Chemotherapy,

antimicrobial agent and

antibiotics
Sugiyanto
Laboratory of Pharmacology and Toxicology
Faculty of Pharmacy
Gadjah Mada University

10/10/2019 1
Chemotherapy

 Antibacterial agents
 Antifungal drugs
 Anthelmintic drugs
 Drugs used in tuberculosis and leprosy
 Antiviral drugs
 Antiprotozoal drugs
 Anticancer drugs

10/10/2019 2
Pharmacotherapy of Infectious
diseases
 CNS infections Infection & Immunologic Dissoder
Propilaxis in Surgery
Vaccines, Toxoids & Other
 LRT infections Immunobiologics
Human Immunodeficiency Virus
 URT infections Infections

 Skin & Soft tissue infections

 Endocarditis (infective)
 TBC
 GI infections
 Intraabdominal infections
 Parasitic disease
 Urinary Tract infections & Prostatitis
 Sexually transmitted diseases
 Bone & Joint infections
 Sepsis & septic Shock
 Superficial Fungal infections
3
 Invasive Fungal infections
Antimicrobial agents

 Any substance that could kill or inhibit the

growth of microorganism.
 Those include antibacterial, antifunggal,
antiprotozoal and antiviral agents.
 Antibiotic is antimicrobial produced by
microorganism

10/10/2019 4
General principles of
chemotherapy
 To be useful antibacterial agent, a compound should
inhibit the growth of bacteria without harming the
human host.
 The drug should penetrate body tissues in order to
reach the bacteria
 whether a drug is orally absorbed and whether it will cross
the blood-brain barrier

10/10/2019 5
General principles of
chemotherapy
 For example, if the patient has a GI infection, then
the patient will be treated by a drug orally that is not
absorbed by GI tract.
 Likewise, the drugs that are used to treat meningitis
are ones that cross the blood-brain barrier.
 The drug that is extremely effective against
Haemophilus influenzae does no good for the
patient if it cannot reach the organism.

10/10/2019 6
Spectrum of the activity

 Spectrum is a term used to convey an impression of the range of

bacteria that a drug is effective against.
 Narrow, broad, and extended
 Drugs are designed as narrow spectrum if they are only effective
against one class of bacteria
 Drugs are designed as broad spectrum if they are effective
against a range of bacteria.
 If a narrow-spectrum drug is modified chemically (as in adding a
new side chain), and the new compound is effective against more
bacteria more than the parent compound, then the new drug is
said to have an extended spectrum

10/10/2019 7
 Bacteriostatic versus bactericidal;
what is the different ?
 If a drug is bacteriostatic, the patient’s
immune system must complete the task to
get rid off the invaders
 These terms are relative: some drugs can kill
one type of bug and only arrest the growth of
enother.

10/10/2019 8
Resistance of bacteria

 Resistance of bacteria to an antibiotic can occur by mutation,

adaptation, or gene transfer.
 bacteria undergo spontaneous mutation at a frequency of about 1
in 1016 cells. Mutation may make bacteria resistant to an
antibiotic, or it may not.
 Adaptation can take several routes.
 The bacteria may alter the uptake of the drugs by changes in their
lipopolysaccharide coat.
 They may improve a transport system that removes the drug from the
cell.
 They may increase metabolism pathway that bypass the effect of the
antibiotic.

10/10/2019 9
Resistance of bacteria

 Gene transfer occurs through plasmids and transposons.

 Plasmids are extra-chromosomal genetic material (pieces
of RNA or DNA that are not part of chromosomes).
 These may code for enzymes that inactivate antimicrobials.
 The plasmids are transferred from bacteria by conjugation and
transduction
 Transposons are segments of genetic material with
insertion sequences.
 They are incorporated into the genetic makeup of bacteria and can
also code for enzymes that inactivate the antimicrobials.

10/10/2019 10
Adverse effects

 Adverse effects can be allergic, toxic, idiosyncratic, or related to

changes in the normal body flora
 The 1st three kategories (allergic, toxic, and idiosyncratic) apply
to all drugs
 The last (changes in normal body flora) is unique to antibiotics.
 Idiosyncratic reactions are reactions that are not related to
immune responses or known drug properties. Far examples,
hemolysis that occur in G-6-PD deficient patients after treatment
with sulfonamides; peripheral neuropathy that developes in
genetically slow acetylators after isoniazid administration.

