gram+ active agents

gram+ bacteria suscepibility

cell wall synthesis inhibitors

• beta lactams e.g. penicillin and cephalosporins

• glycopeptides e.g. vancomycin and teicoplanin

protein synthesis inhibitors

• clindamycin, linezolid, fusidic acid

nucleic acid synthesis inhibitors

• rifampicin

cell wall synthesis inhibitors

glycopeptides

• vancomycin/teicoplanin - staphylococci (MRSA), clostridium difficile

beta lactams

• penicillin

  • benzylpenicillin - streptococci, diphtheria

  • flucloxacillin - staphylococcus

  • ampicillin/amoxicillin - streptococcus pneumonia, enterococcus

• cephalosporins - ceftazidime - streptococcus pneumonia, enterococcus

• carbapenems - imipenem, ertapenem, meropenem - streptococcus, staphylococcus

peptidoglycan synthesis

building of cross linked chains is catalyzed by specific enzymes - transpeptidases which are also referred to as penicillin binding proteins PBP’s

reasons for different spectra of activity

these features and processes are also present in gram- (e.g. cell wall, cell membrane, transcription, translation)

different composition and/or location of target in gram- and gram+ (e.g. cell wall, cell membrane)

gram- have additional outer membrane that may impede entry of some agents

the periplasm, in gram- contains hydrolytic enzymes

porins present in some bacteria may actively remove agents preventing them from reaching target

beta lactams

defined by the presence of a beta lactam ring

four main types: penicillins, cephalosporins, carbapenems, monobactams

cell wall synthesis inhibitor beta lactam

agents that disrupt peptidoglycan. act by inhibiting enzyme transpeptidase (PBP)

transpeptidase (PBP) bunds to a beta lactams as they appear similar to the peptide bond the enzyme usually binds to

beta lactam then inactivating the enzyme, which prevents cross linking in the peptidoglycan wall

weakening the cell wall

the cell lysis = cell death (bactericidal)

penicillins

narrow spectrum

• penicillin G - IM, IV admin

• penicillin V - oral admin

broad spectrum

• amoxicillin/ampicillin

extended spectrum

• piperacillin

anti-staphylococcal penicillins

• flucloxacillin

first generation penicillin

penicillin G (also called benzylpenicillin, benzathine penicillin) - IM/IV admin

penicillin V (also called phenoxymethylpenicillin) - gastric acid resistant, oral admin

first gen penicillin highly active against

gram positive cocci (except penicillinase producing staphylococci, penicillin- resistant pneumococci, enterococci and oxacillin-resistant staphylococci)

gram positive rods such as listeria

gram negatives (limited use)

most anaerobes (with certain important exceptions, including Bacteroides, C. difficile)

first gen penicillin therapeutic uses

endocarditis cause by susceptible bacteria (some streptococci)

meningitis cause by susceptible bacteria (L. monocytogenes, used alone or with an aminoglycoside)

pneumonia cause by susceptible bacteria

cellulitis (e.g. streptococcus pyogenes)

not useful for infections caused by staphylococci as majority are not susceptible due to penicillinase production

group A strep infections

syphilis (treponema pallidum)

anti staphylococcal penicillins

activity

• active against penicillinase-producing staphylococci

• not active against MRSA

• not active against enterococci, listeria

examples - flucloxacillin (oral or IV), cloxacillin, dicloxacillin, nafcillin)

therapeutic uses

• endocarditis cause by staphylococci

• bloodstream infection cause by staphylococci

• septic arthritis caused by S. aureus

broad spectrum penicillins with b-lactamases inhibitor

retain good gram+ activity but also expanded activity against gram-

co-amoxiclav (amoxicillin and clavulanic acid), (IV and PO)

pip - Taz (piperacillin and tazobactam) (IV only)

clavulanic acid and tazobactam inhibits b-lactamases so that amoxicillin and piperacillin remains active

therapeutic uses - provide cover gram+ in treatment of infections with mixed aetiologies e.g. enterococci in abdominal infection, staphylococci in pneumonia

cephalosporins

bactericidal antibiotics. same mechanism as penicillin. generally broad spectrum

1st generation

• good gram positive activity but some gram negative

• orally active e.g. cephalexin

• used in treatment of respiratory and urinary infections

2nd generation

• retain gram positive activity but also exhibit gram negative activity

• oral and IV e.g. cefuroxime used for respiratory infections, complicated UTI and surgical prophylaxis

3rd generation

• good gram negative activity, less staphylococcal activity, have some streptococcal activity

