Chemotherapy 2 antibacterial drugs

CHEMOTHERAPY
HIGHLIGHTS
MOHAMED BAHR; MD, PHD
Antibacterial Drugs

Mohamed Bahr; MD, PhD
CELL WALL
INHIBITORS

I. BETA-LACTAM
ANTIBIOTICS

A. PENICILLINS
1928
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
VR
vancomycin, rifampin

ROUTE DETERMINED BY
Stability of the penicillin
Severity of infection

PENICILLINS CAN:
Cross placenta
Cross inflamed meninges

Essential features of BBB

Elimination

COMMON USES
Streptococcal 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 USES
Meningococcal 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
Infections
Septic arthritis
Osteomyelitis
Pyomyositis
Psoas abscess
Respiratory
Tract Infections
Ventilator-associated or nosocomial pneumonia
Septic pulmonary emboli
Postviral pneumonia (e.g., influenza)
Empyema
Bacteremia and
Its
Complications
Sepsis, septic shock
Metastatic foci of infection (kidney, joints, bone, lung)
Infective endocarditis

Infective
Endocarditis
Injection 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 EFFECTS
Hypersensitivity (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 prophylaxis
In orthopedic surgery: penetrates bone well, penicillinase
resistant (Staph)
2nd
Generation
Cefaclor (PO)
Cefuroxime
(IV)
Cephamycins
(cefoxitin,
cefotetan,
cefmetazole)
(IV)
Less active on G +ve, extended spectrum on G -ve organisms
Cephamycins: 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 EFFECTS
Hypersensitivity: 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
MEMBRANE
INHIBITORS

DAPTOMYCIN G+, IV/ IM
More 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
SYNTHESIS
INHIBITORS

I. TETRACYCLINES

PHARMACOKINETICS
PO
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 USES
Chlamydia, 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 EFFECTS
Epigastric 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. CHLORAMPHENICOL
Rarely 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 EFFECTS
GIT 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.

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 GENERATION
NORFLOXACIN - 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 GENERATION
MOXIFLOXACIN - 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 USES
UTI (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. RIFAMPIN
Binds 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.

PHARMACOKINETICS
Well 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 EFFECTS
Red 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
Sulfamethoxazole
Sulfadoxine
Sulfadiazine
Sulfasalazine
Sulfacetamide
bacteria (TMP+SMX)
malaria
burns
colon (ulcerative colitis)
eyes (eye infection)

ADVERSE EFFECTS
GIT: 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.

TRIMETHOPRIM
Megaloblastic anemia (folate deficiency),
Granulocytopenia and leucopenia.

CO-TRIMOXAZOLE
SMX-TMP 400/80
UTI, 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 Drugs
high 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 Drugs
resistance/ 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 EFFECTS
Hypersensitivity.
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.

ANTILEPROTIC DRUGS
Drug 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.

REFERENCES
Lippincott’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

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