Chemotherapy 2 antibacterial drugs

CHEMOTHERAPYHIGHLIGHTS

MOHAMED BAHR; MD, PHD

Antibacterial Drugs

Mohamed Bahr; MD, PhD

CELL WALL INHIBITORS


I. BETA-LACTAM ANTIBIOTICS


A. PENICILLINS1928

Alexander Fleming


Beta Lactam Ring


Cell wall of gram +ve bacteria


PREPARATIONS


1. NATURAL PENICILLINS (PENICILLIN G [BENZYLPENICILLIN], PENICILLIN V)

Narrow spectrum (gram +ve cocci and bacilli and gram -ve

cocci).

Penicillin V is acid-stable (PO); penicillin G is less stable (IM).

Inactivated by β-lactamase.


2. ANTI-STAPH PENICILLINS (OXACILLIN, CLOXACILLIN, FLUCLOXACILLIN, NAFCILLIN)

Narrow spectrum as natural penicillins.

Stable to gastric acidity.

Stable to β-lactamase.


3. BROAD-SPECTRUM PENICILLINS (AMPICILLIN AND AMOXICILLIN)

Broad-spectrum (as natural penicillins plus some gram -ve

bacilli).

Stable to gastric acidity.



4. ANTIPSEUDOMONAL (OR EXTENDED-SPECTRUM) PENICILLINS (CARBENICILLIN INDANYL, TICARCILLIN, PIPERACILLIN)

Broad-spectrum including Pseudomonas and many gram -ve

bacilli. Piperacillin is also active against Klebseilla

pneumonia.

Unstable to gastric acidity (given parenterally).



5. LONG-ACTING PENICILLINS (BENZATHINE PENICILLIN, PROCAINE PENICILLIN)

Insoluble salts of penicillin G →

allow slow drug absorption with

long duration of action (penicillin

G is short-acting; 6 hours).

Procaine penicillin: given /12

hours.

Benzathine penicillin: given

once/month.


MRSA

VRvancomycin, rifampin


ROUTE DETERMINED BY

Stability of the penicillin

Severity of infection


PENICILLINS CAN:Cross placenta

Cross inflamed meninges


Essential features of BBB


Elimination


COMMON USESStreptococcal infections:

• Acute throat infections, wound sepsis, puerperal fever.

• Bacterial endocarditis: penicillin is given plus an aminoglycoside

(facilitate penetration of aminoglycosides by interfering with

bacterial cell wall synthesis → synergistic bactericidal effect).

Staphylococcal infections.

Pneumococcal infections.

Diphtheria, tetanus and gas gangrene (penicillin plus specific

antitoxins).


COMMON USESMeningococcal meningitis: penicillin G or ampicillin IV plus

chloramphenicol.

Gonorrhea (alternative: fluorinated quinolones).

Typhoid and paratyphoid fever: amoxicillin and ampicillin.

Syphilis

Prophylaxis against:

• Recurrence of rheumatic fever: benzathine penicillin (1.2 million

units/month).

• Bacterial endocarditis (plus an aminoglycoside).


Skin and Soft Tissue Infections Folliculitis

Furuncle, carbuncle

Cellulitis

Impetigo

Mastitis

Surgical wound infections

Hidradenitis suppurativa

Musculoskeletal InfectionsSeptic ar thritis

Osteomy elitis

Py omy os itis

Ps oas abs c es s

Respiratory Tract InfectionsVentila tor -as sociated or nos oc omia l pneumonia

Septic pu lmonary emboli

Pos tvir al pneumonia ( e.g., in fluenza)

Empyema

Bacteremia and Its ComplicationsSepsis, septic shock

Metastatic foci of infection (kidney, joints, bone, lung)

Infective endocarditis


Infective EndocarditisInjection drug use–associated

Native-valve

Prosthetic-valve

Nosocomial

Device-Related Infections (e.g., intravascular catheters, prosthetic joints)

Toxin-Mediated Illnesses

Toxic shock syndrome

Food poisoning

Staphylococcal scalded-skin syndrome

Invasive Infections Associated with Community-Acquired MRSA

Necrotizing fasciitis

Waterhouse-Friderichsen syndrome

Necrotizing pneumonia

Purpura fulminans


Penicillin G


ADVERSE EFFECTSHypersensitivity (most important). Maybe either direct effect, rashes

and phlebitis; or immunological (due to antigenic metabolites),

angioedema (marked swelling of lips, tongue, periorbital area) and

anaphylaxis. This is more with penicillin G, so its use is restricted.

Cross-allergy may occur between β-lactam antibiotics.

