Cell wall synthesis inhibitors/membrane active antibiotics (1&8&9&10&/17/&19) Flashcards
Cell Wall Synthesis Inhibitors & Membrane-Active Antibiotics
Penicillins Cephalosporins Carbapenems. Monobactams. Beta-lactamase inhibitors.
Pharmacotherapy of respiratory infections
Community aquired pneumonia
typical pneumonia: acute fever, chills productive cough pleural pain physical signs (+) lobar consolidation
agents: S. pneumoniae H. influenzae Gr(-)aerop. bacillus anaerobes (Klebsiella pneumoniae Peptostreptococcus, Bacteroides, Fusobacterium, and Prevotella)
atypical pneumonia: subacute subfebrile fever non productive cough nonrespiratory symtopms physical signs (-) non-lobar infiltration
Agents: M. pneumonia C. pneumoniae L. pneumophila virus
types of antibiotic therapy
- emperic
- sensitivity based (definitive)
- prophylactic
Considerations in choice of antimicrobial agent
- antibacterial spectrum
- site of infection
- pharmacokinetics of the antimicrobial agents
- adverse effects
- presence of renal or hepatic failure
- drug interaction
- severity of infection
- general condition of the patient (concomitant disease, state of immune system, age, pregnancy)
- cost
MIC
Minimum Inhibitory Concentration is the lowest drug concentration that prevents visible microorganism growth after overnight incubation
A lower MIC - more effective antimicrobial agents
MBC
The minimum bactericidal concentration (MBC) is the lowest concentration of an antibacterial agent required to kill a particular bacterium
Bactericidal
An antimicrobial drug that can eradicate an infection in the absence of
host defense mechanisms; kills bacteria
Bacteriostatic
An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the infection; does not kill bacteria
osteomyelitis
S. aureus, group A strep. (pyrogens)
septic arthritis
S. aureus, N. gonorrheae (if sexually active), streptococci
cellulitis
beta-hemolytic strep., S. aureus
bactericidal antibiotics
beta-lactams* glycopeptides* aminoglycosides quinolones/fluoroquinolones metronidazol rifampin isoniazid
Bactericidal agents has be given in case of endocarditis, meningitis or infections in immunocompromised patients
- Inhibit but not kill enterococci
ß GAFRIM
bacteriostatic
chloramphenicol lincosamides macrolides tetracyclines sulfonamides trimethoprim nitrofurantoin ethambutol
CHESTT NLM
postantibiotic effect
The post antibiotic effect (PAE) is defined as persistent suppression of bacterial growth after a brief exposure (1 or 2 hours) of bacteria to an antibiotic
perioperative antiobiotic
metronidazole - abdominal surgery?!
Cephalosporin???3rd- surgical prophylaxis
Cefazolin??
Combination of antimicrobial agents
Aim 1. To assure a synergistic effect penicillins + aminoglycosides sulfonamides + trimethoprim 2. To extend the antibacterial spectrum 3. To prevent the development of resistance
e.g. . Ps. Aeruginosa, acinetobacter infection
antimycobacterial agents
Indications for prophylactic treatment
- surgical prophylaxis - cephalosporins
non- surgical prophylaxis
- individuals with high risk e.g. immunocompromised patients, patients with endocarditis
- recurrent infections e.g. urinary, genital herpes, otitis media
- close contacts e.g. meningococcal infection, tuberculosis, pertussis, plague etc.
- risk of infection (endemic area) e.g. malaria, anthrax
N. meningitis, TB, yersenia pestis
dentoalveolar surgeires
abdominal surgeries (perioperative antibiotics)
Narrow spectrum,
G-penicilline, vancomycine, oxazolidine, (linezolid) lincosamide, fuzidic acid (use slide)
P-VOLF
Extended spectrum
aminoglycosides, aminopenicillines, 2nd and 3rd generation cephalosporins, some fluoroquinolones, macrolides (use slide)
CAFAM
Broad spectrum
tetracyclines, carbapenems, 4th generation fluoroquinolones, chloramphenicol, piperacilline+tazobactam (use slide)
FC TCP
Which tissues are hard to penetrate?
°CNS • Prostate • bones • endocarditis vegetation • Ischemic tissues • implants • Intracellular pathogens
Bacterial cell wal synthesis inhibitors
- Beta lactams
1.1. Penicillins
1.2. Cephalosporins
1.3. Carbapenems
1.4. Monobactams- Aztreonam
(ß-lactamase inhibitors) - Glycopeptides: Vancomycin, Teicoplanin
- Bacitracin
- Fosfomycin
2.,3.,4., also inhibit cell wall synthesis but are not nearly as important as the beta-lactam drugs
Beta-lactams mechanism of action
which pathogens are resistant by nature
1) binding of the drug to specific enzymes - penicillin-binding proteins (transpeptidation)
- 2) inhibition of the FINAL transpeptidation reaction that cross-links the linear peptidoglycan chain
- 3) activation of autolytic enzymes that cause lesions in the bacterial cell wall
• b-lactams are ineffective against :
– bacteria without cell wall (mycoplasma, ureaplasma)
– obligate intracellular parasites (chlamydia, rickettsia, legionella)
– facultative intracellular parasites (may have some effect) (e.g. brucella, salmonella)
– slowly growing bacteria (e.g. mycobacteria)
Beta-lactams - Resistance
- b-lactamase production–MAJOR MECHANISM!!!
