bacteria cell wall synthesis inhibitors - beta lactams Flashcards
what are the gram pos cocci
- staphylococcus (aureus, epidermis)
- streptococcus (pyrogenes, pneumoniae)
- enterococcus (faecalis, faecium)
what are the gram pos bacilli
- listeria monocytogenes
- bacillus
- clostridium species
- diphtheria
- actinomyces
- mycobacterium
- corynebacterium
what are the gram neg cocci
- neisseria gonorrhoeae/ gonoccoci
- neisseria meningitis/ meningococcus
- moraxella catarrhalis
what are the gram neg bacilli
- enterobacter, citrobacter, klebsiella, ecoli, salmonella, shigella, serratia
- pseudomonas
- acinetobacter
- h. influenzae
what is the process of gram staining
application of crystal violet -> application of iodine -> alcohol wash (decolourisation) -> application of safranin (counter stain)
what colour is gram neg staining
from colourless in alcohol wash step to pink from safranin
what colour is gram pos staining
remain purple all the way
what is the structure of beta lactams
a four membered beta lactam ring alone or fused with a five membered or six membered ring
what is the different names of beta lactams
five membered: penam (/), penem (//)
six membered: cepham (/), cephem (//)
what are examples of a penam
penicillin, sulbactam, tazobactam
what is an example of a cephem
cephalosporins
differentiate between penams, carbapenams, oxopenams
penams: S atom
carbapenams: C atom
oxopenams: O atom
what is the moa of a beta lactam
beta lactams interfere with the synthesis of bacterial cell wall peptidoglycan by binding to the active site of transpeptidase enzyme called penicillin binding protein which catalyses the crosslinking of terminal peptide components of the linear polymer chain, weakening the bacterial cell wall structure of an actively growing bacterial cell resulting in a buildup in intracellular osmotic pressure and causing lysis of the bacterial cell
what are examples of beta lactams
penicillin, cephalosporins, carbapenems, monobactam (aztreonam), vancomycin
what are the classes of penicillins
natural penicillin, penicillinase resistant penicillin, aminopenicllins, anti pseudomonal penicllins
what are the coverages of the different classes of penicllin
natural penicillin: gram pos and neg
penicillinase resistant penicillin: gram pos
aminopenicillin: gram pos and neg
anti pseudomonal penicillin: gram pos and neg
what are the properties of the R side chain
influences acid stability, PK properties, penicillinase resistance, ability to bind to PBPs
what is beta lactamase
enzyme produced by bacteria that is resistant towards beta lactams
what is inflammed meningitis
swelling of protective membrane covering brain and spinal cord
what are drugs are aminopenicillins
ampicillin, amoxicillin
route, indication, csf, excretion and dose adjustments, structure, others ampicillin
IV/PO, beta lactamase neg gram neg or gram pos, IV has adequate csf penetration and it increases in inflamed meningitis, renal clearance and excreted unchanged in urine, renal dose adjustments required, excreted by tubular secretion so use probenecid to block and prolong effect, incomplete PO absorption can cause D, additional hydrophilic group allows penetration into gram neg via porins, addition of beta lactamase inhibitor can extend spectrum of use to cover beta lactamase producing strains
what are the limitations of ampicillin
does not cover klebsiella and pseudomonas, not effective against amoebae, plasmodia, rickettsiae, fungi and virus, not for MRSA as the PBP is modified so less targetable
route, indication, csf, excretion and dose adjustments, structure, others amoxicillin
IV/PO
beta lactamase neg gram neg or gram pos
IV has adequate csf penetration and it increases in inflamed meningitis
renal clearance and excreted unchanged in urine, renal dose adjustments required, excreted by tubular secretion so use probenecid to block and prolong effect
better PO absorption than ampicillin
additional hydrophilic group allows penetration into gram neg via porins, addition of beta lactamase inhibitor can extend spectrum of use to cover beta lactamase producing strains
what are the limitations of ampicillin
does not cover klebsiella and pseudomonas, ineffective against amoebae, plasmodia, rickettsiae, fungi and virus, not for MRSA as PBP modified so less targetable
what are the drugs that are natural penicilin
penicilin G (benzylpenicilin) and penicilin V (phenoxylmethylpenicilin)
route, indication, csf, excretion, others for penicillin G
IV for PG potassium, IM for PG procaine, IM for PG benzathine
indicated for gram pos (streptococci, bacillus, diphtheria) and gram neg (meningococci, gonococci, spirochetes, beta lactamase neg strain)
