general considerations (1) Flashcards
CHARACTERISTICS of ANTIBIOTIC THERAPY
causative therapy
the pathogens actively response to the challenge
antibiotic use is a permanent interference with the
environment
TYPES of ANTIBIOTIC THERAPY
empiric
sensitivity based (definitive, pinpointed)
prophylactic
Infications 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 regions) e.g. malaria, anthrax
The basic condition of an effective therapy
- the pathogens have to be sensitive to the antimicrobial agent
- the antimicrobial agents have to be in effective cc. at the site of infection, which depends
- on the pharmacokinetics of the drug
- on the route of administration
- on the dose
- on the duration of the therapy
- T>MIC - time-dependent antibacterial activity
beta-lactams serum cc. should exceed MIC for at least 40-60 % of dose interval
multiple dosing or continuous infusion - Cmax/MIC
- concentration-dependent antibacterial activity
aminoglycosides the higher is the cc., the better is the activity high dose once-a-day (not always) - AUC/MIC
fluoroquinolones high AUC/MIC ensure a good activity
AUC (area under the curve) – The total exposure of an antibiotic to an organism
bactericidal agents
- beta-lactams*
- glycopeptides*
- quinolones/ fluoroquinolones
- metronidazol
- rifampin
- isoniazid
- aminoglycosides
Bactericidal agents has be given in case of endocarditis, meningitis or infections in immunocompromesed patients
* Inhibit but not kill enterococci
bacteriostatic agents
- chloramphenicol
- lincosamides
- macrolides
- tetracyclines
- sulfonamides
- trimethoprim
- nitrofurantoin
- ethambutol
narrow spectrum
e.g.. G-penicilline, vancomycine, oxazolidine, lincosamied, fuzidic acid
extended spectrum
aminoglycosides, aminopenicillines, 2nd and 3rd generation cephalosporins, some fluoroquinolones, macrolides
Broad spectrum
tetracyclines, carbapenems, 4th generation fluoroquinolones, chloramphenicol, piperacilline+tazobactam
FC TCP
Consideration 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 (erythromycin, rifampicin)
- severity of infection
- general condition of the patient (concomitant disease, state of immune system, age, pregnancy)
- cost
Combination of antimicrobial agents (general)
Not routinely recommended
Aim:
1. To assure a synergistic effect
penicillins + aminoglycosides
sulfonamides + trimethoprim
- To extend the antibacterial spectrum
- To prevent the development of resistance
e.g. . Ps. Aeruginosa, acinetobacter infection
antimycobacterial agents
Postantibiotic effect
• Reflects the time required for bacteria to return to logarithmic growth
• Proposed mechanims:
– slow recovery after reversible non lethal damage of cell structures
– persistence of the drug at the binding site or within the periplasmic space
– the need to synthesize new enzymes before growth
• PAE is quite common in the case of G+ bacterias
• Agents with relatively long PAE (≥ 1.5 hours) against G – bacterias (not very common):
– aminoglycosides
– carbapenems
– quinolones/fluoroquinolones – rifampin
– tetracyclines
In vivo PAE is longer than the in vitro onev
Der PAE beruht darauf, dass der Schlüssel in der Bindungsstelle „klemmt“. Das führt zu einer langanhaltenden Funktionsstörung im bakteriellen Stoffwechsel, die auch dann noch anhält, wenn kein antibiotischer Wirkstoff mehr in der Umgebung vorhanden ist.
Unter PAE versteht man die in Stunden/Minuten gemessene Fortdauer der antibakteriellen Wirkung eines Antibiotikums nach Absinken unter die minimale Hemmkonzentration (MHK/MIC) bzw. auf nicht mehr messbare Werte in der Umgebung des Erregers
Base penicillins
Penicillin G and V (penamecillin)
Streptococcus species(a) enterococci (a) listeria neisseria meningitidis many anaerobes (not bacteriodes fragilis)(b) spirochetes actinomyces Erysipelothrix spp. Pasteurella multocida (b) S. pyogens T. pallidum
a- altered PBP many
b- ß-lactamase production many
Antistaphylococcal penicillins
methicillin Oxacillin Flucloxacillin Cloxacillin dicloxacillin nafeillin
indicated only for non-methilicillin-resistant strains of staph. aureus and epidermidis
lack activity against Listeria monocytogenes and Enterococcus ssp.
aminopenicillins
Ampicillin (+sulbactam)
Amoxicillin (+clavulanic acid)
extends spectrum of penicillins to include: sensitive strains of enterobacteriaccae (b), escherichia coli, proteus mirabilis, salmonella, shigella haemophilus influenzae (b) helicobacter pylori
Superior to penicillin for treatment of:
Listeria monocytogenes
sensitive enteropcocci
amoxicillin is most active of all oral ß-lactams against penicillin-resistant Streptococcus pneumoniae
carboxypenicillins
Carbenicillin
Ticarcillin
less active than ampicillin against Streptococcus species, enterococcus faecalis Klebsiella Listeria monocytogenes
activity against Pseudomonas aerigunosa is inferior to that of mezlocillin and piperacillin
ureidopenicillins
Piperacillin (+tazobactam)
Mezlocillin
extends spectrum of ampicillin to include Pseudomonasnaerigunosa (d)
Enterobacteriaceae (b)
Bacteriodes ssp. (b)
d- active efflux pump in some strains
Antipseudomonal penicillins
carboxy- and ureidopenicillins
Extended-spectrum penicillins
amino- and antipseudomonal penicillins
carboxypenicillins
Ureidopenicillins
Cephalosporins -as a rule
As a rule: Gram-positive activity diminishes while gram- negative activity increases as one progresses from first to third generation cephalosporins.