• by most staphylococci and many gram-negative organisms
• Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) prevent their inactivation - altered PBP (penicilin-binding-protein?)
• responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci (penicillin resistant Streptococcus pneumoniae (PRSP)) and enterococci. - impaired penetration
- efflux
special considerations of Beta-lactams (resistance by nature)
- No intracellular penetration
– chlamydia, rickettsia, legionella (intrac. bacteria)
http://what-when-how.com/medical-microbiology-and-infection/chlamydia- mycoplasma-and-rickettsia-bacteriology-medical-microbiology-and-infection/
- No effect on bacteria without cell walls
– mycoplasm, ureaplasm - No effect on slow-growing bacteria
– Mycobacteria - Side effects:
– allergy
– seizures
PENICILLINS
Pharmacokinetics:
• oral and/or parenteral use
• short half life (0,5 – 1,5 h) + short PostAE → dosage 3-4 times daily
• Nafcillin is excreted mainly in the bile and ampicillin undergoes enterohepatic cycling
• Good anaerobic spectrum
• extracellular distribution (no effect against intracellular pathogens)
• poor penetration into the eye, prostate, bones and CNS
– in case of meningitis better penetration, but decreases by
therapeutic success
• penicillins cross the placenta and enter the breast milk
• ~ 30 % metabolized in the liver
• ~ 70 % excreted by the kidneys (20 % filtration, 80 % tubular secretion)
– dose reduction in kidney failure
side effects:
• safe during pregnancy
- allergy (most common adverse effect, ~ 1 %)
– skin rash, urticaria, pruritus, fever
– anaphylacticshock(~0,05%)
– pseudoallergic morbilliform rash by aminopenicillins - Ampicillin!!!
• cross allergy between penicillins (in 5 % also with cephalosporins) + Complete crossallergenicity between different penicillins should be assumed
°maculopapular rash (ampicillin) - gastrointestinal (more frequent with oral agents) nausea, diarrhea - direct irritation or by overgrowth of gram-positive organisms or yeasts
- dysbacteriosis, pseudomembranous colitis C.difficile,rare) • Th.: metronidazole, vancomycin - hematologic
– anemia,thrombocytopenia,neutropenia - irritation and local pain (if given i.m.)
- neurotoxicity (seizures, at higher doses, esp. in case of kidney failure)
classifications:
°Penicillin G and close derivatives
– Penicillin G (Benzylpenicillin), depot forms, oral forms
• b-lactamase stable penicillins
• Extended-spectrum penicillins (aminopenicillins)
• Antipseudomonal penicillins
• Combination with b-Lactamase inhibitors
• Narrow-spectrum penicillinase-susceptible agents
penase-susceptible:
– Penicillin G is the prototype (acid sensitive)
– Penicillin V is an oral drug used mainly in oropharyngeal infections. (acid-resistant)
-(streptococcal, meningococcal infections, syphilis)
-rapid renal elimination (frequent dosing)
• Very-narrow-spectrum penicillinase-resistant drugs
(penase-resistant)
– methicillin (the prototype, rarely used owing to its nephrotoxic potential),
nafcillin, oxacillin
– Their primary use in staphylococcal infections
- some biliary clearance (recycling)
– Methicillinresistant (MR) staphylococci
• Wider-spectrum (extended) penicillinase-susceptible drugs
-greater activity against gram negative bacteria
-bactericidal
– Ampicillin and amoxicillin (penase-sensitive, but wider spectrum)
• Their clinical uses include indications similar to penicillin G
• + infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis,
• When used in combination with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced
Broad spectrum
– Piperacillin and ticarcillin
• gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella
species.
• Most drugs in this subgroup have synergistic actions when used with aminoglycosides against such organisms.
• Piperacillin and ticarcillin are susceptible to penicillinases and are often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity.
amoxicillin - clavulanic acid
ampicillin - sulbactam
in case of penicillin allergy
macrolides
PENICILLIN G (Benzylpenicillin)
- only IV administration for Pen G
- Benzathine penicillin G:IM depot injection (slow-release formulation) for:
- Syphilis (spirochete - Treponema pallidum)
- half life: 30 – 40 min (in case of kidney failure ~ 24 h)
- indications : intravenous infusion by
1. serious infections
severe infections:
a)sepsis,
b) osteomyelitis,
c) acute endocarditis (staphylo-, streptococci)
2. S pyogenes (tonsillitis, skin infections (impetigo, erysipelas))
3. pneumococcal pneumonia
4. neurosyphilis,
5. Lyme,
6. gonorrhea,
7. tetanus,
8. diphtheria - depot forms
- i.m. use (parenteral !), slow release of penicillin G
- Clemizolpenicillin, Procaine penicillin G – syphilis, gonorrhea - Benzathine penicillin G – prophylaxis of rheumatic fever
Penicillins - Penicillin G and close derivatives - antibacterial spectrum:
- Gram (+) cocci: streptococci, pneumococci, pepto-, peptostreptococci (+ non-b- lactamase producing staphylococci)
- Gram (-) cocci: meningo- and gonococci, Actinomyces
- Gram (+) rods : corynebacteria, Bacillus anthracis, clostridium
- Gram (-) rods : fusobacteria, Bacterioides spp. (except B. fragilis), Pasteurella multocida
- Spirochetes : leptospira, borrelia neuro Lyme!), Treponema pallidum (syphilis)
- Coccobaccilli: Pasteurella multocida (cat and dog bite)
PENICILLIN V
- oral forms
- oral use
- half life: 30 – 45 min
- Penicillin V (Phenoxymethylpenicillin), Propicillin, Azidocillin, Penamecillin - less effective against Gram (-)
- indications :
1. mild / moderate infections
2. scarlet fever, erysipelas, phlegmon (streptococci) otitis, sinusitis, bronchitis, pharyngitis
- disadvantages : poor bioavailability (low systemic level) short half life (given 4 times daily) narrow spectrum
adverse effects:
1. Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated)
2. Drug-induced hemolytic anemia (IgG-mediated)
3. Interstitial nephritis
4. Jarisch-Herxheimer reaction in treatment
of syphilis (fever, chills, flushing, hyperventilation)
OXACILLIN,
Methicillin,
Nafcillin,
Dicloxacillin, Flucloxacillin
Methicillin – withdrawn - nephrotoxic
- oxacillin - lowest bioavailability
- half life: 30 – 60 min
very narrow spectrum, ß-lactamse resistant
b-lactamase stable penicillins (isoxazolyl penicillins, antistaphylococcal penicillins)
- semisynthetic, acid-stable derivatives (oral and parenteral administration)
- resistance against b-lactamase
- against penicillin-susceptible strains penicillin G is 10-20 x more effective!
