Infectious diseases and oncology
Algemene informatie:
- Never ask anything in the exam what he don’t talk about.
- Pairing exercise in exam probably (drugs-function)
- In exam no historical part
- Book: Bertram G. Katzung, Todd W. Vanderah: Basic Clinical Pharmacology, 14th/15th edition (the given
chapters
- Written exam: multiple choice questions + other exercises (e.g. pairing) and open questions! (e.g. short
answer items and case studies) – answer key and questions: based on the lectures!
➢ what is important? what should be a patient warned about?
Lecture 1 introduction
Anti-microbial therapy/chemotherapy
• probably one of the most successful forms of chemotherapy in the history of medicine
• exposure to antibiotics: e.g. ancient Sudanese Nubia dating back to 350–550 CE - distribution of
tetracycline in bones (from diet)
• “Antibiotic era”: started with Paul Ehrlich and Alexander Fleming
Paul Ehrlich:
➢aniline and other synthetic dyes, could stain specific microbes but not others (pre-equisite of the Gram
staining) – idea of a “magic bullet” against disease causing microbes ➢systematic screening program (as
we would call it today) in 1904 to find a drug against syphilis
➢1909: they came across the sixth compound in the 600th series tested (#606), which cured syphilis-
infected rabbits
➢Salvarsan
➢most frequently prescribed drug until its replacement by penicillin in the 1940s ➢mechanism: still not
completely understood
➢the screening approach became a cornerstone in drug research
→ sulfa drugs (Prontosil by Bayer chemists Josef Klarer and Fritz Mietzsch)
→ sulfonamide derivatives (e.g.)
Alexander Fleming
• the antibacterial properties of mold had been known from ancient times, but no breakthrough for ages
• for 12 years after his initial observation (1929), A. Fleming was trying to get chemists interested –
purification and stability
• 1940: an Oxford team led by Howard Florey and Ernest Chain: purification of penicillin in quantities
sufficient for clinical testing → mass production in 1945
• Fleming's screening method using inhibition zones became widely used in mass screenings for antibiotic-
producing microorganisms
• Fleming was also among the first who cautioned about the potential resistance to penicillin.
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,• First hospital use of an “antibiotic”: Pyocyanase prepared by Emmerich and Löw from Pseudomonas
aeruginosa (~1890s)
➢the results of these treatments were not consistent and the preparation itself was
quite toxic for humans
• 1950s and 1970s was the golden era of discovery of novel antibiotics classes, with no new classes
discovered since then
➢The antibiotic treatment choices for already existing or emerging hard-to-treat
multidrug-resistant bacterial infections are limited
Chemotherapy
• selective toxicity
• as little effect on healthy cells/tissue as possible
• based on the effect:
• bactericide (in cancer: cytotoxic)
➢they kill bacteria at safe plasma conc. levels
• bacteriostatic (in cancer: cytostatic)
➢inhibit bacterial growth
➢immune mechanisms eliminate the bacteria
➢bactericide therapy needed (e.g.): endocarditis, meningitis, immunocompromised patients (infections in
neutropenic cancer)
Important: the two types: Bactericide → kill bacteria, mostly act on the cell membrane
Bacteriostatic → inhibit growth, not inhibit the ones that are
already there. Used for Severe impaired immune system
Bacteriostatic: it stops the bacteria from dividing, but as soon you remove the antimicrobial, the bacterium
will start dividing again. So a bacteriostatic stops the dividing of the bacterium but it will not kill the
bacterium. The immune system will remove the bacterium, so a functional immune system is needed!
Mostly work on the ribosomes.
Anti-microbial therapy/chemotherapy → specific targets (specific for the microorganism)
• unique pathway/target, only found in the pathogen
• similar pathway with some differences
• same pathway, but with different significance
Targets of antimicrobial therapy
Unique pathways (not present otherwise in humans):
• cell wall synthesis inhibition (e.g. β-lactams)
• folic acid synthesis inhibition
• ergosterol synth. inhibition (e.g. azols)
• binding to membrane ergosterol (e.g. amphotericin)
• HIV protease inhibition
• neuraminidase inhibition (influenza)
Similar pathways/target:
• Dihydrofolate reductase inhibition (e.g. trimethoprim, pyrimethamine)
• Topoisomerase inhibition (fluoroquinolones)
• Protein synthesis inhibition (e.g. macrolides, tetracyclines)
• DNA, RNA polymerase inhibition
Same (co-existent) pathways/targets:
• Dihydrofolate reductase inhibition (methotrexate)
• anti-metabolite nucleotides (e.g. 5-fluorouracil)
• DNA polymerase inhibition (e.g. cytarabine)
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,Principles of anti-microbial therapy
Is antimicrobial therapy is warranted for a given patient?
