MG - infectious diseases and oncology 2

Antibiotics 1: Cell wall synthesis inhibitors

which groups belong to the cell wall synthesis inhibitors?

B-lactams, glycopeptides, fosfomycin, bacitracin

what are the common features of the cell wall synthesis inhibitors?

no effect against intracellular pathogens, no effect on microorganisms without peptidoglycanes, time-dependent effect, bactericide effect, excretion mainly via the kidneys, synergic effect with aminoglycosides

which subgroups belong to the b-lactams?

penicillins, cephalosporines, carbapenems, monobactams

what is the mechanism of action of penicillins

binds to the penicillin binding protein(PBP) resulting in the inhibition of the peptidoglycan synthesis(there is inhibition of the cross-linking and there is the build up of toxic peptidoglycan precursors

which bacteria is penicillin generally used for and for which not?

gram positive bacteria are easily penetrated by the penicillins, whereas the gram negative bacteria are more resistant.

what is a main problem with resistance with the penicillins?

b-lactamases: the b-lactam ring is broken down which is the core needed for efficacy.

what are the side effects of penicillin?

generally well tolerated, but there is a chance of allergy(hypersensitivity), with the potential of anaphylaxis, rashes,urticaria, fever, joint swelling, respiratory compromise

what are the side effects in larger doses?

GI upset (in particular nausea, vomiting, diarrhea), development of colitis, convulsions

what are the pharmacokinetics of the penicillins?

good oral absorption on empty stomach, great distribution, excreted by the kidney(making the renal function of importance)

what groups of penicillins are present?

base penicillins, antistaphylococcal penicillins, extended-spectrum penicillins

what characterizes the base penicillins?

greatest activity against gram positive organisms, gram negative cocci, and non b-lactamase producing anaerobes

what characterizes the antistaphylococcal penicillins?

resistant to staphylococcal b-lactamases. active against staphylococci and streptococci, but not against enterococci, anaerobic bacteria and gram-negative cocci and rods

what characterizes extended-spectrum penicillins?

retain the antibacterial spectrum and have improved activity against gram negative rods, hydrolyzed by b-lacatamses(which is why they are given in combination with b-lactamase inhibitors

penicillin G

base penicillin, short half life(30 min, iv), indicated mainly against gram positive. (benzylpenicillin)

for what bacteria is penicillin G indicated?

pneumonia, strepthroat, syphilis, necrotizing enterocolitis, diphtheria, gas gangrene, leptrospirosis, cellulitis and tetanus

penicillin V

(penoxymethylpenicillin), oral administration, low bioavailability, indicated in minor infections

what is penicillin V indicated for

respiratory and skin infections (strep throat, otitis media and cellulitis)

antistaphylococcal penicillins

semisynthetic narrow-spectrum penicillins, not broken down by certain lactamases and indicated only in infections caused by b-lactamase producing staphylococci

methicillin

antistaphylococcal penicillin, not used anymore due to interstitial nephritis

floxacillin(flucloxacillin)

antistaphylococcal penicillin, skin infections, external ear infections, infections of leg ulcers, diabetic foot infections, infection of the bone. indication: non-MRSA SA infections.

amoxicillin

extended-spectrum penicillin, indications: wide spectrum(middle ear infection, strep throat, pneumonia, skin infections, odontogenic infections, UTI, most common for children, oral and iv with good absorption, renal clearance

amoxicillin / clavulanic acid

combination with b-lactamase inhibitor = wider spectrum. indications: otitis media, streptococcal pharyngitis, pneumonia, cellulitis, UTI, animal bites, dental infections, bone infections (abdominal, respiratory, urinary and pelvic infections)

ureidopenicillins: piperacillin

extended-spectrum penicillin. active against Pseudomonas aeruginosa, parental use, indication: gram negative bacteria mainly in complicated infections. used in combination with tazobactam(b-lactamase inhibitor)

what is the mechanism of action of penicillins?

they inhibit the peptidoglycan synthesis

how common is anaphylaxis due to penicillins?

0.05% of recipients

choose the narrow spectrum penicillin(specifically used against Staphylococcus)

floxacillin

what is not true about pencillin pharmacokinetics in general?

they have a great distribution into different tissues

choose the drug that could be specifically used against Pseudomonas aeruginosa infection

piperacillin

what is true about cephalosporines?

should be considered as reserve antimicrobial agents

what are the cephalosporines compared to penicillin

there is less allergy, stronger b-lactamase resistance, low cross-resistance, worse anaerobe spectrum, generally not first choice

what are the side effects of cephalosporines?

allergy, GI symptoms, kidney damage(rarely)

1st generation cephalosporine

mainly effective against gram positive(cocci), no CNS penetration, relatively old drugs and not commonly used

cefazolin

cephalosporine 1st generation, parental(iv) administration

cefalexine

cephalosporine 1st generation, oral administration, indications: respiratory infections, cystitis, non-complicated skin and soft part infections

spectrum of 2nd generation cephalosporines

same as aminopenicillins with b-lactamase inhibitor except anaerobe and Listeria

cefuroxime

2nd generation cephalosporine, iv administration, penetration in CNS

cefuroxime-axetil

2nd generation cephalosporine, oral administration

cefaclor

2nd generation cephalosporine, oral administration, indication: respiratory infections(CAP, otitis media, pharyngitis)