- indication : only indication is non MRSA (methicillin/oxacillin rezistens staph. Aur.) strains!!!
Staphylococcal infections (skin and soft tissue infections, endocarditis, osteomyelitis);
do not cover MRSA
- Interstitial nephritis (methicillin)
- Neutropenia (nafcillin)
AMPICILLIN
AMOXICILLIN
(aminopenicillins)
Broad-spectrum, Beta-lactamase sensitive
• Spectrum: same as that of penicillin G + Gram negative bacteria (Haemophilus influenzae, H. pylori (in combination) ,proteus, E. coli, salmonella, shigella) + enterococci, listeria, pneumococcus
• ampicillin has poor bioavailability (~ 30%), can cause GI problems - given mainly parenterally (3-4 x daily i.m./i.v. – short half life)
has enterohepatic recycling
- amoxicillin has better absorption (60- 80%), D.: 3 x, retard amx-klav 2x
- bacampicillin, pivampicillin - ampicillin esters, complete absorption
• Given in combination:
ampicillin+sulbactam,
amoxicillin+clavulanic acid
Penicillins- Extended-spectrum penicillins (aminopenicillins)
• Indications:
– urinary infections (E.coli, enterococci, proteus)
– respiratory infections, otitis, sinusitis, bronchitis, pneumonia
– Helicobacter pylori infection
– enterococcal endocarditis (combination with aminoglycosides)
– Listeria meningitis
Ampicillin
- E. coli, Enterococci
- L. monocytogen (meningitis in neonates + elderly)
- Anaerobic infections
Amoxicillin
- Otitis media and sinusitis caused by H. influenza,
S. pneumoniae, M. catarrhalis
- Pneumonia caused by S. pneumoniae and
H. influenza (empiric treatment for pneumonia)
- Streptococcal pharyngitis
- H. pylori eradication regimens
- Borrelia burgdorferi (Lyme disease)
- Prophylaxis: high-risk patients prior to dental
procedures, asplenic patients with fever
• typical side effect:
- dysbacteriosis,
- pseudoallergic morbilliform skin rash (5-20%, but much more frequent in the case of EBV/CMV-infection)
- Maculopapular skin rash (pseudo-allergy) – common presentation when used for viral infections (ex. EBV pharyngitis) - GI disturbances (most severe with ampicillin)
- Hepatotoxicity (amoxicillin/clavulanate)
Penicillins - Anti Pseudomonas penicillins (carboxy and ureidopenicillins)
Carboxypenicillins - (Carbenicillin, Ticarcillin)
Ureidopenicillins - (Mezlocillin, Azlocillin), PIPERACILLIN (+tazobactam)
All for iv administration
• Spectrum : that of the aminopenicillins + B. fragilis, Pseudomonas aeruginosa
and other nosocomial G-
• Pseudomonas: An opportunistic, nosocomial pathogen of immunocompromised individuals, typically infects the airway, urinary tract, burns, and wounds
PIPERACILLIN
• Indications:
– severe infections caused by Gram (-) bacteria (urogenital infections, endocarditis, sepsis, intraabdominal infections, skin, pneumonia)
– pseudomonas infections
– immunosuppressed patients, nosocomial infections
• often combined with aminoglycosides, fluoroquinolones
or Piperacillin and ticarcillin are susceptible to penicillinases and are often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity.
• Piperacillin (+tazobactam)
b- Lactamase inhibitors
- No (or very weak) antibacterial activity, but potent, irreversible inhibition of b-lactamase
- Clavulanic acid (with amoxicillin) - oral use (3 x 375-625 mg)
- Sulbactam (with ampicillin) - oral/parenteral use
- Tazobactam (with piperacillin) – only parenterally
• Meropenem + Vaborbactam
– See indications for antipseudomonas penicillins
bind permanently to beta lactamase (allow peniccilin to work)
more effective vs. gram negative bacteria
- gam positive have PBP mutations
Cephalosporins
- contain the beta-lactam ring structure
- oral use or parenteral forms.