1. Is an antimicrobial agent indicated on the basis of clinical findings? Or is it prudent to wait until such
clinical findings become apparent?
2. Have appropriate clinical specimens been obtained to establish a microbiologic diagnosis?
3. What are the likely etiologic agents (a viable microorganism , or its toxin , that causes or may
cause disease in humans or animals) for the patient’s illness?
4. What measures should be taken to protect individuals exposed to the index case to prevent secondary
cases, and what measures should be implemented to prevent further exposure?
5. Is there clinical evidence (e.g., from well-executed clinical trials) that antimicrobial therapy will confer
clinical benefit for the patient?
Once a specific cause is identified based on specific microbiologic tests, the following further questions
should be considered:
1. If a specific microbial pathogen is identified, can a narrower-spectrum agent be substituted for the
initial empiric drug?
2. Is one agent or a combination of agents necessary?
3. What are the optimal dose, route of administration, and duration of therapy?
4. What specific tests (eg, susceptibility testing) should be undertaken to identify patients who will not
respond to treatment?
5. What adjunctive measures can be undertaken to eradicate the infection?
➢Is surgery feasible for removal of devitalized tissue or foreign bodies—or drainage
of an abscess— into which antimicrobial agents may be unable to penetrate?
➢Is it possible to decrease the dosage of immunosuppressive therapy in patients
who have undergone organ transplantation?
➢Is it possible to reduce morbidity or mortality due to the infection by reducing host
immunologic response to the infection (eg, by the use of corticosteroids for the
treatment of severe Pneumocystis jirovecii pneumonia or meningitis due to
Streptococcus pneumoniae)?
The therapy might be:
- targeted
- empiric
- prophylactic
• pre/post operative
• during surgeries
• immune-deficient patients
• recurrent infections (e.g. severe herpes)
• some infections (e.g., HIV, bacterial meningitis, syphilis, gonorrhea)
→ Proper dose for a proper time (with proper schedule)!!
Empiric AB therapy
• therapy and is based on experience with a particular clinical entity
• In some cases it is difficult to identify a specific pathogen (e.g. certain episodes of community-acquired
pneumonia) → clinical response to empiric therapy may be an important clue
• It is indicated:
1. when there is a significant risk of serious morbidity or mortality if therapy is withheld
2. public health reasons: e.g. urethritis in a young sexually active man usually
requires treatment for N gonorrhoeae and Chlamydia trachomatis (the risk of noncompliance with
follow-up visits in this patient population may lead to further transmission of these sexually
transmitted pathogens)
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, The importance of proper treatment regimens
1. effectiveness
• time dependent ABs:
• efficacy relates to the time that the
concentration of a drug remains above the
MIC (T >MIC)
• conc. dependent ABs:
• efficacy relates to the peak
concentration/minimum inhibitory
concentration (Cmax/MIC) ratio
• AUC/MIC for fluoroquinolones – both time
and conc. are crucial
• both (FQs)
➢another aspect to consider: post-antibiotic effect (PAE)
• suppression of bacterial growth after brief antimicrobial exposure to microorganisms
• e.g.: carbapenems, aminoglycosides, tetracyclines, quinolones, rifampicin
T: the time required for the viable count in the test culture to
increase 10-fold above the count observed immediately before
drug removal
C: the time required for the count in an untreated culture to
increase 10-fold above the count observed immediately after
completion of the same procedure used on the test culture.
• Possible mechanisms of PAE:
• slow recovery after reversible nonlethal damage to cell structures
• persistence of the drug at a binding site or within the periplasmic space
• the need to synthesize new enzymes before growth can resume
•?
• In vivo PAEs are usually much longer than in vitro PAEs – post antibiotic leukocyte
enhancement (PALE)
• Aminoglycosides and quinolones possess concentration-dependent PAEs → high
doses, once daily
➢serum concentrations that are below the MICs of target organisms remain
effective for extended periods of time
The importance of proper treatment regimens
1. effectiveness
• time dependent ABs vs conc. dependent ABs vs both (FQs)
• PAE
• pharmacokinetic considerations
• iv administration: more costly, and more possible complications
➢for critically ill patients; for patients with bacterial meningitis or
endocarditis; for patients with nausea, vomiting, gastrectomy, ileus, or
diseases that may impair oral absorption; and when giving
antimicrobials that are poorly absorbed following oral administration
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