As a rule: tissue penetration improves from first to third generation cephalosporins.
Cephalosporins in general
- Lack of activity against anaerobs (exception: Cephoxitin), Enterococci, Listeria, MRSA (exception: Ceftaroline)
- Spectrum changes by the generations:
- I. Gen. mainly G+ cocci (Staphylo-, Streptococci)
- II. Gen. like the Aminopenicillins+ β-lactamase inhibitors (without Anaerobs, Listeria, Enterococci)
- III. Gen. mainly G-, weaker G+ (however for ex. Ceftriaxone works against Pneumococci, Ceftazidime acts mainly against G- ex. Pseudomonas ae.)
- IV. Gen. mainly G- (Pseudomonas Ae. too)
- V. Gen. MRSA
Things in common:
• Lack of activity against: - enterococci
- Listeria monocytogenes
- anaerobs (exception cefoxitin) - MRSA (exception ceftaroline)
• More pH & temperature stable • Water soluble
N-MTT (N-methylthiotetrazole) side chain:
• Cefamandol!!! , cefotetan, cefmetazol
• Vit K production ↓ (→ prolonged bleeding) • Disulfiram-like activity (→ cave ethanol)
5th Gen:
Cefalosporins active against MRSA:
Ceftaroline, ceftobiprol –broad G- spectrum, some activity against enterococci; not active against ESBL; for skin & soft tissue infections & community-acquired pneumonia
Ceftolozane (+ tazobactam):
developed for resistant G- bacteria (P. aeruginosa, G- facultatively anaerobic rods); complicated urinary tract- & intra-abdominal inf.
CNS penetration:
Cefotaxime, ceftazidime, Ceftriaxone, Cefepime =(cefazoline + ceftazidime)
Gen III/1: cefotaxim, ceftriaxon
meningitis, severe urinary tract & abdominal
inf.,
gonorrhea, cholecystitis
Gen III/2: ceftazidime; cefoperazone (no CNS penetration)
nosocomial inf.
Ceftriaxon:
Both biliary & renal excretion In infants:
- biliary sludging – hyperbilirubinemia
B. fragilis; peritonitis, diverticulitis: Cefoxitin
H.influenza, Klebsiellasp., domestic airway& urogenital infections: Cefuroxime, Cefuroxime acetil
penicillin resistant Pneumococcus: Cefotaxime
P.aeruginosa: Ceftazidime
penicillin resistant Pneumococcus: Ceftriaxone
Carbapenems
Broadest spectrum beta-lactams, G+/- aerobs and anaerobs: Pneumococci, Enterococci, Pseudomonas aeruginosa, Acinetobacter, Bacteroides fragilis
Monobactams-Aztreonam
Narrow spectrum, only G- aerobs, Pseudomonas aeruginosa, Acinetobacter
Glycopeptides
Vancomycin, Teicoplanine Dalbavancin, Telavancin, Oritavancin
Narrow spectrum, only G+ aerob and anaerob bacterias MRSA, Enterococci, Pneumococci
Corynebacterias
Clostridium dificcile
Membrane-active agents
Polymyxins (polipeptide ABs):
Lipopeptide
Polymyxins (polipeptide ABs)
polymyxin B and polymyxin E (colistin)
- G- bacteria, incl. MACI (multirezisztens Acinetobacter baumannii), P. aeruginosa, carbapenemase-producing K. pneumoniae
- local use (e.g. bladder irrigation), in aerosol (cystic fibroses); parenterally for multidrug resistant G- infections (bacteremia, sepsis, pneumonia, complicated UTIs)
- Nephrotoxicity; neurotoxicity (less common)
Lipopeptide:
Daptomycin – vancomycin like activity (alternative for vanco; active against G+ cocci, incl. MSSA, MRSA; enterococci incl. VRE), resistant G+ & Staph. for skin and soft tissue infections (once daily in bacteremia and endocarditis); surfactant antagonizes! (cave pneumonia!)
50S ribosome subunit inhibitors:
- Chloramphenicol
- Macrolids
- Ketolids
- Lincosamid (Clindamycin)
- Streptogramins (A és B)
- Oxazolidinones (Linezolid)
MOLSCK
30S ribosome subunit inhibitors:
- Tetracyclins
* Aminoglycosides
Aminoglycosides
• Streptomycin • Gentamicin • Tobramycin • Netilmicin • Amikacin - Kanamycin - neomycin
- Spectrum: mainly G-, in combinations G+ too
- Lack of effectivity against anaerobs and intracellular pathogens!