- major elimination mechanism for drugs in this class is renal excretion via active tubular secretion
- Most first- and second-generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed.
- bactericidal effect, resistance mechanisms same as with penicillins
- ineffective against E. faecalis, MRSA, Listeria monocytogenes, intracellular pathogens
- more stable to b-lactamases
- Less allergic reactions - patients with a history of anaphylaxis to penicillins should not be treated with a cephalosporin
- less anaerobe activity than with penicillins
• 4 generations, with increasing generation
– better activity against Gram negatives but less against Gram positives
– better tissue penetration(betterCNS penetration in higher generations)
– More parenteral use
benzathin-penecillin
- Syphilis (spirochete - Treponema pallidum) IM depot injection (slow-release formulation)
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Drug-induced hemolytic anemia (IgG-mediated)
- Interstitial nephritis
- Jarisch-Herxheimer reaction in treatment
of syphilis (fever, chills, flushing, hyperventilation)
Cephalosporins – 1st generation
- Oral agents : CEFALEXIN, (Cefradin, Cefadroxil)
- Parenteral agents : CEFAZOLIN
• spectrum :
– Lactamase stable penicillins – (minus) anaerobs
– Gram (+) cocci – streptococci, pneumococci, staphylococci, pepto-, peptostreptococci (anaerob)
- but Ø effect against MRSA and enterococci
– Gram (-) rods – E. coli, Klebsiella, proteus
• indications :
– mild urogenital, respiratory, bone, joint, skin infections (caused by sensitive strains) – Cefalexin, (Cefadroxil)
– perioperative prophylaxis (parenteral agents) - Cefazolin
skin, soft tissue UT infections
• Ø CNS penetration
1st and 2nd gen’ do not enter CNS (even when meninges are inflamed), 3rd and 4th gen’ can cross blood-brain-barrier
• painful IM admin
renal elimination, blocked by probenecid
complte cross reactivity between cephalosporins (partial between penecillins)
GI distress
- Hypersensitivity/allergic reaction 2%:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
CEFAZOLIN + CEFALEXIN
1st gen cephalosporins
parenteral: Cefazolin
oral: Cefalexin
- Gram-positive cocci (Staph, Strep)
- UTI’s caused by gram-negative organisms
(Proteus, E. coli, Klebsiella) - Surgical prophylaxis - CEFAZOLIN
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
Renal excretion (dose-adjustment in renal impairment); blocked by probenecid
1st and 2nd gen’ do not enter CNS (even when meninges are inflamed), 3rd and 4th gen’ can cross blood-brain-barrier
Cephalosporins – 2nd generation
• Oral agents : (Cefaclor), CEFUROXIME AXETIL, (Cefprozil, Loracarbef)
• Parenteral agents : (Cefamandole, Cefonicid,) CEFUROXIME, (Cefotiam, Ceforanide,)
CEFOXITINE, (Cefmetazole, Cefotetan)
Renal excretion (dose-adjustment in renal impairment); blocked by probenecid
1st and 2nd gen’ do not enter CNS (even when meninges are inflamed), 3rd and 4th gen’ can cross blood-brain-barrier
• spectrum :
– same as with 1. generation (or as aminopenicillins + lactamase inhibitors) but
better activity against G (-), and weaker against G (+)
– H. influenzae, Moraxella catarrhalis
– B. fragilis (only cephamycins)
- more stable to b-lactamase, less dysbacteriosis
- no penetration to CNS (exception : cefuroxime)
• Indications: anaerobe Bacteroides fragilis (cefotetan, CEFOXITIN) and sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, CEFUROXIME, cefaclor)
more active vs. S. pneumoniae and H. influenza, B. fragilis and M. catarrhalis
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
CEFUROXIME AXETIL
CEFUROXIME
CEFOXITINE
2nd gen cepaholsporins
oral: CEF. Axetil
parenteral: CERFUROXIME; CEFOXITINE
Renal excretion (dose-adjustment in renal impairment); blocked by probenecid
1st and 2nd gen’ do not enter CNS (even when meninges are inflamed), 3rd and 4th gen’ can cross blood-brain-barrier
- Similar activity as 1st gen’ with extended gram-negative coverage
- Bacteroide fragilis (cefotetan, CEFOXITIN)
- Sinus, ear, and respiratory infection caused by
H. influenza, M. catarrhalis (CEFUROXIME) - Similar activity as 1st gen’ with extended gram-negative coverage
- Bacteroide fragilis (cefotetan, CEFOXITIN)
- Sinus, ear, and respiratory infection caused by
H. influenza, M. catarrhalis (CEFUROXIME) - Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
Cephalosporins – 3rd generation
Oral agents :
CEFIXIME, (Ceftibuten, Cefpodoxime proxetil)
Parenteral agents : CEFOTAXIME, CEFTRIAXONE,
CEFTAZIDIME, (Ceftizoxime, Moxalactam)
- Renal excretion (dose-adjustment in renal impairment); blocked by probenecid
- Biliary clearance (ceftriaxone, cefoperazone)
- T1/2 1.5 h’ (given every 8 h’)
- 1st and 2nd gen’ do not enter CNS (even when meninges are inflamed), 3rd and 4th gen’ can cross blood-brain-barrier
spectrum :
– same as with 2. generation
– even better activity against G (-), and weaker
against G (+)
– + lactamase-producing H. Influenzae (PNEUMONIA), N. Meningitidis (MENINGITIS) and gonorrhoeae
– + serratia, citrobacter, proteus
– + pseudomonas (only ceftazidime, cefoperazone)
!!Drugs in this subclass should usually be reserved for treatment of serious infections (empirical therapy of sepsis ) meningitis
parenteral agents are brain penetrable!!!