10/10/2019 11
Adverse effects
 Alteration in the normal body flora usually refers to changes that occurs
within the GI tract.
 If an antibacterial agent is given orally, it may kill the “good” bacteria
whose normally help in the digestion of the food.
 Other bacteria that are resistant to the antimicrobial can overgrow and
repopulate the GI tract.
 This secondary infection is some time called a superinfection.
 The most common example is the overgrowth of Clostridium difficile. It
produces a toxin that cause a disorder called pseudomembranous
colitis.

10/10/2019 12
Combination of antimicrobial
agents
 The combination can take advantage of the
mechanisms of action to produce a synergistic
effect.
 For example, a combination between a protein synthesis
inhibitor (bacteriostatic) with a drug that affects cell wall
synthesis. Does this combination make sense?
 This combination does not make sense. Why ?

10/10/2019 13
Combination of antimicrobial
agents

 Another example, two drugs both inhibit

production of a key metabolic product, but at
two fifferent sites in the metabolic pathway.
Does this combination make sense?
 This combination is useful. Combination of
trimethoprim and sulfamethoxazole inhibit the
synthesis of folic acid at different steps in the
pathway

10/10/2019 14
Combination of antimicrobial
agents

 Last example, the combination of a cell wall

synthesis inhibitor and a drug that needs to act
intracellularly. Does this combination make
sense?
 This combination is extremely useful. It describes
the combination of penicillins and
aminoglycosides. The penicillins alter the cell wall
and enhance the penetration of the
aminoglycoside.

10/10/2019 15
Classification of antimicrobials

 Inhibitors of nucleic acid synthesis:

 Folate Antagonists
 Sulfonamides
 Trimetoprim
 Quinolones and Other Drugs
 Quinolones
 Urinary tract antiseptics

10/10/2019 16
10/10/2019 17
Classification of antimicrobials
 Inhibitors of Cell Wall Synthesis:
 β_lactams
 Aztreonam
 Cephalosporins
 Imipenem
 Penicillins
 Polypeptides
 Bacitracin
 Vancomycin
 Protein Synthesis Inhibitors
 Aminoglycosides
 Chloramphenicol
 Clindamycin
 Erythromycin
 Tetracyclines

10/10/2019 18
10/10/2019 19
10/10/2019 20
References
 Stringer, J.L., 2001, Basic Cocepts in Pharmacology; A
student’s survival guide, McGraw-Hill International
Editions, Health Professions Series, Boston, p 153
 Neal, M.J., 1997, Medical Pharmacology at a Glance, 3rd
edition, Blackwell Scientific Publication, London, pp
35,36, 37
 Hardman, J.G. and Limbird, L.E.(Editors in Chief) 1996
Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, 9th Edition, International Eition, McGraw-
Hill, New York pp 1027-1233
 DiPiro, JT, et al., 2005, Pharmacotherapy: a
Pathophysiologic Approach, 6th edition, McGraw-Hill,
New York pp 1891- 2255
10/10/2019 21
Inhibitors of Cell Wall
Synthesis
 The penicillins
 The cephalosporins
 Vancomycin
 Imipenem
 Aztreonam

 The final step in the synthesis of bacterial cell wall is a cross-

linking of adjacent peptidoglycan strands by a process called
transpeptidation.

 The penicillins and the cephalosporins are structurally similar to

the terminal portion of the peptidoglycan strands and can
compete for and bind to the enzymes that catalyze
transpeptidation and cross-linking (penicillin-binding proteins =
PBPs)


10/10/2019 >>> weeken cell wall, oddly shaped bacteria, and death 22
β-lactams & Polypeptides

 β-lactams
 Contains a β-lactam ring in their structure
 Some bacteria inactivate the β–lactam antibiotics by an
enzyme that opens the β–lactam ring.
 β-lactamase
 The most common mode of drug resistance is plasmid
transfer of the genetic code for the β–lactamase enzyme
 Penicillinase & cephalosporinase

10/10/2019 23
Β-lactam antibiotics

 The inactivation of these drugs by the β–lactamase

can be dealt with by two approaches:
 1. give a β–lactamase inhibitor at the same time
 2. make chemical modifications in the structure of the drug
to make it more resistant to inactivation
 Clavulanic acid and Sulbactam are β–lactamase
inhibitors
 tazobactam