Diarrhea: disruption of normal balance of intestinal flora; more with

incompletely absorbed and broad-spectrum agents.

Seizures: IT - RF.

Cation disturbance: hyperkalemia with penicillin G.


B. CEPHALOSPORINS


1st Generation Cephalexin (PO)Cefazolin (IV)

G +ve cocci (Strept - Staph), some G -ve organisms (E coli - Klebsiella)

Cephalexin: Broad spectrum in URTI, UTI

Cefazolin: 1st choice in surgical prophylaxisIn orthopedic surgery: penetrates bone well, penicillinase resistant (Staph)

2nd GenerationCefaclor (PO)Cefuroxime (IV)Cephamycins (cefoxitin, cefotetan, cefmetazole) (IV)

Less active on G +ve, extended spectrum on G -ve organismsCephamycins: aerobic and anerobic G –ve bacilli

Oral agents are used in sinusititis, otitis

Cefuroxime: also in community acquired pneumonia (H influenza).

Cephamycins are structurally related to cephalosporins, used in mixed anaerobic infections (including B fragillis), e.g., peritonitis


3rd Generation Cefoperazone, Cefotaxime, Ceftriaxone (IV)

↑ activity against resistant G -ve organisms (e.g. Pseudomonas)

Used in serious infections

Most agents cross BBB (used in meningitis)

Ceftriaxone (Longest t½): used in gonorrhea (single injection), typhoid (resistant cases)Bone: good penetration. BBB: crosses BBB, so can be used in meningitis. Bile: excreted in bile (40%), used in biliary infection and in renal dysfunction.

4th Generation Cefepime (IV)

Similar spectrum to 3rd generation on G –ve, effective on penicillin-resistant Strept and Staph

Crosses BBB well


5th Generation: Ceftarolene fosamil (IV)

Broad spectrum prodrug, effective against MRSA,

VRSA, H influenza, G -ve organisms (plus

aminoglycosides).

Used in skin infections and community-acquired

pneumonia.

Adjust dose in renal impairment.


Reverse type, PO


ADVERSE EFFECTSHypersensitivity: cross-allergy with penicillins → avoided in patients

with serious (immediate) hypersensitivity to penicillin.

Hypoprothrombinemia and bleeding.

Nephrotoxicity especially if used with aminoglycosides.

Local irritation → severe pain after IMI and thrombophlebitis after IVI.

Intolerance to alcohol → disulfiram-like reaction.

Cross-resistance with penicillins: avoided in penicillin-resistant

infections.


C. CARBAPENEMS: IMIPENEM (IV) BROADEST

Effective against gram +ve, -ve organisms and anaerobes.

Resistant to β-lactamase.

High cross-allergy with penicillin.

High risk of toxicity:

• Metabolized in the kidney to an inactive nephrotoxic metabolite, thus

it is given with cilastatin to inhibit renal metabolism.

• High risk of convulsion → avoided in meningitis.

Meropenem and ertapenem are similar to imipenem with less renal

degradation (cilastatin is not required) and less risk of convulsions.


D. MONOBACTAMS: AZTREONAM (IV & IM) NARROW

Effective against aerobic gram -ve organisms (as

aminoglycosides).

Resistant to β-lactamase.

No cross-allergy with β-lactams.


COMBINATION


II. VANCOMYCIN G+, IVI• Staph resistant to penicillin (MRSA): drug of choice. It is used

in serious infections as Staph pneumonia, endocarditis and

osteomyelitis.

• Severe Staph infections in patients allergic to penicillins or

cephalosporins.

• Pseudomembranous colitis following antibiotic use.


Vancomycin

Mohamed Bahr; MD, PhD Daptomycin


ADVERSE EFFECTS• Fever, chills, rigors and phlebitis.

• Shock with rapid infusion → red man syndrome (due to

histamine release). Avoided by slow infusion and

pretreatment with antihistamines.

• Ototoxic.

• Nephrotoxic.


DRUG-INDUCED PSEUDOMEMBRANOUS COLITIS

Clindamycin.

Broad-spectrum antimicrobials: tetracyclines, co-trimoxazole, chloramphenicol → kill intestinal flora → flourishing of Clostridium difficile (G +ve anaerobe) and its toxins → colitis

Treatment

Vancomycin

Metronidazole

Cholestyramine (Why?)


Broad-spectrum antimicrobials can induce pseudomembranous colitis


CELL MEMBRANEINHIBITORS


DAPTOMYCIN G+, IV/ IMMore rapidly bactericidal. Vancomycin-resistant organisms.

Skin and soft tissue infections.

Bacteremia and endocarditis.

