ANTIMICROBA

History of Antimicrobials

• 1600s

– Quinine for malaria

– Emetine for amebiasis (Entamoeba histolytica)

• 1900-1910

– Arsphenamines for syphilis

• 1935

– Sulfonamides - broadly active

• 1940

– Penicillin - substantially more active than sulfa drugs

– Originally discovered in 1929 by Alexander Fleming (Scottish)

• Nobel Prize, 1945

• Knighted, 1944

– Produced by fungus Penicillium chrysogenum

Cara masuk

• kuman patogen dapat masuk melalui kulit rusak, atau oleh konsumsi, inhalasi, atau kontak dengan selaput lendir seperti hidung, kencing, atau mukosa vagina

• Kemampuan microba dalam menimbulkan penyakit tergantung dari beberapa hal:

- imunitas host

- virulensi

Jenis

1. Pewarnaan

- gram negatif

- gram positif

2. Bentuk

- batang

- spiral

- sferis

3. Kemampuan menggunakan O2

- anaerob

- aerob

Klasifikasimekanisme kerja

• cell wall inhibitors

• protein synthesis inhibitors

• folic acid inhibitors

• reverse transcriptase inhibitors

PENGGOLONGAN ANTIBIOTIK BERDASARKAN MEKANISME AKSI

1. Cell Wall

2. Cell membrane

3. Protein synthesis

4. Nucleic Acid Synthesis

5. Antimetabolites

Spectrum of Activity• Range of microorganisms that are affected by agent

– Broad spectrum

• Wide range, e.g. both gram-pos & gram-neg

• Used when infective bacterial agent on is not precisely

identified

– Narrow spectrum

• Limited number, or specific group of bacteria

• Used to prevent development of resistance

• Less of an affect on normal bacterial flora

AntibioticSpectrum

Obligate intracellular microorganisms

Chlamydia – tiny, non-motile, spherical bacteria

Rickettsia – small, non-motile, gram-negative bacteria

• Tujuan utama pemberian antibiotik adalah untuk membantu pertahanan tubuh melawan microba pathogen

• Anti microba yang kerjanya mematikan microba bakteriosidal

• Anti microba yang kerjanya mengurangi pertumbuhan bakteri bakteriostatik

Prinsip Dasar Penggunaan Antibiotik Terapi:

• Terapi Empiris : Guidelines, pola kuman

• Terapi Definitif : sesuai hasil kultur

Langkah pemilihan antibiotic(definitif)

• Px lab( darah, urin, feses, sputum, cairan spinal, sekret)identifikasi kumanIdentifikasi kuman test sensitivitas antibiotik

• Cultur and sensitivity (C&S testing)

• Pemeriksaan diatas membutuhkan waktu, sedangkan proses terus berjalan broad spectrum antibiotik

• Beberapa kasus penggunaan antibiotik secara single drug (jika kombinasi akan menurunkan efikasi antagonisme)

• Contoh penggunaan antibiotik kombinasi pada kasus TB paru

• Salah satu efek merugikan penngunaan antibiotik superinfeksi/sekunder infeksi flora normal yang ada di organ mati pertumbuhan kuman pathogen akan meningkat.

• Flora normal non spesifik imunologi• Infeksi opotunistik flora normal menjadi

pathogen oleh karena imun turun

Faktor Host

• Kekebalan host

sistem kekebalan host dibutuhkan dalam membantu antibiotik untuk membunuh/mengurangi pertumbuhan kuman

• Kondisi jaringan

vaskularisasimenentukan tingkat efektivitas pengobatan

Perhatian

• Riwayat alergi obat

innitial assesment riwayat obat yang diminum, reaksi alergi??deskripsikan

alergi salah satu antibiotik usahakan tidak memilih antibiotik yang segolongan

• Kondisi lain

usia, kehamilan,genetik

Penicillin

• was originally extracted from the mould Penicillium notatum.

• Penicillin consists of thiazolidine ring fused with a beta lactam ring which is essential for its antibacterial activity.

• Penicillin has a 4-member ring

• “looks like” part of the cell wall to the cross-linking enzyme

• Penicillin competes with the normal cell wall component for the

cross-linking enzyme, i.e. competitive inhibition

• Prevents this enzyme from cross-linking cell wall

penicillin

Cell Wall

Mechanism of Action

• The bacterial cell wall is a rigid outerlayer that completely surrounds the cytoplasmic membrane.