ceftriaxone!!!! - even more active, single dose IM get meningeal levels
Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin- resistant pneumococci (PRSP strains)
3rd gen enter the CNS
many uses including: meningitis and gonorrhea, pneumonia
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
CEFIXIME
CEFOTAXIME, CEFTRIAXONE,
CEFTAZIDIME
3rd gen cephalosporins
oral: CEFIXIME
parenteral: rest
- Renal excretion (dose-adjustment in renal impairment); blocked by probenecid
- Biliary clearance (CEFTRIAXONE, cefoperazone)
- T1/2 1.5 h’ (given every 8 h’)
- 1st and 2nd gen’ do not enter CNS (even when meninges are inflamed), 3rd and 4th gen’ can cross blood-brain-barrier
- Increased activity against gram-negative
- Empiric treatment of bacterial meningitis
(N. meningitidis, H. influenza, S. pneumoniae) - Empiric treatment of sepsis
- Community- and hospital-acquired pneumonia,
including PRSP strains (ceftriaxone) - Pseudomonas (ceftazidime)
- B. fragilis, B. burgdorferi
- N. gonorrhoea (single dose, IM injection)
- Endocarditis caused by S. viridans, HACEK group
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
Cephalosporins 4th and 5th
• Only parenteral agents : CEFEPIME,
(Cefpirome)
• spectrum : better action againts G (-) but also effective against G (+) - S. aureus, streptococci + pseudomonas, Beta lactamase stable G-
• brain penetration
• used in case of serious, life-threatening
infections
- broad activity, beta-lactamase-stable
- Broad-spectrum, resistant to most beta-lactamase
- Enterobacter, Hemophilus, Neisseria,
Pneumococci, Pseudomonas
• 5th generation (newer cephalosporins against MRSA: CEFTAROLINE (-fosamil??), Ceftobiprole))
5th gen’
- Ceftaroline fosamil
- Ceftolozane/tazobactam
- Broad-spectrum, including MRSA strains
- Complicated UTI’s, abdominal infections
adverse effects for both:
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
ceftolozane+tazobactam
5th gen’ cephalosporin
- Broad-spectrum, including MRSA strains
- Complicated UTI’s, abdominal infections
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
ceftarolin fosamil
5th gen’ cephalosporin
- Broad-spectrum, including MRSA strains
- Complicated UTI’s, abdominal infections
- Hypersensitivity/allergic reaction:
fever, urticaria, pruritus, joint swelling, angioedema, anaphylaxis (IgE-mediated) - Vitamin K deficiency
- Disulfiram-like reaction
- Complete cross-allergenicity between individual cephalosporins, partial cross-allergenicity with penicillins
- Pain at intramuscular injection site
- Phlebitis following IV administration
- May increase the nephrotoxicity of aminoglycosides when administered together
Not covered by 1-4 gen’ cephalosporine (‘LAME’):
- Listeria
- Atypicals (chlamydia, mycoplasma)
- MRSA
- Enterococci
Carbapenems
- IV ADMINISTRATION
- Low susceptibility to beta-lactamases (they contain modified beta lactam ring)
• Spectrum: Broad spectrum: - Effective against 1. gram-positive, 2. gram-negative, 3. anaerobes, 4. aerobes
- Serratia, Enterobacter, Pseudomonas, Acinetobacter
- Used in hospital-acquired infections, including pneumonia and sepsis
- Considered as ‘reserve antibiotics’ for complicated resistant infections
– newest, most potent class of b-lactams, with very broad spectrum and resistance against most b-lactamases
– wide, almost every Gram (+), Gram (-) and anaerobes, pseudomonas
• Indications: multiresistent nosocomial infections
2nd gen' Imipenem Meropenem • IMIPENEM with Cilastatin (1:1) • MEROPENEM, (Doripenem) (• Ertapenem – not effective againts pseudomonas)
- dehydropeptidase is an enzyme found in the kidney and is responsible for degrading the antibiotic imipenem. Cilastatin can therefore be combined intravenously with imipenem in order to protect it from degradation, prolonging its antibacterial effect
- Parenteral administration
- Imipenem is given with cilastatin, a renal dehydropeptidase inhibitor, which inhibits imipenem’s metabolism to a nephrotoxic metabolite
- Resistant to most beta-lactamases (including ESBL)
• Pharmacokinetics :
– poor absorption → parenteral application
– wide distribution, also in CNS
– renal elimination
• Indications :
– Carbapenems are reserve antibiotics !
– life-threatening nosocomial infections (e.g. unknown pathogen, acinetobacter, ESBL-producing G (-) )
– severe polymicrobial infections (e.g. diffuse peritonitis)
– multiresistant bacterial infections
• Adverse effects :
- allergic (skin rashes) – cross-allergy with penicillins is possible
- Hypersensitivity reaction
- Skin rash
- gastrointestinal (diarrhea, vomiting)
- local irritation
- CNS (dizziness, confusion, seizures) – high doses of imipenem
MEROPENEM does not cause seizure
- MRSA strains are resistant to carbapenem
- Carbapenemase (MBL – metallo beta-lactamase); potentially expressed by
1. Klebsiella,
2. Acinetobacter,
3. Pseudomonas,
4. Enterobacter
Vaborbactam (beta-lactamase inhibitor) is administered in combination with meropenem (meropenem/vaborbactam) in the treatment of complicated UTI, pyelonephritis, and abdominal infections caused by carbapenem-resistant Enterobacteriaceae (CRE); *highly-expansive drug regimen.
