BACTERIAL PROTEIN SYNTHESIS INHIBITORS

Drugs Pharmacodynamics/Pharmacokinetics Clinical Use Adverse Effects Drug Interactions

Drugs that bind to 30s ribosomal subunit (Tetracycline and Aminoglycosides)
TETRACYCLINE Short Acting: Chlortetracycline, tetracycline, oxytetracycline
Intermediate acting: demeclocycline and methacycline
Long acting: doxycycline and minocycline, tigecycline
 Tetracycline-resistant strains may be susceptible to doxycycline, minocycline, tigecycline
 Resistance:
1. Impaired influx or increased efflux by an active transport protein pump
a. Gram negative: Resistant to tetracycline, doxycycline, and minocycline but susceptible to tigecycline
b. Staphylococci: Resistant to tetracycline but not to doxycycline, minocycline, and tigecycline
2. Ribosome protection d/t production of proteins that interfere with tetracycline binding to ribosome
a. Gram positive: resistant to tetracycline, doxycycline, minocycline but not to tigecycline
3. Enzyme inactivation
 Proteus and pseudomonas aeruginosa, resistant to all tetracycline including tigecycline
 Doxy and Tige, eliminated by nonrenal mechanisms and does not accumulate
Tetracycline  Bind reversibly to 30s subunit, blocks the binding to Active against gram positive and Cross the placenta and excreted in Avoided in pregnant
aminoacyl tRNA to the acceptor site on mRNA- gram negative milk women and children
ribosome complex preventing the addition of amino younger than 8
acids to the growing peptide DOC in rickettsia infections Can damage growing bones and
 Acids and are fairly stable (except chlortetracycline) Mycoplasma pneumonia, teeth, as a result of calcium chelation None should be orally
 Chelates divalent metal ions, which can interfere their chlamydia, and some spirochetes (fluorescence, discoloration, enamel administered with milk,
absorption and activity dysplasia) antacids, or ferrous SO4
 Enter microorganisms via passive diffusion and in part Prophylaxis of protozoal infections C. difficile-associated colitis
by an energy-dependent process of active transport Nephrotoxic if given with
 Absorption: upper small intestines and impaired by Nausea and vomiting (controlled by diuretics
food (except doxycycline and minocycline), by food or carboxymthylcellulose)
divalent cations (calcium, magnesium, iron,
aluminum), dairy products and antacids, and alkaline Impair hepatic function
pH Renal tubular acidosis, Fanconi Sx
Tigecycline  Newly approved tetracycline analog Skin and skin-structure infections, Nausea
 Glycylcycline and a semisynthetic derivative of intraabdominal infections, (With Black box warning)
minocycline community-acquired pneumonia
 Poorly absorbed orally, must be given IV (T ½ 36hrs)
Minocycline  Reaches very high concentration in tears and saliva eradication of meningococcal Dizziness, vertigo, n/v
carrier state
Doxycycline  Oral tetracycline of choice Dizziness, vertigo, nausea and Carbamazepine, phenytoin,
 Absorption not significantly impaired by food vomiting barbiturates and chronic
 Preferred tetra IV alcohol shortens half-life of
doxy
Demeclocycline  Inhibits the action of ADH in the renal tubule SIADH Sensitivity to sunlight or UV
 AMINOGLYCOSIDES  Irreversible inhibitors of protein synthesis (bind to specific 30s subunit ribosomal proteins)
 Mostly used against aerobic gram negative bacteria; no activity against anaerobes
 Initial event: passive diffusion via porin channels across outer membrane; Drug is then taken actively across cell
membrane into the cytoplasm by an oxygen-dependent process
 More active at alkaline than at acid pH; Low anaerobic conditions inhibit transport by reducing the electrochemical
gradient
 Transport may be enhanced by cell wall-active drugs (penicillin or vancomycin) – synergistic killing
 Inhibits protein synthesis by:
1. Interference with the initiation complex of peptide formation
2. Misreading of mRNA, causes incorporation of incorrect amino acid
3. Breakup of polysomes into nonfunctional monosomes
 Resistance:
1. Production of transferase enzyme or enzyme inactivation by adenylylation, acetylation, phosphorylation
2. Impaired entry into the cell; deletion of porin protein or proteins involved in transport and maintenance of
electrochemical gradient or nonfunctional oxygen-dependent process
All are ototoxic and nephrotoxic
3. Deletion of receptor protein on the 30s ribosomal subunit
most ototoxic: Neomycin, kanamycin, amikacin