• Penicillin and other betalactam antibiotics inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis

• Penicillin is effective against gram positive and negative cocci and some gram positive bacilli. Among the cocci, streptococci are highly sensitive.

• Gonococci, pneumococci and meningococci are sensitive to penicillin.

• Among the bacilli gram positive: Bacillus anthracis, Corynebacterium diphtheriae, Clostridium species are highly sensitive. Among the spirochetes, Treponema pallidum is highly sensitive to penicillin.

• Gram negative bacilli, fungi, protozoa,rickettsiae, chlamydiae, viruses and Mycobacterium tuberculosis are totally insensitive to penicillin.

Pharmacokinetic

• Setelah masuk PO benzyl penisillin akan rusak di lambung absorbsi di duodenum

• Absorbsi cepat lewat IM, IV lewat cairan tubuh

• Dalam darah terikat oleh protein albumin

• Cepat di dikeluarkan lewat ginjal urin (porsi besar)

Adverese effect

• Penisillin obat non toxic dan tergolong aman

• 5-10% reaksi hypesensitivitas, syok anafilaksis

• Efek minor: nausea, vomiting, pain, inflamasi di daerah suntikan.

• Efek samping mayor adalah allergic reactions and anaphylaxis skin rash, pruritus, serum sickness like syndrome, eosinophilia, angioneurotic edema, asthma, haematuria, albuminuria, haemolytic anemia, granulocytopenia and anaphylaxis

• Pencegahan terjadinya adverese effect skin test 10,000 U benzyl penicillin per mldaerah suntikan edema, merah, gatal (+) jangan digunakan

Semisynthetic penicillins

• produced by combining the specific side chains in place of benzyl side chain.

• They have been produced to overcome the shortcomings of benzyl penicillin like poor bioavailability, susceptibility to penicillinase and narrow spectrum of activity

• Ex; PHENOXYMETHYL PENICILLIN

PENICILLINASE RESISTANT PENICILLIN

• It is resistant to degradation by penicillinase.Mainly it exhibits activity against gram positive microorganisms and is useful against penicillinase producing Staph. Aureus

• Ex: CLOXACILLIN,dicloxacillin and flucloxacillin

BROAD SPECTRUM PENICILLINS

• They have broad antibacterial spectrum andare effective against both gram positive andgram negative organisms. They are hydrolysed by penicillinase.

• Ex; AMPICILLIN, AMOXYCILLIN

1. AMPICILLIN

• It is a broad spectrum penicillin which is not destroyed by gastric acid but is penicillinase susceptible. It is more effective than benzyl penicillin against a variety of gram negative microorganisms

• Adverse effects skin rash, nausea, epigastric distress, diarrhoea, drug fever, urticaria etc. It is used in infection caused by susceptible gram positive and gram negative organisms

2. AMOXYCILLIN

• Amoxycillin is a semisynthetic penicillin, a close congener of ampicillin and active against gram positive and negative organisms.

• Its absorption is more complete than ampicillin. Food does not interfere with its absorption.

β-LACTAMASE INHIBITORS

• It ‘progressively’ inhibits a wide variety of β-lactamases produced by gram positive and negative organisms and is obtained from Streptomyces clavuligerus. It has no antibacterial activity of its own. It is used along with amoxycillin invarious infections as discussed above.

• Ex; CLAVULANIC ACID, SULBACTAM

1. CLAVULANIC ACID

• It ‘progressively’ inhibits a wide variety of β-lactamases produced by gram positive and negative organisms

• obtained from Streptomyces clavuligerus. It has no antibacterial activity of its own.

• It is used along with amoxycillin in various infections as discussed above.

2. SULBACTAM

• It is another semisynthetic β-lactamaseinhibitor used along with ampicillin.

• It is related to clavulanic acid both chemicallyand in activity

ANTIPSEUDOMONAL PENICILLINS

• These are indicated mainly to treat gramnegative bacilli infection by pseudomonas,proteus and enterobacter.

• Ex; CARBENICILLIN, TICARCILLIN

CEPHALOSPORINS

• Cephalosporins are important bactericidalbroad spectrum β-lactam antibiotics used forthe treatment of septicaemia, pneumonia,meningitis, urinary tract infections, peritonitisand biliary tract infections.

• They are obtained from fungus Cephalosporium acremonium and arechemically related to penicillin

• It consists of beta lactam ring fused to a dihydrothiazine ring.