(monobactams) not on the list
• Low susceptibility to beta-lactamases (they contain modified beta lactam ring)
• Aztreonam
• Spectrum: only G- aerobs
• no activity against grampositive bacteria or anaerobes
• Mechanism of action
– binding to a specific penicillin-binding protein
• Admin: intravenously and is eliminated via renal tubular secretion
• no cross-allergenicity with penicillins.
• Indication: G- nosocomial pneumonia
Glycopeptides
Vancomycin, Teicoplanin, Oritavancin
Glycopeptides antibiotics
Mechanism of action:
Cell wall and Membrane-active agents (Non beta-lactams antibiotics)
- Binding at the D-ala-D-ala terminal of the nascent peptidoglycans pentapeptide side chains → inhibits the transglycosylation reactions involved in elongation of peptidoglycan chains (interfere with cross-linking)
- Bactericidal effect (slower effect and less pronounced compared to beta-lactam antibiotics)
VANCOMYCIN TEICOPLANIN, ORITAVANCIN
Glycopeptides antibiotics
Mechanism of action:
Cell wall and Membrane-active agents (Non beta-lactams antibiotics)
- Binding at the D-ala-D-ala terminal of the nascent peptidoglycans pentapeptide side chains → inhibits the transglycosylation reactions involved in elongation of peptidoglycan chains (interfere with cross-linking)
- Bactericidal effect (slower effect and less pronounced compared to beta-lactam antibiotics)
-glycopeptides
• bactericidal
• Inhibits transglycosylation (and transpeptidation?) – prevents elongation of the peptidoglycan chain
• Resistance: vancomycin-resistant enterococci [VRE] and staphylococci (vancomycin-resistant S aureus [VRSA])
• Spectrum:
– narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin-resistant staphylococci (MRSA), and in combination with a third-generation cephalosporin for treatment PRSP
– backup drug for treatment of infections caused by Clostridium difficile.(in that case oral admin.)
• not absorbed from the gastrointestinal tract and may be given orally for bacterial enterocolitis or parenterally (primarily)
• Toxic effects:
- ototoxicity
- nephrotoxicity
- red- men syndrome
fosfomycin
- prevents the formation of N-acetylmuramic acid (essential precursor molecule for peptidoglycan chain formation)
- Fosfomycin is excreted by the kidney
- G+ and G-
- With multiple dosing, resistance emerges rapidly and diarrhea is
- For UTI
- Inhibits the bacterial enzyme enolpyruvate transferase → blocking synthesis of N-acetylglucosamine (precursor of bacterial cell wall synthesis)
- Bactericidal effect
- Gram-positive and -negative
- Used in the treatment of uncomplicated lower UTI’s in women (oral, single dose)
- Oral and parenteral
- Renal elimination – excreted unchanged, with urinary concentrations exceeding MIC’s for most urinary tract pathogens
- GI distress (diarrhea)
BACITRACIN
-peptide?
- Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall synthesis in gram-positive organisms.
- G+ spectrum
- marked nephrotoxicity
- the drug is limited to topical use (skin infections)
Binds to bactoprenol and inhibits it. Bactoprenol transfers peptidoglycan monomers through the plasma membrane
Polypeptide antibiotics
Mechanism of action:
- Inhibition of peptidoglycan precursor translocation across the bacterial membrane (BACTOPRENOL)
- Bacteriostatic or bactericidal effect (depending on the concentration of the drug and the susceptibility of the microorganism)
- Gram-positive organisms
- Used in the treatment of mixed bacterial flora
infections on skin or mucus surfaces - Parenteral
leads to - Nephrotoxicity (severe)
- Hypersensitivity
*Due to severe nephrotoxicity with systemic administration, the use of bacitracin in clinical practice is limited to TOPICAL applications only.
Neomycin-Bacitracin-Polymyxin-B → combination available as ointment preparation; marketed as over-the-counter drug (Neosporin) to prevent and treat minor skin infections caused by small cuts or burns.
DAPTOMYCIN
Lipopeptide
aggregation of daptomycin and calcium alters and this alters membranes and creates holes
• Cell membrane synthesis inhibitor
• Spectrum:
– Same as for vancomycin but effective in case of vancomycin resistance (enterococcus, staphylococcus)
– Indication: endocarditis, sepsis
Lipopeptide antibiotics
Mechanism of action:
The drug inserts into the cytoplasmic membrane (irreversibly), results in disruption of ionic gradients and membrane depolarization
Bactericidal effect (more rapid effect compared to vancomycin)
Narrow spectrum:
- Gram-positive organisms
- MRSA, VRSA, VRE
- Parenteral administration
- Renal elimination
- Pulmonary surfactant antagonizes daptomycin; cannot be used to treat pneumonia
- Myopathy (may be additive with statins); requires monitoring of creatine phosphokinase levels
- Rhabdomyolysis (rare)
- Pneumonitis (therapy > 2 w’)
FUSIDIC ACID
- 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
- 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
Polymyxins
- Era of their use again due to multiple resistance
- COLISTIN : Gram- (multiple drug-resistant Pseudomonas aeruginosa or carbapenemase-producing Enterobacteriaceae)
- Binding to LPS, structural changes in cell membrane
- SE: neurotoxicity and nephrotoxicity – only in severe infections
Mycobacterial cell wall
mycolic acid-
Isoniazid + ethambutol
(pyrazinamide?)