10/10/2019 24
Penicillins

 Some time has been classified into 3 or 4

groups:
 Naturally occurring penicillins: produced by
microorganism
 Chemically modified to improve the spectrum and
the resistance to the penicillinase

10/10/2019 25
Penicillin type Spectrum
Natural
Penicillins G Narrow spectrum (gram +)
Penicillin V Sensitive to penicillinase
Benzathine penicillin G
Penicillinase resistant
Methicillin Narrow spectrum (Gram
Cloxacillin +)
Dicloxacillin
Synthesized to be
Nafcillin
oxacillin penicillinase resistant
Aminopenicillins Broad spectrum (some
Amoxicillin Gram – also); penicillinase
Ampicillin sensitive
Extended spectrum Active against
Azlocillin Pseudomonas; relatively
Carbenicillin ineffective against Gram +
Mezlocillin
Piperacillin
Ticarcillin
10/10/2019 26
Penicillins

 The oral absorption of the penicillins is poor. There are

exceptions ! What are they ?
 Most of the penicillins only cross BBB if it is inflamed. Treatment
of meningitis
 Penicillins are excreted by tubular secretion that can be blocked
by probenecid
 The most important adverse effect of penicillins is the
hypersensitivity reaction. It can be fatal.

10/10/2019 27
Cephalosporins

 Classified into generation:

 1st generation: cefazolin, cephalexin
 Narrow spectrum, sensitive to cephalosporinase
 2nd generation: cefaclor, cefamandole, cefoxitin
 Increased activity toward gram -; increased stability

10/10/2019 28
Cephalosporins

 3rd generation: cefotaxime, ceftazidime, ceftriaxone

 Broader spectrum, more resistant to β-lactamase
 4th generation: cefepime, cefpirome
 Gram +&- activity, especially against P aeruginosa;
includes gram – with multiple drug resistance patterns
 Some can be given orally (cephalexin & cefaclor)

10/10/2019 29
Cephalosporins

 In general, 3rd (and some of the 2nd ) generation

penetrate the CNS and can be used to treat
meningitis
 The 3rd generation are used extensively
 The 4th generation, relatively vary new, they are
designed to target organism with multiple drug
resistance

10/10/2019 30
Cephalosporins

 There is some cross-allergy with penicillins

 Some of them have anti-vit K effects (bleeding)
 Some of them can cause a disulfiram-like reaction,
because they block alcohol oxidation, causing
aldehyde to accumulate

10/10/2019 31
Carbapenems

 Imipenem & meropenem

 Administered IV only
 Imipenem + cilastatin >> broad spectrum
 Imipenem can be hydrolyzed by a renal dipeptidase >> toxic
metabolite & inactive. CIlastatin inhibits dipeptidase
 Meropenem more stable, does not need the coadministration
with cilastatin

10/10/2019 32
10/10/2019 33
Polypeptides

 Vancomycin
 Teicoplanin,
 are glycopeptides
 Vancomycin is only effective against Gram
+ organism. It is very poorly absorbed
orally
 Adverse effect: ototoxicity

10/10/2019 34
Polypeptides

 Bacitracin; a mixture of polypeptides

 Used topically
 Adverse effect: serious nephrotoxicity

10/10/2019 35
Inhibitor sintesis protein
 Inhibitor sinthesis protein berikatan dengan
subunit ribosomal 30S atau 50S dan
mengusik transkripsi mRNA ke protein
 Subunit ribosomal bakteria berbeda dengan
subunit ribosomal mamalia >>> selektifitas

10/10/2019 36
Klasifikasi inhibitor sintesis
protein
 Gol Aminoglikosida (bekterisidal)
 Gol tetrasiklin
 Gol makrolida
 Kloramfenikol
 Klindamisin
 Empat kelompok terakhir bersifat bakteriostatik
 Resistensi bakteri thd kelompok antibakteri ini
terkait dg penurunan uptake obat atau perubahan
subunit ribosomalnya

