OBAT ANTIMIKROBA

Tujuan:

Setelah kuliah & diskusi,

mahasiswa diharapkan memiliki:

- Pemahaman mengenai klasifikasi antimikroba

- Pemahaman mengenai dasar-dasar penggunaan antimikroba

- Pemahaman mengenai akibat penggunaan antimikroba serta penanggulangannya

ANTIMIKROBA

• Bactericidal– Penisilin - Sefalosporin– Aminoglikosid - Kotrimoksazol– Rifampisin - Isoniasid - dll

• Bacteriostatic– Tetrasiklin - Kloramfenikol– Sulfonamid - Trimetoprim– Linkomisin - Klindamisin– PAS - dll

The Action of Antimicrobial Drugs

Figure 20.2

Golongan beta-lactam : – penicillins, – cephalosporins, – monobactams– carbapenems

PENGHAMBAT SINTESA DINDING SEL KUMAN

• Penicillin– Natural penicillins– Semisynthetic penicillins

• Cephalosporins– 1st, 2nd, 3rd, and 4th Generation

Inhibitors of Cell Wall Synthesis

Penicillins

Klasifikasi

• Penicillins (penicillin G) – efektif melawan gram+, gram-cocci, non-beta-lactamase-producing anaerobes

• Antistaphylococcal penicillins (nafcillin) – resistant to staphylococcal beta-lactamases, active to staphylococci and streptococci

• Extended-spectrum penicillins (ampicillin) – retain antibacterial spectrum of penicillin with improved activity against gram- organisms, but are destroyed by beta-lactamases.

– Penicilinase-resistant penicillins• Methicillin, nafcillin, dicloxacillin• Use: MSSA

– Extended-spectrum penicillins• Ampicillin, Amoxicillin• USE : HELPS – H.flu, E. coli, Listeria,

Proteus, and Salmonella– Anti-Pseudomonal penicillin

• Ticarcillin, piperacillin, carbenicillin• Usually combined with -lactamase

inhibitors– Penicillins + -lactamase inhibitors

• Broad spectrum – G+/G- and anerobic!

Mechanisms of Bacterial Resistance to Penicillins

• Resistance to penicillins and other beta lactams is due to one of four general mechanisms:– Inactivation of the antibiotic by beta lactamase– Modification of target PBPs– Imparied penetration of drug to target PBPs– The presence of an efflux pump.

Other resistance mechanisms

• A reduction in the permeability of the outer membrane.

• Thus there is a decreased ability of the drug to penetrate to the target site.

• The occurrence of modified penicillin binding sites. This mechanism is responsible in methicillin resistance in Pneumococci.

Adverse effects

• Hypersensitivity Reactions. Hypersensitivity reactions are by far the most common adverse effects noted with the penicillins, and these agents probably are the most common cause of drug allergy. There is no convincing evidence that any single penicillin differs from the group in its potential for causing true allergic reactions.

• The basis of which is the fact that degradation products of penicillin combine with host protein and become antigenic.

• These are cross-reactions between various types of penicillins.

• In approximate order of decreasing frequency, manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis The overall incidence of such reactions to the penicillins varies from 0.7% to 10% in different studies.

• Very high doses of penicillin G can cause seizures in kidney failure.

Stevens Johnson Syndrome

Adverse drug reactions. • Painful Blistering of the skin and mucous

membrane involvment. • In many cases preceded with flu like symptoms

and high fever. • As it evolves the skin literally sloughs off. • Ocular involvement includes severe conjunctivis,

iritis, palpebral edema, conjunctival and corneal blisters and erosions, and corneal perforation.

Cephalosporins

• 1st Gram positive coverage

• 2nd – broader coverage

• 3rd Serious Gram negative infections– Know ceftriAXone and cefotAXime for

meningitis– Ceftazidime – anti-Pseudomonal

• 4th cefepime – Anti-Pseudomonal coverage

Cephalosporins  

First Generation        Second Generation     Third Generation       Fourth Generation

                    * Oral Agent

Cefadroxil *   Cefaclor * Cefdinir Cefepime

  Cefazolin    Cefamandole  Cefoperaxone   

  Cefelixin *   Cefonicid  Cefotaxime  

  Cephalothin    Ceforanide Ceftazidime  

  Cephaprin    Cefotetan Ceftibuten  

  Cephradine *   Cefoxitin  Ceftizoxime  

   Cefuroxime

moxalactamCeftriaxone

First generation cephalosporins:• cephalothin, cefazolin, cefalexin. These drugs

have good activity against most Gram positive cocci (Streptococcus, pneumococcus but not or methicillin-resistant Staphylococcus). They are more active against Gram negative organisms (Escherichia co1i Kiebsiella pneumoniae, and the indole negative Proteus mirabilis) than are the natural penicillins. They are effective against some anaerobic cocci (Peptococcus and Peptosteptococcus, but NOT Bacteroides fragilis).

• They are ineffective against Pseudomonas aeruginosa, Enterobacter, and indole-positive Proteus species.