VANCOMYCIN
I. Glycopeptides antibiotics
Mechanism of action:
Cell wall and Membrane-active agents (Non beta-lactams antibiotics)
- Binding at the D-ala-D-ala terminal of the nascent peptidoglycans pentapeptide side chains → inhibits the transglycosylation reactions involved in elongation of peptidoglycan chains (interfere with cross-linking)
- Bactericidal effect (slower effect and less pronounced compared to beta-lactam antibiotics)
Narrow spectrum: - Gram-positive bacteria - Used to control infections caused by MRSA and PRSP - Clostridium difficile (2nd line) - Empiric treatment: endocarditis, meningitis (with 3rd gen' cephalosporin) - Osteomyelitis - Prosthetic joint infectio
- Parenteral administration
- T1/2 6 h’
- Not absorbed when given orally
(implies potential benefit in the
treatment of bacterial colitis) - Renal elimination (dose
adjustment in renal dysfunction) - Narrow therapeutic index
(requires monitoring of drug plasma concentrations)
*Resistant to most beta-lactamases - VRSA – vancomycin resistant S. aureus
- VISA – vancomycin intermediate S. aureus
- VRE – vancomycin resistant Enterococci
- Resistance involves alteration of the terminal D-ala to D-lactate
- Chills, fever
- Injection-site phlebitis
- Ototoxicity (additive risk)
- Nephrotoxicity (additive risk
with aminoglycosides) - DRESS syndrome (Drug reaction with eosinophilia and systemic symptoms)
- Rapid IV administration may cause diffuse flushing
(‘red man syndrome’)
due to histamine release
*Teicoplanin is generally less toxic than vancomycin
TEICOPLANIN
I. Glycopeptides antibiotics
Mechanism of action:
Cell wall and Membrane-active agents (Non beta-lactams antibiotics)
- Binding at the D-ala-D-ala terminal of the nascent peptidoglycans pentapeptide side chains → inhibits the transglycosylation reactions involved in elongation of peptidoglycan chains (interfere with cross-linking)
- Bactericidal effect (slower effect and less pronounced compared to beta-lactam antibiotics)
Narrow spectrum: - Gram-positive bacteria - Used to control infections caused by MRSA and PRSP - Clostridium difficile (2nd line) - Empiric treatment: endocarditis, meningitis (with 3rd gen' cephalosporin) - Osteomyelitis - Prosthetic joint infectio
- Parenteral administration
- T1/2 6 h’
- Not absorbed when given orally
(implies potential benefit in the
treatment of bacterial colitis) - Renal elimination (dose
adjustment in renal dysfunction) - Narrow therapeutic index
(requires monitoring of drug plasma concentrations)
*Resistant to most beta-lactamases
WORKS WELL FOR VANCOMYCIN RESITANCE - VRSA – vancomycin resistant S. aureus - VISA – vancomycin intermediate S. aureus - VRE – vancomycin resistant Enterococci
- Resistance involves alteration of the terminal D-ala to D-lactate
- Chills, fever
- Injection-site phlebitis
- Ototoxicity (additive risk)
- Nephrotoxicity (additive risk
with aminoglycosides) - DRESS syndrome
- Rapid IV administration may cause diffuse flushing
(‘red man syndrome’)
due to histamine release
*Teicoplanin is generally less toxic than vancomycin
ORITAVANCIN
I. Glycopeptides antibiotics
Mechanism of action:
Cell wall and Membrane-active agents (Non beta-lactams antibiotics)
- Binding at the D-ala-D-ala terminal of the nascent peptidoglycans pentapeptide side chains → inhibits the transglycosylation reactions involved in elongation of peptidoglycan chains (interfere with cross-linking)
- Bactericidal effect (slower effect and less pronounced compared to beta-lactam antibiotics)
Narrow spectrum: - Gram-positive bacteria, aerobic and anaerobic - Used to treat severe skin infections
- Parenteral administration
- Mechanism of action similar to vancomycin
IS MAINLY USED FOR C. DIFF
- Similar to vancomycin
- GI symptoms
- Elevated liver enzymes
- Elevated CK
(asymptomatic usually)
lipopeptides
Mechanism of action: - - The drug inserts into the cytoplasmic membrane (irreversibly), results in disruption of ionic gradients and membrane depolarization Bactericidal effect (more rapid effect compared to vancomycin)
Daptomycin
Narrow spectrum:
- Gram-positive organisms
- MRSA, VRSA, VRE
- Parenteral administration
- Renal elimination
- Pulmonary surfactant antagonizes daptomycin; cannot be used to treat pneumonia
- Myopathy (may be additive with statins); requires monitoring of creatine phosphokinase levels
- Rhabdomyolysis (rare)
- Pneumonitis (therapy > 2 w’)
Polypeptide antibiotics
Bacitracin
Mechanism of action:
- Inhibition of peptidoglycan precursor translocation across the bacterial membrane
Binds to bactoprenol and inhibits it. Bactoprenol transfers peptidoglycan monomers through the plasma membrane
- Bacteriostatic or bactericidal effect (depending on the concentration of the drug and the susceptibility of the microorganism)
- Gram-positive organisms
- Used in the treatment of mixed bacterial flora
infections on skin or mucus surfaces - Parenteral
- Nephrotoxicity (severe)
- Hypersensitivity
*Due to severe nephrotoxicity with systemic administration, the use of bacitracin in clinical practice is limited to topical applications only.