• most IV e.g. ceftriaxone (IV), cefotaxime (IV)

carbapenems

very broad spectrum (gram+ and gram-)

similar to other beta lactams - binds to transpeptidase enzyme (or PBP) which inhibits cell wall synthesis

dissimilar to other beta lactams - have aa modified ring in their structure. they are less effected by resistance mechanisms of bacteria

imipenem, meropenem, eratpenem

monobactams

no active against gram positive and anaerobes

Aztreonam is the only antibiotic in this class

cell wall synthesis inhibitors glycopeptides

agents that disrupt peptidoglycan, binds to the peptide chain e.g. vancomycin, teicoplanin

unlike B-lactams, do not inhibit the enzyme transpeptidase (PBP)

glycopeptides bind to the peptide side chains of NAM sugars

binding to the peptides prevents the PBP from linking with the chains, then preventing cross-linking

weakening the cell wall

cell lysis = cell death

glycopeptide activity

narrow spectrum, gram positive only

used for treatment of MRSA (IV only) and C. difficle (oral only)

bactericidal

gram negative outer membrane prevents entry of glycopeptides, hence gram- intrinsically resistant

glycopeptide therapeutic uses

staphylococcal infections resistant to penicillin e.g. MRSA infections

susceptible enterococci (e.g. bloodstream infections)

viridians streptococci

severe C. difficile infection

nucleic acid synthesis inhibitors

inhibit folate synthesis → trimethoprim (combined with sulfamethoxazole = co-trimoxazole) → staphylococcus, saprophyticus

inhibit DNA gyrase → flouroquinones (ciprofloxacin, levofloxacin, ofloxacin) → streptococcus, staphylococcus, bacillus

bind to RNA polymerase → rifamycin (rifampicin) → staphylococcus (endocarditis)

break DNA strands → nitroimidazoles (metronidazole) → clostridium difficile

rifampicin mode of action

binds to RNA polymerase and inhibits initiation of mRNA synthesis

rifampicin activity

bactericidal

spectrum:

• gram+ ve (staphylococcus, enterococcus)

• mycobacterium tuberculosis

gram- resistant due to decreased uptake of hydrophobic antibiotic

generally used in combination with other agent

PO or IV

rifampicin therapeutic uses

bone infections - as 2nd anti staphylococcal agent for osteomyelitis

tuberculosis - 1 agent in combined therapy

protein synthesis

fully functional protein synthesis is essential to bacterial cell survival and growth

protein synthesis (translation) is mediated by the bacterial ribosome which decode the information contained in mRNA to make proteins with the correct amino acid sequence

antibiotics that bind to the ribosome at various locations can disrupt this process

protein synthesis inhibitors

macrolides → clarithromycin, erythromycin, azithromycin → streptococcus pneumonia, S. aureus

lincosamide → clindamycin → clostridium spp., streptococcus spp., staphylococcus spp. (including penicillin resistance)

tetracyclines → tetracyclines, doxycycline → broad spectrum S. aureus, S. pneumonia, S. pyogenes

fusidane → fusidic acid → staphylococcus, enterococcus

antimicrobials

narrow spec gram+

• linezolid

• clindamycin

• fusidic acid

broad spec gram-

• erythromycin

• clarithromycin

• azithromycin

linezolid mode of action

oxazolidinone: inhibits protein synthesis by binding to 50S subunit of the prokaryotic ribosome, preventing formation of the initiation complex

linezolid activity

S. aureus (including MRSA)

S. epidermidis

enterococcus (including VRE)

streptococcus

bacteriostatic against most susceptible bacteria

bactericidal against some streptococcus

IV or oral formulation

linezolid therapeutic uses

MRSA, VRE bloodstream infection reserved for antibiotic resistant infections

macrolides mode of action

bind to 50S ribosomal subunit and prevent translocation along mRNA

macrolides activity

some gram positives: staphylococcus (not MRSA), streptococcus, NOT enterococcus

some gram negatives: legionella spp., H. influenza, NOT Enterobacteriaceae

some anaerobes

some others: H. pylori, C. trachomatis

bacteriostatic mainly but bactericidal at higher concentrations

IV and oral admin

many drug drug interactions

fusidic acid mode of action

binds to a bacterial elongation factor and prevents peptide chain elongation at the ribosome

fusidic acid activity

staphylococcus (e.g. s. aureus, S. epidermidis)

enterococcus (nut not VRE)

bacteriostatic

administer as: IV, oral, topical, ophthalmic (most common)

fusidic acid therapeutic uses

staphylococcal infections including MRSA (e.g. staphylococcal impetigo)

as 2nd anti staphylococcal agent for osteomyelitis

used in combination to reduce development of resistance

daptomycin mode of action

lipopeptide: lipophilic tail inserts directly into gram+ cell membrane (aerobes and anaerobes), causing rapid membrane depolarization and potassium efflux, followed by DNA, RNA and protein synthesis resulting in cell death

daptomycin activity

gram positive cocci: MSSA, MRSA, staph. epidermidis, streptococcus pneumonia, viridians streptococcus, group A strep, enterococcus faecium and faecalis

no activity against gram-

concentration dependent bactericidal activity

calcium dependent activity (needed for insertion of lipophilic tail)

IV admin only

daptomycin therapeutic uses

skin and soft tissue

S. aureus/MRSA bacteremia and right sided endocarditis

usually reserved for antibiotic resistant infections