aq PG has greater csf penetration than procaine and benzathine, penetration increases with inflamed meningitis
renal, excreted unchanged in urine, excreted by tubular secretion so can use probenecid to block and prolong effect
PG procaine and PG benzathine can distribute into storage tissues to be released slowly
limitations of penicillin G
not effective against amoebae, plasmodia, rickettsiae, fungi, virus
not for MRSA as PBP modified
benefit of natural penicillins over aminopenicillins
natural penicillins cover klebsiella and pseudomonas
route, indication, csf, excretion, others for penicillin V
PO
gram pos (streptococci, bacillus, diphtheria), gram neg (meningococci, gonococci, spirochetes, beta lactamase neg strain)
penetration increased with inflamed meningitis
renal, unchanged in urine, excreted by tubular secretion so can use probenecid to block and prolong effect
PO absorption better than PG because more acid stable
limitations of penicillin V
not effective against amoebae, plasmodia, rickettsiae, fungi, virus
not for MRSA as PBP modified
what are the drugs that are penicillinase resistant pencillin
cloxacillin, oxacillin, flucloxacillin
what are penicillinase resistant penicillin known as
anti staphylococcus penicillin
route, indication, csf, excretion, others, structure of cloxacillin
IV/ IM/ PO
staphylococci and other gram pos, MSSA
not therapeutic levels in csf
renal, unchanged in urine, excreted by tubular secretion so can use probenecid to block and prolong effect
best taken on empty stomach
bulky side chains allow for narrower spectrum of activity
limitations of cloxacillin
not effective against amoebae, plasmodia, rickettsiae, fungi, virus
not for MRSA as PBP modified
route, indication, csf, excretion, others, structure of oxacillin
IV/ IM/ PO
staphylococci and other gram pos, MSSA
non therapeutic levels in csf
renal, unchanged in urine, excreted by tubular secretion so can use probenecid to block and prolong effect
best taken on empty stomach
bulky side chains allow for narrow spectrum of activity
limitations of oxacillin
not effective against amoebae, plasmodia, rickettsiae, fungi, virus
not for MRSA as PBP modified
route, indication, csf, excretion, others, structure of flucloxacillin
IV/ IM/ PO
staphylococci and other gram pos, MSSA
non therapeutic levels in csf
renal, unchanged in urine, excreted by tubular secretion so can use probenecid to block and prolong effect
best absorbed on an empty stomach
bulky side groups allow for narrow spectrum of activity
limitations of flucloxacillin
does not cover amoebae, plasmodia, rickettsiae, fungi, virus
not effective for MRSA as PBP modified
what drugs are anti pseudomonal penicillin
piperacillin
route, indication, csf, excretion, others of piperacillin
IV
gram neg (pseudomonas, klebsiella, proteus, bacteremia, pneumoniae), non beta lactamase producing gram pos strains of streptococci and enterococci
fairly well in inflamed meningitis
renal, 70% unchanged in urine, excreted by tubular secretion so can use probenecid to block and prolong effect
greater activity against other penicillin for pseudomonas, klebsiella and proteus, susceptible to inactivation by bacterial beta-lactamase production
limitation of piperacillin
not effective against MRSA as PBP modified
what are examples of beta lactamases inhibitors
clavulanic acid, sulbactam, tazobactam
what are the combination products with penicillins and beta lactamases inhibitors
clavulanic acid with amoxicillin (augmentin)
sulbactam with ampicilin (unasyn)
tazobactam and piperacillin (zosyn)
what is the moa of beta lactamase inhibitors
work primarily by inactivating serine beta lactamases which are enzymes that hydrolyse and inactivate the beta lactam ring especially in gram neg bacteria, has strong affinity for beta lactamases and allows them to bind to it and inactivate or bind irreversibly to protect beta lactam abx from being targeted by beta lactamases
how does clavulanate interact with beta lactamase
it is a suicide inhibitor and acts by covalently bonding to a beta lactamase which causes permanent restructuring thus inactivating it
how does sulbactam interact with beta lactamases
sulbactam irreversibly binds to beta lactamase at or near its active site
how does tazobactam interact with beta lactamases
tazobactam irreversibly binds to beta lactamase at or near its active site
route, indication, csf, excretion of augmentin
IV, PO
beta lactamase producing gram pos (staphylococcus), gram neg (influenzae, gonoccoci, e coli)
modest penetration of clavulanate thus not recc for cns infection
renal, excreted unchanged in urine, renal dose adjustments required
what kinds of infections would augmentin be used for
