broad spectrum antibiotics

agents for gram negatives

compared to gram positive, fewer antibiotics are available from gram negative infections

in addition to intrinsic resistance among gram negatives more and more infections now involve antibiotics resistant strains

urgent unmet need to develop further classes of agents with gram negative activity

UTI agents

• nitrofurantoin

• cephalexin

• trimethoprim

• Fosfomycin

colistin mode of action

Polymyxin group of antibiotics, polycationic peptide, binds to LPS outer membrane and phospholipids of cytoplasmic membrane causing destabilization, leakage and cell death. Has important anti-endotoxin activity

colistin activity

• renewed interest dur to good gram negative activity

• enterobacterales e.g. E. coli, K. pneumoniae

• P. aeruginosa

• some gram negs are intrinsically resistant e.g. Serratia

• concentration dependent bactericidal activity

• IV prodrug

colistin therapeutic use

• combination therapy only

• infections cause by some MDR gram negative bacilli

• P. aeruginosa infection in CF (as it is often MDR in these patients)

broad spectrum agents

co-amoxiclav

cefalexin

cefuroxime

ceftriaxone

piperacillin-tazobactam

meropenem

ceftazidime

third generation cephalosporin, improved gram negative spectrum, especially P. aeruginosa

bind to penicillin binding proteins and interfere with cell wall enzymes. Unable to synthesize a cell wall, the bacteria dies

therapeutic uses: pseudomonas infections, e.g. in CF

ceftazidime activity

gram negative bacilli inducing P. aeruginosa

gram negatives that produce ESBLs are resistant

Poor gram pos activity

IV

aminoglycosides

gentamicin, tobramycin, amikacin

mode of action:

• inhibits synthesis by binding to 30S ribosomal subunit

• misreading of codons leading to non-functional proteins

aminoglycosides activity

• aerobic gram negatives including pseudomonas

• S. aureus

• Mycobacterium

• Bactericidal

• IV

aminoglycosides therapeutic uses

often in combination with other antibiotics to provide gram negative cover

part of empirical combination treatment for serious infections e.g. endocarditis, pyelonephritis

significant adverse effects, nephrotoxicity, ototoxicity

therapeutic drug monitoring required for gentamicin

Gentamicin toxicity

• renal toxicity

• oto toxicity

• toxicity usually from accumulation of the drug

• therapeutic drug monitoring required for patient administered gentamicin

protein synthesis inhibitors mechanism

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

protein synthesis (translation) is mediated by the bacterial ribosome (2 subunits, 50S and 30S) which decode the info contained in mRNA to make proteins with the correct amino acid sequence

antibiotics that bind to ribosome at various location can disrupt this process

translation process may be prevented or may be compromised e.g. non-functional proteins produced

aminoglycosides provide good gram negative cover: gentamicin, tobramycin, amikacin

Tetrracyline

doxycycline, tetracycline, tigecycline

mode of action:

• bind reversibly to 30S ribosomal subunit

• prevents transfer RNA binding to attachment site and amino acids cannot be incorporated into proteins

tetracycline activity

bacteriostatic agents, tetracycline PO, tigecycline IV, doxycycline PO or IV

active against gram-pos (MSSA) and some gram neg, spirochetes e.g. treponema pallidum

tigecycline has improved gram neg spectrum, including enterobacterials

doxycycline - very good activity against atypical, Rickettsia, Chlamydia trachomatis, mycoplasma pneumoniae

tetracyclines therapeutic use

infections due to Rickettsia and other tick-borne disease, Chlamydia and mycoplasma pneumonia (doxycycline)

treatment of early gonorrhea or syphilis if patient is penicillin allergic

tigecycline SSTI, intra abdominal infection

tetracycline toxicity/adverse effects

photosensitivity, tooth discoloration especially tetracycline, not recommended for childeren

nucleic acid synthesis inhibitor ciprofloxacin mode of action

replication of DNA is essential for bacterial survival and growth

DNA gyrase/topoisomerase IV catalyzes the negative supercoiling of DNA for replication

quinolones inhibit DNA gyrase (a type II topoisomerase) and topoisomerase IV, preventing replication of DNA

selectivity - humans have an alternative topoisomerase II alpha for which quinolones have no affinity

ciprofloxacin activity

quinolones can enter easily via porins and therefore are often used to treat intracellular pathogens

bactericidal

IV or PO

most gram negs e.g. E. coli, L. pneumoniae, shigella

but also S. aureus and other staphylococci

ciprofloxacin therapeutic uses

pyelonephritis (where IV to oral switch is desirable)

gonorrhea (but resistance is a problem)

nor recommended for use in primary care unless UTI where there is proven resistance to other agents`

ciprofloxacin safety

FDA advise that a serious side effects of the antibiotic generally outweighs the benefit for patients which acute sinusitis, acute bronchitis or uncomplicated UTI where other options are available

systemic use may result in disabling or potentially permanent side effect involving tendons, muscles, joints, nerves, perhaps aorta and CNS

penicillins and cephalosporins mode of action

beta lactams binds directly to transpeptidase preventing cross linking

bactericidal

beta lactams

defined by the presence of a beta lactam ring

four main types: penicillins, cephalosporins, carbapenems e.g. meropenem, monobactams e.g. aztreonam