• All cephalosporins act by inhibiting bacterial cell wall synthesis and are bactericidal. Also the autolytic enzymes in cell wall may be activated leading to bacterial death.

• They are widely distributed afteradministration throughout body fluids.

• Cephalosporins are mainly excreted by thekidneys and dose should be altered in patients with renal disease

Pharmacokinetics

• Cephalosporins are distributed in the body after oral or parenteral administration in same manner as penicillin is distributed.

• The majority are not metabolized and areeliminated by kidney.

Adverse Reactions

• pain at the site of injection and can also cause thrombophlebitis.

• Allergic reactions ; skin rash, fever, serum sickness, eosinophilia, neutropenia and rarely anaphylactic reaction.

• CNS side effects; nystagmus and hallucinations.

• Larger doses can cause nephrotoxicity

FIRST GENERATION CEPHALOSPORINS

Highly active against gram positive but weaker against gram negative bacteria.

1. CEPHALEXIN

• orally active first generation cephalosporin

• less active against penicillinase producing staphylococci

2. CEFAZOLIN

• a semisynthetic potent cephalosporin for parenteral administration.

• It can be administered less frequently because of its long half life

3. CEFADROXIL

• It has good tissue penetration.

• Excreted unchanged in urine

SECOND GENERATION CEPHALOSPORINS

1. CEFUROXIME

• It is effective against a wide range of gram positive and negative organisms.

• Indication; Lower respiratory tract infections pneumonia, acute bronchitis and acute exacerbations of chronic bronchitis.

• ENT infections, such as otitis media, sinusitis, tonsillitis and pharyngitis

2. CEFACLOR

• spectrum of cefaclor: Staphylococci (coagulase-positive, coagulase-negative and penicillinase producing strains), Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis, H.influenzae including beta-lactamase producing strains, E. coli, P. mirabilis, Klebsiella sp., N. gonorrhoeae

• well absorbed after oral administration

• 25 % of the drug is protein bound.

• Cefaclor is widely distributed in the body.

• It is rapidly excreted by the kidneys,up to 85% appears unchanged in the urine within two hours

3. CEFTAZIDIME

• It is a broad spectrum cephalosporin having anti-pseudomonal activity

• Used in serious infections of respiratory tract,ENT and soft tissue infection, septicae�mia, meningitis, GI and biliary tract in�fections

4. CEFOXITIN

• It is produced by an Actinomyces.

• Used in the treatment of anaerobic and mixedsurgical infections and lung abscess.

THIRD GENERATION CEPHALOSPORINS

1. CEFOTAXIME

• A broad spectrum cephalosporin, effective against staphylococci, Haemophilus influenzae, Salmonella, Shigella, Serratia, Citrobacter, Neisseria and Proteus

• The drug is given by parenteral route and is deacetylated in body to active metabolite which acts synergistically with parent drug

2. CEFTRIAXONE

• It is a broad spectrum cephalosporin having a long half life and administered once daily.

• Indicated in meningitis,septicaemia, typhoid, urinary tract infections, prophylaxis in surgical infections, pneumonia, STD, bacteremia and pelvic inflammatory disease

3. CEFTIZOXIME

• It is a parenteral, semisynthetic thirdgeneration cephalosporin.

• approximately 90 percent of drug is excreted by the kidney in unchanged form.

• indicated in lower respiratory tract, skin and soft tissue infection, septicaemia, urinary tract infection and gonorrhoea

4. CEFIXIME

• an orally active antibiotic which has marked in-vitro bactericidal activity against a wide variety of gram positive and negative organisms.

• given orally is about 40 to 50 % absorbed whether administered with or without food

• indicated in respiratory tract infections, gonorrhoea, otitis media, urinary tract infection and typhoid fever

5. CEFOPERAZONE

• broad spectrum cephalosporin with anti-pseudomonal activity.

• It is more susceptible to β-lactamases and is primarily excreted in bile.

• Cefoperazone is also used in combination with sulbactam

FOURTH GENERATION CEPHALOSPORINS

1. CEFPIROME

• used mainly in serious infections includingsepticaemia and respiratory tract infectionsand infections acquired from hospitals.

• It is resistant to many β-lactamases

2. CEFEPIME

• Its antibacterial spectrum is similar to that of third generation cephalosporins.

• It is highly resistant to β-lactamases.

• indicated in bacteremia, septicaemia, febrile neutropenia and hospital acquired infections

AminoglycosidesAntibiotic

• Bactericidal antibiotics originally obtained from various Streptomyces species.