skin, lrti, uti
route, indication, csf and excretion of unasyn
IV
beta lactamase producing strains of gram pos (staphylococci), gram neg aerobes, anaerobes
pentration of sulbactam variable, depends on presence of inflamed meningitis
renal, excreted unchanged in urine, renal dose adjustments required
what kinds of infections would unasyn be used for
skin, intra abdominal, gynaecological
route, indication, csf and excretion of zosyn
IV
enterobacteriaceae, bacteriodes species
modest penetration of tazobactam, discouraged for use of cns infections
tazobactam and its metabolised excreted in urine, renal dose adjustments required
what kinds of infections would zosyn be used for
appendicitis, moderate to severe nosocomial pneumonia
what are the mechanisms of resistance to penicillins
- alteration to PBP resulting in less affinity for penicillins (MRSA expresses PBP2a)
- production of beta lactamases by bacterial which causes hydrolysis of beta lactam ring
- decreased ability of reaching PBP when bacteria decreases porin production
- presence of efflux pumps
what are the adverse drug reactions of penicillins
- allergy, hypersensitivity
- clostridiodes difficile associated diarrhoea with ampicillin, amoxicillin, augmentin
- neurotoxicity
- hepatotoxity with oxacillin, flucloxacillin
- anosmia
- seizures
what are the chemical properties of cephalosporins
modifications at position 7 at beta lactam ring associated with alterations in antibacterial activity
substitution at position 3 of the dihydrothiazine ring alters metabolism and PK properties of the drugs
what are the properties of cephalosporins
relatively stable in dilute acid, widely distributed, third forth fifth gen have excellent csf penetration
what are the first gen cephalosporins
cefazolin, cephalexin, cefadroxil, cephradine
what are the second gen cephalosporins
cefuroxime
what are the third gen cephalosporins
cefotaxime, ceftriaxone, ceftazidime
what are the forth gen cephalosporins
cefepime
what are the fifth gen cephalosporins
ceftaroline, ceftobiprole
how does the gram neg activity vary between the different cephalosporins
low activity for first gen, higher activity for second and third gen, highest activity for forth gen
how does the resistance to beta lactamases vary between different cephalosporins
low for first gen, moderate for second gen, high for third and forth gen
how does the csf distribution vary between different cephalosporins
poor for first and second, good for third and forth
what is LAME
listeria monocytogenes, atypicals (mycoplasma, chlamydia, legionella), MRSA, enterococus
route, indication, excretion of cefazolin and what is it a good alternative for
IV, IM, eyedrops
gram pos (streptococci, staphylococci)
renal
good alternative for if allergic to anti-staph penicillin
what are the limitations of cefazolin
does not cover gram pos (enterococci), gram neg (pseudomonas)
lack activity against LAME
route, indication, excretion of cephalexin
PO
gram pos (streptococci, staphylococci)
renal
what is the limitation of cephalexin
does not cover gram pos (enterococci) and gram neg (pseudomonas)
lack activity against LAME
route, indication, excretion of cefuroxime
PO
gram neg (e coli, klebsiella, proteus, influenzae), CAP
renal
what is the limitation of cefuroxime
does not cover gram pos (enterococci) and gram neg (pseudomonas)
lack activity against LAME
route, indication, csf, excretion of cefotaxime
IV, IM
gram neg (enterobacteriaceae, pseudomonas, gonococci), gram pos (strep, staph)
good cns penetration
renal
benefit of cefotaxime
good resistance against beta lactamases and good coverage of gram neg
limitations of cefotaxime
lack activity against LAME
route, indication, csf, excretion of cetriaxone
IV, IM
gram neg (enterobacterieae, pseudomonas, gonococci) and gram pos (staph, strep)
good cns penetration
hepatic
benefits of ceftriaxone
good resistance against beta lactamases, good coverage of gram neg
limitations of ceftriaxone
lack activity against LAME
route, indication, csf, excretion of ceftazidime
IV, IM
gram neg (enterobacterieae, pseudomonas, gonococci) and gram pos (staph, strep)
good cns penetration
renal
limitations of ceftazidime
lack activity against LAME
route, indication, csf, excretion of cefepime
IV, IM
gram neg (enterobacterieae, pseudomonas, gonococci) and gram pos (staph, strep)
good cns penetration
renal
benefit of cefepime
more resistant to beta lactamases
limitations of cefepime
lack activity against LAME
route, indication, csf, excretion of ceftaroline
IV
gram pos (MRSA, VRSA, strep) and gram neg (influenzae, morazella catarrhalis)
good cns penetration
renal
route, indication, csf, excretion of ceftobiprole
IV