10/10/2019 37
Aminoglikosida
 Gentamisin
 Tobramisisn
 Amikasin
 Kanamisin
 Neomisin
 Netilmisin
 Steptomisin
 Klindamisin, dan erithromisin serta klarotromisin
(makrolida) bukan golongan aminoglikosida
 Broad-spectrum, ttp bakteri anerob resisten
 Absorpsi di GI jelek, sangat polar, susah nembus membran
kecuali dg bantuan penisilin dan transport khusus.
10/10/2019 38
Adverse Effect Aminoglikosida
 Ototoksik, nefrotoksik, toksik pd sistem neuromuskular
 Indeks terapi obat ini sempit
 Ototoksisitas: cochlear & vestibular: tinnitus, deafness, vertigo,
high-frequency hearing loss.
 Cochlear toxicity results from selective destruction of the outer
hair cells in the organ of Corti.
 Nephrotoxicity is related to the rapid uptake of the drug by
proximal tubular cells. The cells are then killed. The toxicity is
reversible.
 The neurotoxicity is caused by the blockade of presynaptic
release of ACTH at the neuromuscular junction. Blockade of
postsynaptic also occur.
 >>> weakness and can lead to respiratory depression

10/10/2019 39
 Gol Tetrasiklin
 Tetrasiklin
 Klortetrasiklin
 Demeklosiklin
 Doksisiklin
 Minosiklin
 Oksitetrasiklin
 Serupa dg aminoglikosida gol tetrasiklin numpuk di
sitoplasma melalui sistem transport yg butuh energi.
 Sistem transport ini tdk terdapat di sel mamalia
 Resistensi terjadi bila bacteria bermutasi shg tdk bisa
mengakumulasi obat tsb.
10/10/2019 40
Gol tetrasiklin
 Broad-spectrum
 Aktif thd Gram +, gram – dan anaerob bakteri
 Digunakan untk rickettsial diseases, chlamydial
diseases, cholera, spirochetal diseases, pneumonia
mycoplasmic
 Makanan mengganggu absorpsinya, kecuali
doksisiklin dan minosiklin.
 Dapat membentuk khelat dg bbrp kation: Ca, Mg, Fe
dll.
 Pemakaian bersama antasida tidak dianjurkan

10/10/2019 41
AdEf tetrasiklin
 Staining of the teeth
 Retardation of bone growth
 Photosensitivity
 Efek terhadap gigi (discolored) dan tulang
(retardation of the growth) >>> tdk diberikan pada
anak dan atau ibu hamil
 Insidensi reaksi sensitivitas thd sinar matahari krn
tetrasiklin semakin tinggi

10/10/2019 42
Macrolida
 Eritromisin
 Azitromisin
 Klaritromisin
 Mudah diabsorpsi dari GI, ttp dipengaruhi oleh
adanya makanan
 Ekskresinya lewat empedu.

10/10/2019 43
Eritromisin
 Eritromisi dan derivatnya utamanya
digunakan untuk infeksi Mycoplasma,
penumonia, infeksi Chlamydia, difteri dan
pertussis.
 AdEf: gangguan pencernaan, not unique for
macrolides

10/10/2019 44
kloramfenikol
 Broad-spectrum
 Efektif thd bakteri aerob dan anaerob, kecuali
Pseudomonas aeruginosa
 Hanya digunakan untuk infeksi2 yg
mengancam kehidupan mengingat AdEf nya
 AdEf: bone marrow depression, aplastic
anaemia; a dose-related or idiosyncratic
 Gray-baby syndrome
10/10/2019 45
kloramfenikol
 Diabsorpsi oleh saluran pencernaan
 Dpt menembus CSF
 Inaktivasi didlm hepar mll konjugasi
 Bayi blm mampu mengkonjugasi
kloramfenikol dng baik shg kadar dlm darah
tinggi yg dpt mengakibatkan:
 Abdominal distention, vomiting, cyanosis,
hypothermia, decreased respiration, and
vasomotor colaps
10/10/2019 46
klindamisin
 Klindamisin dan linkomisin seringkali disebut
linkosamida berdasarkan struktur kimianya.
 Linkomisin jarang digunakan
 Aktivitas antibakteri klindamisin mirip dg eritromisin
 Klindamisin dapat menembus hampir semua
jaringan termasuk tulang.
 Aktiv terhadap bakteri anaerob
 Biasa digunakan untk pengobatan infeksi bakteri
anerob di GI dan dikaitkan dg timbulnya
pseudomembranous colitis karena Clostridium
difficile terhadap klindamisin.

10/10/2019 47