3rd generation cephalosporine 1st subtype

strong gram negative spectrum, but not used in nosocomial infections, good CNS penetration, but no efffect against Pseudomonas. indications: severe infections(meningitis, endocarditis, severe urinary or GI infections, gonorrhea, syphilis, respiratory infections, sepsis and severe Lyme)

cefotaxime

3rd generation cephalosporine, 1st subtype. classic kinetics, short half life

ceftriaxone

3rd generation cephalosporine, 1st subtype. metabolized in the liver, long half life. cannot be given to newborns

ceftazidime

3rd generation cephalosporine, 2nd subtype. also effective against nosocomial gram negative infections. used against complicated, severe infections(respiratory infections, meningitis, uriniary, GI, bone and joint, skin and soft tissue)

ceftazidime/avibactam

cephalosporine 3rd gen 2nd subtype with b-lactamase inhibitor. indicated in complicated intraabdominal, urinary and pneumonia infections

cefepime

4th generation cephalosporine. indicated in nosocomial and complicated, severe infections(both gram positive and negative)

cefiderocol

5th generation cephalosporine, active against aerobe gram negative. indicated for complicated urinary tract infection

ceftolozane/tazobactam

5th generation cephalosporine. active against aerobe gram negative. indicated for complicated urinary and intra-abdominal infections

ceftaroline fosamil

5th generation cephalosporine, anti-MRSA activity. indicated for community-acquired pneumonia and complicated skin and skin structure infection.

carbapenems

b-lactams, wide spectrum drugs(gram negative bacteria and somewhat narrower activity against gram-positive bacteria), reserved for known or suspected MDR bacterial infections. strong b-lactamase stability.

resistance for carbapenems

natural resistance: staphylococci, enterococci, pseudomonas, acinetobacter(efflux mechanism).

gained resistance: huge problem in clinical practice with few alternative options

imipenem/cilastatine

carbapenem with dehydropeptase inhibitor(protection from degradation)

used for pneumonia, sepsis, endocarditis, joint infections, intraabdominal infections and urinary tract infections

can also be given in combination with b-lactamase inhibitor: imipenem/cilastatine/relebactam

ertapenem

carbapenem

meropenem

carbapenem

also used against meningitis(good CNS penetration)

aztreonam

carbapenem

narrow spectrum antibiotic: aerobe gram negative(Pseudomonas)

synergic with aminoglycosides and piperacillin

specific indication: P. aeruginosa lung infection in patients with CF

glycopeptides

mechanism of action: inhibition of the peptidoglycan synthesis by causing an error in the cross binding, but there can be resistance due to the D-alanine being changed to lactate.

the effect is time-dependent bactericide effect

synergic effect with aminoglycosides

spectrum: only gram positive

PK: no GI absorption, poor penetration, excretion kidney

SE: nephrotoxicity, ototoxicity, local irritation, allergy, red men syndrome(vacomycin)

seems to be safe during pregnancy and breastfeeding

vancomycin

glycopeptide

indications: MRSA, MRSE, other gram positive infections(complicated skin and soft tissue infections, bone and joint infections, CAP, HAP, VAP, endocarditis - in combination with other drugs)

orally: C. difficile infection.

dalbavancin

glycopeptide, semisynthetic lipoglycopeptide

indicated for skin and soft tissue infections

bacitracin

MOA: inhibition of the transport of peptidoglycan subunits, effective only against gram positive. (cell wall synthesis inhibitor)

used only locally(due to severe nephrotoxicity)

hydrocortison/colistine/bacitracine

fosfomycin

MOA: inhibits bacterial cell wall biogenesis by inactivating an enzyme in the peptidoglycan synthesis

spectrum: both gram positive and gram negative pathogens

indication: UTI

resistance under therapy is a frequent occurence resulting in it being unsuitable for sustained therapy

orally - high water consumption is important

polymyxins

cell membrane damaging antibiotic

MOA: creates pores on the cell membrane, bactericide effect

active against only gram negative

iv, no CNS penetration

indication: locally - bladder irrigation, systemic: poly-resistant bacteria

SE: nephrotoxicty, neurotoxicity

daptomycin

cell membrane damaging antibiotic

MOA: incorporated into the bacterial membrane via Ca2+-dependent manner resulting in channel formation and with that cell death

spectrum: gram positive coccus

gets inactivated in the lung - cannot be used for lung infections

indication: skin and soft tissue infections, endocarditis, S. aureus

SE: CV, rash, injection site reaction, fever, hypersensitivity, hepato and nephrotoxicty

choose the correct statement. in contrast to penicillins, cephalosporines

have a worse anaerobe spectrum

in the 3rd generation of cephalosporines, there are two subtypes. what is the difference between these subtypes

the 2nd subtype is also used against gram negative nosocomial infections

which of the cephalosporine generations have a similar spectrum to amoxicillin

2nd generation

which of the following cephalosporines can be used against MRSA

ceftaroline fosfamil

which of the following drugs is only active against gram positive bacteria

vancomycin

why should fosfomycin be used carefully?

frequent resistance under therapy

what is false about carbapenems

they are effective against MRSA