Adverse effects

1. GIT upset and elevated liver enzymes.

2. Myopathy → avoid with statins.


PROTEIN SYNTHESISINHIBITORS


I. TETRACYCLINES


USES


PHARMACOKINETICSPO

Bile

Bone

BBB

Urine

Pregnancy


ADVERSE EFFECTS AND CONTRAINDICATIONS• Epigastric pain due to gastric irritation (noncompliance).

• Teeth discoloration and bone hypoplasia.

• Hepatotoxicity (in renal failure or pregnancy).

• Phototoxicity (sensitivity of skin to sun light).

• Superinfection with Candida, C difficile or resistant Staph in intestine.

• Fanconi-like syndrome: renal tubular dysfunction with outdated

tetracyclines.

• Contraindicated in renal dysfunction.


TIGECYCLINE (SLOW IVI)• Similar to tetracycline in structure, mechanism, and adverse

effects; with less resistance.

• Effective against gram +ve, gram -ve, and anaerobes; a wide

variety of multidrug-resistant nosocomial infections.

• Causes nausea.

• Adjust in liver impairment.


II. AMINOGLYCOSIDES


SPECTRUM AND ACTIVITY• Effective against aerobic organisms.

• Ineffective against anaerobes (requires O2 for transport into

cells).

• Act mainly against gram -ve organisms, e.g., E coli,

Pseudomonas, cholera.

• Gentamycin is also effective against Staph infections.

• Amikacin resists bacterial enzymatic inactivation, thus it is the

most effective aminoglycoside against gram -ve bacilli.


PHARMACOKINETICS• Absorption: not absorbed orally thus have to be given

parenterally.

• Distribution: do not cross BBB even when meninges are

inflamed. They are concentrated in renal cortex, perilymph and

endolymph of inner ear → nephrotoxicity and ototoxicity.

• Excretion: unchanged through the kidney (care in renal

dysfunction).


THERAPEUTIC USES• Peritonitis, septicemia, pneumonia.

• Complicated UTI.

• Bacterial endocarditis.

• Streptomycin is used in TB.

• Amikacin and netilmicin are reserved for resistant cases.

• Neomycin (too nephrotoxic for systemic use): used orally in

hepatic coma and intestinal antiseptic before surgery (not

absorbed) and topically in infected wounds.


ADVERSE EFFECTS Nephrotoxicity: acute tubular necrosis (may be irreversible).

Risk ↑ by dehydration, old age, ↑ dose, ↑ duration or concurrent

use of nephrotoxic drugs.

Ototoxicity: may be irreversible. Coadministration of loop

diuretics or quinidine → ↑ risk.

Neuromuscular paralysis (inhibit ACh release), especially after

intraperitoneal or intrapleural infusion of large doses.

Allergy: contact dermatitis with topically applied neomycin.


SPECTINOMYCIN

Gonorrhea in patients allergic to

penicillin or patients with penicillin-

resistant gonococcal infection

(single deep IMI).


III. MACROLIDES


Macrolides


Erythromycin

Clarithromycin Azithromycin Roxithromycin


SPECTRUM AND USESChlamydia, Mycoplasma, Spirochetes, gram +ve cocci

and bacilli as an alternative to penicillins and

tetracyclines. They are of choice in:

Patients with allergy to β lactam antibiotics.

Urogenital Chlamydia infection in pregnancy.

Mycoplasma pneumonia in children (tetracyclines are

contraindicated).


ADVERSE EFFECTSEpigastric pain and GIT distress (increases bowel

motility).

Cholestatic jaundice (erythromycin estolate). CI in

liver disease.

Ototoxicity and may lead to transient deafness.

Thrombophlebitis if injected IV.

Prolonged QT interval.


Enzyme inhibitor: ↑ level of theophylline,

warfarin, carbamazepine and terfenadine (→

arrhythmias).

↑ Digoxin level (inhibits intestinal flora that

inactivate digoxin).


IV. CLINDAMYCIN

Bone

Anaerobic

Pseudomembranous

colitis


V. CHLORAMPHENICOLRarely used

Typhoid fever (not carrier), but replaced by fluoroquinolones.

Bacterial meningitis (e.g., H influenza) plus penicillin.

Anaerobic infection, e.g., anaerobic brain abscess.

Topically in eye infections.


ADVERSE EFFECTSGIT upsets and superinfection.

Bone marrow depression: may be dose-independent or

idiosyncratic.

Gray baby syndrome in neonates (↓ drug clearance due to

undeveloped liver and kidney functions).

Optic neuritis.