• These drugs do not cross the blood-brain barrier.

Second generation cephalosporins:

• cefuroxime, cefamandole, cefoxitin, cefaclor. The spectrum is extended to more Gram negative bacteria Enterobacter species, Klebsiella species, and indole-positive Proteus species. Also, Haemophilus influenza is covered by cefuroxime, cefamandole, cefaclor; Bacteroides fragilis by cefoxitin.

• These drugs do not achieve adequate levels in the CSF.

Third generation cephalosporins:

• moxalactam, cefaperazone, ceftazidirne, ceftriaxone. These drugs demonstrate extended Gram negative coverage, are more resistant to non-Staphylococcus b-lactamase, and readily cross the blood-brain barrier. The spectrum is extended to include: Enterobacter, Pseudomonas (ceftazidime and cefaperazone only), Serratia, b-lactamase producing Haemophillus influenza and Neisseria species.

• Only cetizoxime and moxalactam retain good activity against Bacteroides fragilis.

Fourth generation

• forth generation of cephalosporins (e.g. cefepime) are available, these are comparable to third-generation but more resistant to some beta lactamases.

Adverse effects

• Hypersensitivity reactions very similar to those that occur with penicillins may be seen.

• Nephrotoxicity and intolerance to alcohol (disulfiram like reaction) has been reported. (cefamandole, cefotetan, moxalactam, cefoperazone )

• Diarrhea may occur with oral forms. Many second and particularly third generation cephalosporins are ineffective against Gram-positive organisms, especially methicillin resistant Staphylococci and Enterococci.

• During treatment with such drugs, these resistant organisms as well as fungi, often proliferate and may induce superinfection.

• Hyperprothrombinemia, Thrombocytopenia, Platelet dysfunction. Administration of vitamin K (10mg) twice a week can prevent this.

beta-Lactamase Inhibitors

• Clavulanic Acid, Sulbactam and tazobactam • Mechanism of action: These drugs have poor

antimicrobial activity. They are inhibitors of bacterial beta-lactamase.

• They are potent inhibitors of many bacterial beta-lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes.

• They are included in combination with amoxacillin (Augmentum) or with ticaricillin. In particular, clavulanic acid is an irreversible, "suicide" inhibitor of beta-lactamase.

• They are available only in fixed combinations with specific penicillins:

• Ampicillin + sulbactam

• Amoxicillin + clavulanic acid

• Ticarcillin + clavulanate potassium

• Piperacillin + tazobactam sodium

• Aminoglycosides– Streptomycin, neomycin, gentamycin

• Irreversibly bind 30S so ONLY ONE that is cidal.• Serious Gram Negative Infections

– Requires O2 to work – NO Anerobes

• Synergistic w/ Beta-lactams • NEPHROTOXIC and OTOTOXIC

• Tetracyclines– Broad spectrum

• Binds 30S subunit

– Use: Rickettsia, Borrelia, Erlichia, and Atypical.– Toxicity: Discolored teeth (Kids), Fanconi’s (Type II

RTA – Proximal), Inhibits bone growth, photosensitivity.

Inhibitors of Protein Synthesis

• Chloramphenicol– Broad spectrum

• Binds 50S subunit• Use: Meningitis• Concerns: Aplastic Anemia (0.1%). Grey baby syndrome

(infants who lack UDP-gluc transferase)

• Macrolides– Erythromycin and azithromycin– Binds 50S, prevents and translocation– Gram-positives and Atypical pneumonias– Azythromycin has very long ½ life so 7 day dose

lasts 10-14 days.– Tox – GI upset

Inhibitors of Protein Synthesis

• Oxazolidinones– Linezolid– Binds 50S subunit, prevents formation of

70S ribosome– Gram-positives

• VRE and MRSA– Oral form only– Developed as antidepressant

Inhibitors of Protein Synthesis

• Clindamycin– Blocks 50S Subunit– Use: Anaerobic infection– Tox: C.Dif

• Rifamycin– Inhibits RNA synthesis– Antituberculosis– Can treat N.Meningitis carrier state as monotherapy– Improves abx penetration on hardware by getting

through biofilm– Tox: RAPID RESISTANCE (NOT MONOTHERAPY),

Red fluids(tears, urine), Revs up P450 system• Quinolones and fluoroquinolones

– Ciprofloxacin, levofloxacin, etc– Inhibits DNA gyrase– USE: Gran neg, Gram positive, pneumonia, UTI – broad

spectrum– Cipro best gram negative – only one truly for

Pseudomonas– Tox: Tendonitis/rupture. Damage cartilage in kids (Don’t

use in pregnancy)

Inhibitors of Nucleic Acid Synthesis

– Sulfonamides (Sulfa drugs)• Inhibit folic acid synthesis

• Broad spectrum

• Use: Gram positive, Negative, PCP. Great urinary penetration.

• Tox: hypersensitity, hemolysis in G6PD. Bone marrow suppression

• Trimethoprim inhibits excretion of creatinine – so raises serum level.

Competitive Inhibitors

Figure 5.7

Figure 20.13