ESBL- producing Enterobacter ales produce extended spectrum beta lactamases to destroy beta lactam ring of penicillin. can be treated with carbapenems

cephalosporins (generally broad spec)

1st generation

• good gram + activity

• orally active e.g. cefaclor

• used in treatment of respiratory and urinary infections

2nd generation

• retain gram + activity but also exhibit gram - activity

• oral and IV cefuroxime used for respiratory infections and surgical prophylaxis

3rd generation

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

• most IV

• ceftriaxone

cefuroxime activity

broad spectrum

bactericidal;

S. aureus (not MRSA), penicillin susceptible S. pneumoniae, E. coli, Klebsiella spp.

available PO and IVce

cefuroxime therapeutic uses

prophylaxis for those undergoing orthopedic surgery, give gram+ cover also

given with metronidazole for intra abdominal infection or as prophylaxis before intra abdominal surgery

ceftriaxone activity

broad spectrum

bactericidal

S. aureus (not MRSA), penicillin susceptible S, pneumoniae, Aerobic gram- (e.g. E. coli, Klebsiella spp.), Neisseria spp.

lack of activity against P. aeruginosa, enterococci, listeria

available PO and IV

ceftriaxone therapeutic uses

prophylaxis for those undergoing orthopedic surgery, gram+ cover also

gram- cover for septic arthritis if suspicion of gonorrhea

given with metronidazole for intra abdominal infection or as prophylaxis before intra abdominal surgery

piperacillin tazobactam (tazocin) mode of action

combination of anti pseudomonal piperacillin and a beta lactamase inhibitor tazobactam

piperacillin - inhibits cell wall synthesis by inhibiting transpeptidase enzyme

tazobactam - protects piperacillin from degradation by beta lactamases

piperacillin tazobactam (tazocin) activity

MSSA, H. influenza, pseudomonas aeruginosa

IV

bactericidal

piperacillin tazobactam (tazocin) therapeutic uses

empiric therapy for healthcare associated infections e.g. pneumonia or abdominal infections

carbapenems

meropenem, ertapenem

mode of action:

• same as cephalosporins/penicillins inhibit transpeptidase which is needed for crosslinking or peptidoglycan

carbapenems activity

broad spectrum against aerobes and anaerobic gram- bacilli that produce ESBLs

carbapenems therapeutic uses

intra abdominal infections where susceptibility confirmed

bloodstream infection where susceptibility confirmed

complicated UTI involving confirmed ESBL organism

ventilator associated pneumonia if ESBL confirmed

UTI agents hitrofuranation mode of actionn

unique and poorly understood mechanism. Binds to ribosomal proteins, blocking translation. Also directly damages DNA

UTI agent nitrofurantoin activity

some enterobacterales (e.g. urinary pathogens K. pneumoniae, E. coli including ESBL)

S. saphrophyticus

E. faecalis, E. faecium

bactericidal against urinary pathogens

PO (by mouth)

UTI agent nitrofurantoin therapeutic uses

acute uncomplicated urinary tract infections (acute cystitis) cause by susceptible strains of Escherichia coli or staphylococcus saprophyticus

UTI agents Fosfomycin mode of action

phosphonic acid derivative. inhibits bacterial wall synthesis (bactericidal) by inactivating the enzyme, pyruvyl transferase, which is required for synthesis of the cell wall

UTI agent Fosfomycin activity

S. aureus (including MRSA), P. mirabilis, E.coli (including ESBL), enterococci (including VRE)

bactericidal

PO but IV also available in some countries

UTI agent Fosfomycin therapeutic uses

urinary tract infection, including complicated UTI, pyelonephritis

UTI agent trimethoprim mode of action

folate synthesis inhibitor

bacteria have metabolic pathways to synthesize tetrahydrofolic acid

tetrahydrofolic acid is a cofactor needed for bacteria to make nucleotide bases (purines) for DNA synthesis

trimethoprim and sulphonamides block enzymes required for synthesis of tetrahydrofolate

no tetrahydrofolate = no purines = cell death

UTI agent trimethoprim activity

alone or inf combination with sulphmethoxazole (called co-trimoxazole)

also antifungal agent

E. coli, K. pneumoniae, S. aureus, S. epidermidis

PO, bacteriostatic

UTI agent trimethoprim therapeutic uses

susceptible uncomplicated urinary tract infections

reported increased resistance rates in Ireland

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