Enzyme inhibitor: ↑ warfarin, phenytoin and oral hypoglycemics

level.


VI. STREPTOGRAMINS: QUINUPRISTIN/DAFLOPRISTIN (IVI)

Complex with bacterial 50S ribosomal subunits to

inhibit protein synthesis.

Serious infections with resistant gram +ve organisms,

e.g., MRSA and Streptococcus pneumoniae (when?)


ADVERSE EFFECTS

Arthralgia and myalgia.

Thrombophlebitis.

Enzyme inhibitor (similar to erythromycin).


VII. OXAZOLIDINONES: LINEZOLID

Binds to a unique site on the 50S subunit →

inhibits initiation complex → inhibits protein

synthesis.


Linezolid


SPECTRUM AND USES (PO, IV; 100% F)

Restricted to serious infections with gram +ve

organisms resistant to vancomycin or MRSA in

patients intolerant to vancomycin or if IV

access is unavailable.


Linezolid


ADVERSE EFFECTS

GIT: Nausea, vomiting and diarrhea.

Thrombocytopenia.


NUCLEIC ACID INHIBITORS


I. QUINOLONES


Inhibit bacterial:

topoisomerase II (DNA gyrase)

topoisomerase IV


Nonfluorinated Quinolones

1st - generation•Nalidixic Acid•Not used in systemic infections, as 90% of drug is bound to plasma proteins → insufficient plasma conc.•Used only in UTI with G -ve bacilli•Rapid resistance limits its use

Fluorinated Quinolones

2nd to 4th generation•2nd → 4th Generation•Newer Fluorinated derivatives achieving systemic levels•Used in systemic Infections


GENERATIONS OF FLUOROQUINOLONES

Originally developed because of their excellent

activity against gram -ve aerobic bacteria; they

had limited activity against gram +ve

organisms.

Several newer agents have improved activity

against … and …


2ND GENERATIONNORFLOXACIN - CIPROFLOXACIN - OFLOXACIN - PEFLOXACIN

Norfloxacin

the least active against both gram -ve and gram +ve organisms. Only in UTI as it

does not achieve systemic levels.

Newer agents

excellent gram -ve activity

moderate to good activity against gram +ve bacteria

MRSA?

Ciprofloxacin

the most active fluoroquinolone against gram -ve organisms esp. Pseudomonas.


3RD GENERATION LEVOFLOXACIN

Greater activity on G +ve, including

Streptococcus pneumoniae


4TH GENERATIONMOXIFLOXACIN - CLINAFLOXACIN

Improved activity against gram +ve organisms,

particularly S pneumoniae and some Staph.

Fluoroquinolones also are active against agents of

atypical pneumonia (e.g., Mycoplasma and

Chlamydiae) and against intracellular pathogens

such as Legionella species and some Mycobacteria.

Potent against anaerobic bacteria.


THERAPEUTIC USESUTI (gram -ve bacilli) and prostatitis.

RTI resistant to β-lactams and atypical pneumonia due to chlamydia,

mycoplasma, legionella (levofloxacin- moxifloxacin).

Typhoid and infective diarrhea (ciprofloxacin: 1st choice for empiric

therapy).

Gonorrhea (ofloxacin single dose, levofloxacin).

Bone and soft tissue infection.

Resistant TB.

Anaerobes.


ADVERSE EFFECTS AND CONTRAINDICATIONS (CI)GIT: Nausea, vomiting and diarrhea (most common).

CNS: Headache, dizziness, insomnia, convulsions in susceptible

patients.

Phototoxicity.

Hepatotoxicity.

Reversible arthropathy (children < 18 years).

Prolonged QT.

Enzyme inhibitor.


CI

Quinolones are contraindicated in

pregnancy and lactation.

Not routinely recommended in patients <18

years (→ arthropathy).


Fluoroquinolones


II. RIFAMPINBinds and inhibits DNA-dependent RNA polymerase →

inhibition of RNA synthesis.


SPECTRUM

Effective against mycobacteria at all sites and

leprosy.

Potent broad spectrum bactericidal. Effective

against MRSA.

Antiviral effect.


PHARMACOKINETICSWell absorbed after oral administration.

Widely distributed in body tissues and fluids and can reach TB

cavities and sputum and penetrate macrophages killing slowly

growing TB bacilli inside.

Crosses BBB.

Metabolized in the liver and it is a potent enzyme inducer.

Excreted mainly in bile (enterohepatic recycling) and slightly in

urine.


THERAPEUTIC USES

TB (main use), leprosy.

MRSA.

Meningitis Prophylaxis.

Brucellosis; plus doxycycline (1st choice).