Tetracyclines /Glycylcyclines
Spectrum
Doxycicline : - gram (-) rods (H. influenzae, Brucella spp., P. multocida, Yersinia, Vibrios, Francisella tularensis + E. coli and Klebsiella with ~ 30 % resistance)
- intracellular pathogens (Rickettsiae, Chlamydiae)
-spirochetes (Leptospira, Borrelia, Treponema p.)
- H. pylori
- Mycoplasmas, Ureaplasmas
- some protozoa (e.g. Plasmodium falciparum, E. hystolytica)
- anaerobes (e.g. Propionibacteria, but not B. fragilis)
Tigecycline has broader spectrum (acts against all relevant bacteria, including MRSA, Vancomycin-resistant Staphylococci and Enterococci, multiresistant Acinetobacter strains, gram (-) bacteria with ESBL)
Proteus and Pseudomonas are resistant against all tetracyclines!
Streptogramins:
(A - dalfopristin, B – quinupristin)
Spectrum: only G+!
Reserve antibiotics, mainly in life threatening infections
Oxazolidinons
linezolid, tedizolid
Spectrum: only G+!
Reserve antibiotics, mainly in life threatening infections
flouroqinolones
G0: nalidixic acid, oxolinic acid (quinolons)
E. coli, Salmonella, Shigella, H. infl.
G1: norfloxacin
stronger effect
G2: - ofloxacin, pefloxacin
- ciprofloxacin
weak effect - G+ cocci, good - IC pathogens + Pseudomonas (!)
G3: levofloxacin (L-ofloxacin)
fluoroquinolones effective in RTI (strong-Staphylo, Strepto, IC)
weaker against- G-rods
G4: moxifloxacin, gemifloxacin
broad spectrum, +MRSA and effect against anaerobs
Sulfamethoxazole+Trimethoprim (Cotrimoxazole)
Spectrum • Gram-positive cocci • Gram-negative rods (Haemophilus influenzae, E.coli, Klebsiella spp, Enterobacter spp, Shigella, Salmonella spp) • Nocardia asteroides, Yersinia • Pneumocystis jirovechi
Miscellaneous antibiotics
Metronidazole- damage of DNA
- Anaerobs and protozoons (ex. pseudomembranosus colitis (c. difficile infection), brain abscess, giardiasis, amoebiasis, trichomoniasis)
Nitrofurantoin: damage of DNA - urinary antispetic
Rifamycins: rifampin (rifampicin, RMP), rifabutin - RNA polymerase inhibitors
- TBC, osteomyelitis
Fidaxomicin: RNS polymerase inhibitor– C. difficile
Gram positive aerob – Cocci
• 1. Penicillin G / Ampicillin / Oxacillin (Cephalosporins)
– Macrolids / Clindamycin / 3 gen. Fluoroquinolons (RTI)
• 2. Glycopeptids (aminoglycosids) / 5. gen cephalosporins
• 3. Oxazolidinons / Streptogramins / Lipopeptid / Glycylcyclins
• (Fusidic acid, Mupirocin, Fosfomycin)
Gram positive aerob – Rods
• Aminopenicillins (Listeria, C. diphteriae), ciprofloxacin (B. anthracis)
Gram negativ aerob – Cocci (Neisserria)
• Ceftriaxone / cefotaxim (spectinomycin, ciprofloxacin, rifampicin,
chloramphenicol)
Gram negativ aerob – Rods
– Enterobacteriaceae
– Haemophylus
– Pseudomonasaeruginosa
– Acinetobacter
Gram negativ aerob – Enterobacteriaceae
- changeablesusceptibility
- Aminopenicillins/ureidopenicillin/2-4gencephalosporins -> fluoroquinolones -> carbapenems -> tigecyclin ?, colistin + aminoglycosid (-> amikacin) (fosfomycin)
Gram negativ aerob – Haemophylus
Aminopenicillins/2-3gen.cephalosporins/macrolids/ fluoroquinolons (/ chloramphenicol)
Gram negativ aerob – Pseudomonasaeruginosa
Ureidopenicillin/3-4gen.cephalosporins/carbapenems/aztreonam
/ ciprofloxacin (ofloxacin) / +aminoglycosides ( amikacin) / colistin
Gram negativ aerob – Acinetobacter
Colistin (+ carbapenem + amikacin?)
Spirochaetes
– Treponema
• Basicpenicillins, aminopenicillins, cephalosporins, doxycyline
– Leptospira
• Doxycycline, ceftriaxone
– Borrelia
• Doxycycline, aminopenicillins, cephalosporins
Intracellularpathogens
Macrolids, 3 gen. Fluoroquinolones, Doxycycline, chloramphenicol
• Anaerobs
- Metronidazol, Clindamycin
- Penicillins (basic / amino / ureido) / carbapenems
- Doxycycline
- Glycopeptids