gram pos (MRSA) and gram neg (ecoli, klebsiella, pseudomonas, enterobacter)
good cns penetration
renal
what are the adverse drug reactions to cephalosporins
- hypersensitivity
- GI disturbances (D for PO, CDAD)
- thrombophlebitis
how to minimise risk for thrombophlebitis
give slowly and in diluted form and rotate infusion sites
what is the chemical structure of carbapenems
fused beta lactam ring with a five membered ring
what properties does carbapenems have
poor oral absorption and five membered ring gives protection against most beta lactamases
what type of bacteria does resistance to carbapenems occur
gram neg (klebsiella, pseudomonas, acinetobacter)
what is the indication for carbapenems
ESBL, gram neg and anaerobic
what are the drugs that are carbapenems
imipenem (with cilastatin), meropenem, ertapenem
route, indication, excretion of imipenem
IV
gram pos (strep, entero excl faecium, staph) and gram neg (pseudomonas) and anaerobes
renal, hydrolysed rapidly by dehydropeptidase 1 (DHP1), metabolite can be nephrotoxic so renal adjustments needed
what is the role of cilastatin added to imipenem
cilastatin is a DHP1 inhibitor and can recover more of active imipenem
what can imipenem treat
moderate to severe nosocomial infections, intra abdominal, skin, septicaemia
what can imipenem treat
moderate to severe nosocomial infections, intra abdominal, skin, septicaemia
limitation of imipenem
MRSA is resistant
route, indication, csf, excretion of meropenem
IV
gram pos (strep, entero excl faecium, staph), gram neg (pseudomonas) and anaerobes and some imipenem resistant pseudomonas
good csf penetration in inflamed meningitis
renal, unchanged in urine as stable against hydrolysis by DHP1
which special population can meropenem be used in
in children <3m with meningitis
limitations of meropenem
MRSA is resistant
is imipenem or meropenem more active against gram pos cocci
imipenem
what can meropenem treat
moderate to severe nosocomial infections, skin, intra abdominal, septicaemia
what is the additional limitation of ertapenem
lack activity against pseudomonas and enterococci
what are the adverse effects of carbapenems
- GI disturbances (N, V, D for tienam)
- neurotoxicity
- rashes
- cross hypersensitivity with penicillin (avoid with reported penicillin allergy)
what is an example of a monobactam
aztreonam
route, indication, csf, elimination of aztreonam
IV, IM
gram neg and beta lactamase producing gram neg (enterobacteriae, pseudomonas, influenzae, gonococci)
penetrate BBB in inflamed meningitis
renal, excreted unchanged in urine, renal dose adjustments required
what can aztreonam treat and what bacteria spp is in each of these diseases
- uti (enterobacter)
- lrti (influenzae, e coli, klebsiella, pseudomonas)
- septicemia (e coli, klebsiella, pseudomonas, enterobacter)
- intra absominal (e coli, klebsiella, pseudomonas, enterobacter)
what are the adverse effects of aztreonam
- occasional skin rash and transaminaesemia
- little or no cross reactivity with other penicillin
what are the adverse effects of aztreonam
- occasional skin rash and transaminaesemia
- little or no cross reactivity with other penicillin
what is the moa of vancomycin
binds with high affinity to the D-Ala-D-Ala terminus of pentapeptide of the NAM component of peptidoglycan and interferes with the transglycosylation of the cell wall precursor units hence inhibiting bacterial cell wall synthesis
what is the coverage of vancomycin and why
gram pos coverage as vancomycin is large in size thus unable to penetrate outer membrane of gram neg
route, indication, excretion of vancomycin
IV, PO
gram pos (staph incl MRSA, MSSA, enterococci, strep, bacillus, clostridium)
renal, excreted unchanged in urine, renal dose adjustments required
what can vancomycin treat
osteomyelitis, endocarditis, CDAD, abx assoc pseudo membrane colitis (AAPMC), penicillin allergy, prophylaxis for MRSA, meningitis
how is PO absorption for vancomycin and which disease do we use PO
poor absorption, use for CDAD and AAPMC
is vancomycin safe in pregnancy and lactation
IV category C, PO category B
what are the adverse effects of vancomycin
- thrombophlebitis
- redman syndrome
- nephrotoxicity and ototoxicity
what are the mechanisms of resistance to vancomycin
- enterococcal resistance due to expression of enzymes that modify cell wall precursor by substituting D-Ala for D-lactate or D-serine which reduces binding affinity of vancomycin by up to 1000x
- emergence of VRSA
what is red man syndrome
rash above nipple line involving neck, face, upper torso and is accompanied by hypotension
why does redman syndrome occur and how to prevent
due to histamine release when vancomycin infused too quickly,. infuse for 1-2h