• act by inhibiting protein synthesis of bacteria by directly combining with ribosomes.

• All aminoglycosides are poorly absorbed after oral administration, more active in alkaline pH and excreted unchanged by glomerular filtration

• All the aminoglycosides produce cochlear and vestibular damage (ototoxicity)

• Another serious side effect is nephrotoxicity.

• reduce the acetylcholine release from the motor nerve endings neuromuscular blockade.

1. STREPTOMYCIN

• The aminoglycoside antibiotic, obtained from Streptomyces griseus is the first antitubercular drug.

• its action by combining with bacterialribosome and induces misreading of mRNA codons.

• sensitive bacteria, disruption of cytoplasmic membrane occurs resulting in leakage of amino acids, ions, leading to bacterial death

• oral administration it is not absorbed.

• After IM injection the absorption is rapid.

• It is excreted unchanged in urine.

• Half life is prolonged in patients of renalfailure

• Adverse effects include pain at injection site, ototoxicity, nephrotoxicity, skin rash, fever, exfoliative dermatitis and eosinophilia. Anaphylaxis is rarely seen. Optic nerve dysfunction

• Indication; all forms of tuberculosis along with other antitubercular drugs, tularemia, plague,brucellosis, bacterial endocarditis, entero�coccal endocarditis

2. GENTAMICIN

• It is obtained from Micromonospora pupurea.

• broader spectrum of action and is effective against Pseudomonas aeruginosa, E. coli, Klebsiella, Enterobacter and Proteus.

• Indication; Pseudomonas or Proteus infections in burns, urinary tract infections, lung abscesses, osteomyelitis, middle ear infection, septicaemia; menin�gitis caused by gram negative bacilli, peri�tonitis, in skin and soft tissue infections and postoperative infection.

• Topical administration in the form of drop and ointment for the treatment of infected burns, wounds and the prevention of intravenous catheter infections and in the treatment of ocular infections

• Adverse effects include ototoxicity (in�cidence is related to dose and duration of therapy)

3. TOBRAMYCIN

• It belongs to family nebramycins, is isolated from Streptomyces tenebrarius.

• antibacterial activity is similar to gentamicin and slightly more active than gentamicin against Pseudomonas aeruginosa and Proteus.

4. AMIKACIN

• It is semisynthetic derivative of kanamycin.

• It is active against gentamicin resistant organisms e.g. Pseudomonas aeruginosa, Klebsiella, E. coli and Proteus.

• It is resistant to bacterial aminoglycoside inactivating enzymes

5. KANAMYCIN

• It is derived Streptomyces kanamyceticus.

• It is active against Pseudomonas, but due to severe ototoxicity and nephrotoxicity, it is replaced by other aminoglycosides and occasionally used in multidrug resistant cases of tuberculosis

5. NEOMYCIN

• It is isolated from Streptomyces fradiae and is effective against most gram negative bacilli and some gram positive cocci.

• Because of its high ototoxicity andnephrotoxicitynot used systemically

• used locally in various skin and eye infections

6. FRAMYCETIN

• It is derived from Streptomyces lavendule.

• It is similar to neomycin and used locally invarious skin infections and eye/ear infections

MACROLIDE ANTIBIOTICS

• their name indicates are characterized by a large or macrocyclic lactone ring with attached sugar residue(s).

1. ERYTHROMYCIN

• Erythromycin was isolated from Streptomyces erythreus.

• widely used antibiotic both in children as well as in adults.

• It acts by binding with 50S ribosomal subunit of bacteria and inhibit protein synthesis.

• It is a narrow spectrum antibiotic, low concentration are bacteriostatic, however high concentrations are bactericidal

• Erythromycin is effective against gram positive and few gram negative organisms which mainly includes pneumococci, streptococci, staphylococci, Neisseria and some strains of C. diphtheriae, H. influenzae,Rickettsiae and Treponema

• Adverse effects ; gastrointestinal side effects like nausea, epigastric pain are common. Diarrhoea occurs occasionally.

• Skin rashes, hypersensitivity reaction,hepatotoxicity, oral candidiasis, thrombophlebitis and fever have been reported

• Erythromycin is used as a substitute to penicillin in allergic patients for upper respiratory tract infections, e.g. tonsillitis, pharyngitis and mastoiditis, pneumococcal infection and prophylaxis of rheumatic fever.