ADVERSE EFFECTSRed discoloration of urine, tears, sputum and soft contact

lenses.

Flu-like syndrome (malaise, headache and fever...).

Liver damage and jaundice.

Resistance: rapid (but no cross-resistance with other anti-TB

drugs).

Enzyme induction (serious drug interactions).


FOLATE INHIBITORS


SULFONAMIDES

SulfamethoxazoleSulfadoxineSulfadiazineSulfasalazineSulfacetamide

bacteria (TMP+SMX)malariaburnscolon (ulcerative colitis)eyes (eye infection)


ADVERSE EFFECTSGIT: nausea, vomiting, diarrhea.

Hypersensitivity reactions, rashes, fever, exfoliative dermatitis. Steven-

Johnson Syndrome.

Crystalluria and nephrotoxicity: metabolites formed in liver precipitate in

acidic urine. Advise fluid intake and urine alkalinization.

Hematopoietic disturbances: granulocytopenia and thrombocytopenia,

hemolytic anemia in G6PD deficiency.

Kernicterus (jaundice and CNS affection): displace bilirubin from plasma

protein. Free bilirubin crosses BBB (immature in newly-born) and

reaches CNS.


TRIMETHOPRIMMegaloblastic anemia (folate deficiency),

Granulocytopenia and leucopenia.


CO-TRIMOXAZOLESMX-TMP 400/80UTI, gonococcal urethritis and prostatitis.

RTI due to H influenza and S pneumoniae.

Typhoid fever.


ADVANTAGES?Synergistic combination.

Less and delayed bacterial resistance

More potent (Bactericidal) and wider-spectrum including

Proteus, Salmonella, Shigella, H. influenza and

Gonococcus.


Growth of E coli


ANTITUBERCULOUS DRUGS


1st Line Drugshigh efficacy - accepted toxicity• Rifampin: affects the organisms at all sites• Isoniazid (INH): affects intracellular and extracellular organisms

• Pyrazinamide:affects mainly intracellular organisms (resistant

strains)• Ethambutol• Streptomycin: affects only extracellular organisms 2nd Line Drugsresistance/ intolerance• Ceftriaxone• Clarithromycin• Fluoroquinolones (ciprofloxacin, levofloxacin and moxifloxacin)• Cycloserine (peripheral neuritis and CNS dysfunction)• Ethionamide (peripheral and optic neuritis)• Capreomycin (nephrotoxic and ototoxic)


INH (CELL WALL MYCOLIC ACID)Good PO

Slow vs. Rapid


ADVERSE EFFECTSHypersensitivity.

Neurotoxicity with slow acetylators (B6 deficiency):

peripheral neuritis, optic neuritis, memory impairment and

convulsions → vitamin B6 supplements.

Hepatitis: rare but fatal, risk is increased with age.

Enzyme inhibitor: ↑ phenytoin and carbamazepine serum

level.


Bimodal distribution of isoniazid half-lives caused by rapid and slow acetylation of the drug


PYRAZINAMIDE(FAS-I GENE)Good PO

TB meningitis


ETHAMBUTOL (RNA)Bacteriostatic. It enters active mycobacteria → inhibit RNA

synthesis.

Side Effects: optic neuritis → red/green color blindness - ↓

visual acuity.


LEPROSY


ANTILEPROTIC DRUGSDrug combinations are used to ↓resistance:

Paucibacillary leprosy: dapsone + rifampin (for 6 months).

Multibacillary leprosy: dapsone + rifampin + clofazimine (for

2 years).


1. Rifampin: the most active agent.


2. Dapsone

Bacteriostatic. It is related to sulfonamides and achieves ↑ skin

concentration.

Antagonist to PABA → inhibits folate synthesis.

Adverse Effects

Hemolysis (esp. in G6PD deficiency) - methemoglobuinemia.

PN.

Erythema nodosum leprosum (ENL) → suppressed by corticosteroids.


3. Clofazimine (PO)

A dye accumulating in phagocytes and skin → bactericidal effect

through:

• Binding to DNA, preventing template formation and DNA

replication.

• Formation of cytotoxic oxygen radicals.

Anti-inflammatory: no ENL → used in patients developing ENL

with dapsone.

Adverse effects: skin discoloration (red-brown) - enteritis.


REFERENCESLippincott’s Illustrated Reviews, 5th ed.

Color Atlas of Pharmacology, 2nd ed.

Goodman and Gilman's The Pharmacological Basis of

Therapeutics, 12th ed.

Chemotherapy 2 antibacterial drugs

Health & Medicine

Transcript of Chemotherapy 2 antibacterial drugs