Neomycin-Bacitracin-Polymyxin-B → combination available as ointment preparation; marketed as over-the-counter drug (Neosporin) to prevent and treat minor skin infections caused by small cuts or burns.
Vaborbactam
Vaborbactam (beta-lactamase inhibitor) is administered in combination with meropenem (meropenem/vaborbactam) in the treatment of complicated UTI, pyelonephritis, and abdominal infections caused by carbapenem-resistant Enterobacteriaceae (CRE); *highly-expansive drug regimen.
imipenem
2nd gen’
Imipenem Meropenem
Vaborbactam (beta-lactamase inhibitor) is administered in combination with meropenem (meropenem/vaborbactam) in the treatment of complicated UTI, pyelonephritis, and abdominal infections caused by carbapenem-resistant Enterobacteriaceae (CRE); *highly-expansive drug regimen.
Broad spectrum: - Effective against gram- positive, gram-negative, anaerobes, aerobes - Serratia, Enterobacter, Pseudomonas, Acinetobacter - Used in hospital-acquired infections, including pneumonia and sepsis - Considered as 'reserve antibiotics' for complicated resistant infections
- Parenteral administration
- Imipenem is given with
cilastatin, a renal dehydropeptidase inhibitor, which inhibits imipenem’s metabolism to a nephrotoxic metabolite - Resistant to most beta-lactamases (including ESBL)
- MRSA strains are resistant to carbapenem
- Carbapenemase (MBL – metallo beta-lactamase); potentially expressed by Klebsiella, Acinetobacter, Pseudomonas, Enterobacter
- Hypersensitivity reaction
- GI symptoms
- Skin rash
- CNS presentation at high
plasma levels (seizures); most common with imipenem
meropenem
2nd gen’
Imipenem Meropenem
Vaborbactam (beta-lactamase inhibitor) is administered in combination with meropenem (meropenem/vaborbactam) in the treatment of complicated UTI, pyelonephritis, and abdominal infections caused by carbapenem-resistant Enterobacteriaceae (CRE); *highly-expansive drug regimen.
Broad spectrum: - Effective against gram- positive, gram-negative, anaerobes, aerobes - Serratia, Enterobacter, Pseudomonas, Acinetobacter - Used in hospital-acquired infections, including pneumonia and sepsis - Considered as 'reserve antibiotics' for complicated resistant infections
- Parenteral administration
- Imipenem is given with
cilastatin, a renal dehydropeptidase inhibitor, which inhibits imipenem’s metabolism to a nephrotoxic metabolite - Resistant to most beta-lactamases (including ESBL)
- MRSA strains are resistant to carbapenem
- Carbapenemase (MBL – metallo beta-lactamase); potentially expressed by Klebsiella, Acinetobacter, Pseudomonas, Enterobacter
- Hypersensitivity reaction
- GI symptoms
- Skin rash
- CNS presentation at high
plasma levels (seizures); most common with imipenem
tazobactam
Activity enhanced of ß-lactams if used in combination with Beta-lactamase inhibitors (Clavulanic acid, Sulbactam, Tazobactam) – ‘suicide inhibitors’ which cause irreversible
inactivation of the lactamase enzymes
- Piperacillin/Tazobactam
- Pseudomonas infection
(known as ‘anti-pseudomonal penicillins’) - Sepsis
severe diverticulitis
pneumonia and pseudomonas are suspected
Ceftolozane/tazobactam
- Broad-spectrum, including MRSA strains
- Complicated UTI’s, abdominal infections
clavulanate
Activity enhanced of ß-lactams if used in combination with Beta-lactamase inhibitors (Clavulanic acid, Sulbactam, Tazobactam) – ‘suicide inhibitors’ which cause irreversible
inactivation of the lactamase enzymes
- Hepatotoxicity (amoxicillin/clavulanate)
- Amoxicillin/Clavulanic acid (Augmentin)
Acute sinusitis, otitis media
Amoxicillin/Clavulanate PO 1st line
severe diverticulitis: Ticarcillin/Clavulanate IV 2nd line
nitrofuantoin
Classified as urinary antiseptic: oral drug that is rapidly-excreted into the urine and acts there to suppress bacteriuria; lacks systemic antibacterial effects
- Active against many urinary tract pathogens (NOT Proteus and Pseudomonas)
- Used in the treatment of uncomplicated lower UTI’s
- Oral
- Urine acidification enhances
drug activity - Rapid renal elimination (dose adjustment in renal impairment)
*Under normal conditions, rapid elimination in urine limits systemic toxicities; side effects are more common with prolonged use or in renal impairment
- GI distress
- Skin rash
- Pulmonary infiltrate
- Phototoxicity
- Acute hemolysis in G6PD
deficient patients
Uncomplicated UTI
˃ Acute cystitis in women
Nitrofurantoin PO
1st line
