost all gram negatives are intrinsically resistant
Effective against MDR organisms (MRSA, enterococci, PRSP)
Vancomycin mechanism of resistance
Modification of D-Ala-D-Ala binding site (replaced by D-lactate)***
Plasmid-mediated changes in drug permeability
Vancomycin clinical applications
Treatment of serious infections causes by b-lactam resistant gram positive organisms (like MRSA)***
Treatment of gram positive infections in patient severely allergic to beta-lactams ***
Given in combination with aminoglycoside = empiric treatment of infective endocarditis and to treat PRSP
Given orally when local effect in GI tract is needed: antibiotic-associated pseudomembranous colitis (C.difficile)
Vancomycin PK
Poor oral absorption
Requires slow IV infusion (60-90 minute)***
Almost completely excreted by kidneys
Vancomycin AE
‘Red man’ or ‘red neck’ syndrome = infusion related flushing over face and upper torso (not an allergic reaction)
Ototoxicity and nephrotoxicity due to drug accumulation***
Daptomycin MOA
Binds to cell membrane via Ca2+ insertion of lipid tail –> depolarisation of cell membrane –> K+ efflux –> cell death –> bactericidal
Novel MOA –> useful against MDR bacteria***
Daptomycin antibacterial spectrum
Effective against resistant gram positive bacteria (MRSA, enterococci, VRE and VRSA)
Inactive against gram negatives
Not effective in treatment of pneumonia as drug is inactivated by surfactant in lungs
Daptomycin clinical applications
Treatment of severe infections caused by MRSA or VRE (resistant to vancomycin)
Treatment of complicated skin/structure infections caused by susceptible S.aureus
Daptomycin PK
Given IV only
Can accumulate in renal insufficiency
Daptomycin AE
Elevated creatinine phosphokinases –> might cause myopathies (recommended to discontinue co-administration of statins)***
Others: constipation, nausea, headache, insomnia
Bacitracin MOA, uses and AE
Interferes in late stage cell wall synthesis –> unique MOA –> no cross resistance***
Effective against gram positive bacteria
Marked nephrotoxicity –> mainly topical use for wounds or burns in skin (never given systemically)***
Fosfomycin MOA and uses
Inhibits cytoplasmic enolpyruvate transferase in early stage of cell wall synthesis
Active against gram positive and gram negative bacteria
Given oral
Used for treatment of uncomplicated lower UTIs