2. ROXITHROMYCIN

• Roxithromycin is a semisynthetic macrolide antibiotic

• It is effective against Streptococcusnpyogenes, Streptococcus viridans, Streptococcus pneumoniae, Staphylococcus mitis, S. aureus and coagulase negative staphylococci, Neisseria meningitidis, Bordetella pertussis,

• Moraxella catarrhalis, Corynebacterium diphtheriae, Listeria monocytogenes, Clostridium, Mycoplasma pneumoniae, Pasteurella multocida, Chlamydia trachomatis/psittaci/pneumoniae, Ureaplasma urealyticum, Legionella pneumophila, Helicobacter pylori, Gardnerella vaginalis

• It is more stable in acid media than other macrolides

• Found in the serum after 15 minutes ofadministration. It is more than 90% plasmaprotein bound and more than half the dose is excreted unchanged in urine and faeces.

• Adverse effects like other macrolide generally

• Hypersensitivity reactions like rash, urticaria, angioedema,exceptionally bronchospasm, anaphylactic shock; dizzy sensations (caution in driving or use of machinery

3. AZITHROMYCIN

• Azithromycin is an azalide antibiotic, a sub-class of the macrolides.

• Differs chemically from erythromycin in that a methyl substituted nitrogen atom isincorporated into the lactone ring.

• Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body

• indication:

1. Lower respiratory tract infections

2. Ear, nose and throat infections like tonsillitis, sinusitis, otitis media and pharyngitis.

3. Skin/skin structure infections

4. CLARITHROMYCIN

• It is a macrolide antibiotic obtained bysubstitution of hydroxyl group by a CH3Ogroup in the erythromycin lactone ring.

• Found to be 2 to 10 times more active thanerythromycin.

• Clarithromycin is readily and rapidly absorbed after oral administration and is metabolized significantly in liver. Active metabolite is excreted by kidney and other routes

5. CLINDAMYCIN

• It is a lincosamide and act by binding exclusively to 50S submit of the bacterial ribosomes and hence suppresses proteinsynthesis. It is 7-chloro-7-deoxylincomycin, a semisynthetic derivative of lincomycin

• It inhibits most of the gram positive cocci e.g. streptococci, staphylococci and pneumococci, C. diphtheriae, Actinomyces, Nocardia and Toxoplasma

• Oral absorption is good. It is largelymetabolized and metabolites are excreted in urine and bile.

• Adverse effects include pain at injection site, stomatitis, glossitis, angioneurotic edema, serum sickness, vertigo, tinnitus, aplastic anaemia. Hypotension and cardiac arrest after rapid IV use. Anorexia, metallic taste, oesophagitis, abdominal pain

• It is used in the treatment of severe anaerobic infections caused by bacteroides and other anaerobes. It is also used in combination with aminoglycoside.

6. LINCOMYCIN

• It is mainly bacteriostatic and inhibits the growth of gram positive organisms which includes staphylococci, streptococci,pneumococci, C. diphtheriae and B. anthracis. Like erythromycin it act by interfering with protein synthesis

• indication; upper and lower respiratory tract infections, skin infections, septicaemia, bone and joint infection including acutehaematogenous osteomyelitis

7. VANCOMYCIN

• It is a glycopeptide antibiotic and primarily active against gram positive bacteria, strains of Staph. aureus which are resistant to methicillin are inhibited by vancomycin. It is also effective against Strep. viridans, enterococcus, Clostridium difficile and diphtheroids

• It is bactericidal drug and it exerts it action by inhibiting the synthesis of the cell wall in sensitive bacteria.

• It is given by parenteral route and high concentration of drug may accumulate when renal function is impaired

• Indication; serious life threateningstaphylococcal infections resistant to otherantibiotics, in severe staphylococcal infections in patients who are allergic to penicillin and cephalosporin

POLYPEPTIDE ANTIBIOTICS

• They have bactericidal activity against gram negative bacteria only and are low molecular cationic polypeptide antibiotics

1. POLYMYXIN B

• Has detergent like action on cell membrane and have high affinity for phospholipids. They penetrate into and disrupt the structure of cell membranes, as a result of which amino acids and ions leak out.

• After oral administration negligible or no absorption occurs.

• It is used systemically in enteric infections caused by gram negative organisms

• Topically for pseudomonal infections of conjunctiva and cornea, burns and skin

2. COLISTIN

• Also known as polymyxin E, is also a cationic detergent used only orally. Side effects and uses are similar to polymyxin B.