 Absorbed poorly from the intact GIT; drug may be absorbed if ulceration is present
most vestibulotoxic: Streptomycin and gentamicin
most nephrotoxic: Neomycin, Tobramycin, and Gentamicin  Have concentration-dependent killing, also have a significant postantibiotic effect
 In very high doses, can produce a curare-like effect with neuromuscular blockade (resp. paralysis) – reversed by
calcium gluconate or neostigmine
Streptomycin  Ribosomal resistance to streptomycin develops Mycobacterial Infections (2nd line) Fever, skin rash, other allergic SSx Not in pregnancy (cause
readily Nontuberculous Infections Disturbance in vestibular function deafness in newborn)
(plague,tularemia, brucellosis), (vertigo and loss balance): most
given IM with oral tetracycline serious toxic effect
Enterococcal Endocarditis
(+penicillin)
Gentamicin  Effective against both gram negative and gram IM or IV: for severe infections Nephrotoxicity (reversible)
positive organisms (sepsis and pneumonia) given in Irreversible ototoxicity
 Resistant: strep and enterococci; failure of drug to combination Loss of hearing
penetrate the cell Topical: infected burns, wounds,
skin lesions, prevent IV catheter
infections
Intrathecal: gram neg meningitis
Sisomicin  Very similar to the C1a component of gentamicin
Tobramycin  Almost same antibacterial spectrum with gentamicin Inhalation: treatment of P. Nepthrotoxic (lesser than genta)
except: aeruginosa LRTI complicating Ototoxicity
 Less active against S. marcescens but more active cystic fibrosis
against P. aeruginosa
 E. faecalis is susceptible to both genta and tobra, but
E. faecium is resistant
Amikacin  Semisynthetic derivative of kanamycin Nephrotoxic
 Resistant to many enzymes that inactivate genta and Ototoxic
tobra
Netilmicin Active against some genta-resistant and tobra-resistant bacteria
Neomycin  Poorly absorbed in the GIT Bowel preparation for bowel Nephrotoxic
Kanamycin  Oral, intestinal flora is suppressed or modified surgery Ototoxic
Paronomycin  Limited to topical and oral route. Too toxic for Paronomycin: visceral Curare-like neuromuscular blockade
parenteral leishmaniasis and E. histolytica Neomycin: too toxic for parenteral
Hepatic encephalopathy use
Drugs that bind to 50s ribosomal subunit
MACROLIDES
Erythromycin  Activity is enhanced by alkaline pH Corynebacterial infections, Anorexia, nausea, vomiting, diarrhea Increase serum conc of oral
 Peptide chain elongation is prevented by blocking of respiratory, neonatal, ocular, or Erythromycin estolate – acute digoxin by increasing its
the polypeptide exit tunnel (transpeptidation) genital chlamydial infections, and cholestatic hepatitis, greatest risk for bioavailability
 Resistance: plasmid-encoded community acquired pneumonia a/e
1. Reduced permeability of the cell membrane or
active efflux Penicillin substitute for allergic to
2. Production of esterases that hydrolyze penicillin
macrolides
3. Modification of ribosomal binding site Prophylaxis against endocarditis
 Destroyed by stomach acid, must be with enteric during dental procedures in
coating valvular heart disease
 Food interferes with absorption
 Taken up by polymorphonuclear leukocytes and
macrophages
 Traverses the placenta
Clarithromycin  Derived from erythromycin by addition of methyl
group and has improved acid stability and oral
absorption
 Same activity with erythro except it is more active
against M. avium complex
 Lower incidence of gastric intolerance and less
frequent dosing
Azithromycin  Derived from erythromycin by addition of methylated Community acquired pneumonia Prolong QT interval >> torsades de Does not inactivate
nitrogen into the lactone ring Chlamydia pointes cytochrome P450; no drug
 Penetrates into most tissues (except CSF) and interactions
phagocytic cells
 Tissue half-life (2-4days)
 Administered 1hr before or 2hrs after meals
Ketolides  Indicated only for treatment of Slightly prolong QT interval C/I: myasthenia gravis
(Telithromycin) community acquired bacterial Hepatitis and liver failure
pneumonia
CLINDAMYCIN
 Chlorine-substituted derivative of lincomycin Skin and soft tissue infections by Diarrhea, nausea, skin rash
 Interfere with the formation of initiation complexes staph and strep Impaired liver function
and with amino acyl translocation reactions Anaerobic infections Neutropenia
 Resistance C. difficile assoc colitis
1. Mutation of ribosomal receptor site Combined with aminoglycoside or
2. Modification of the receptor cephalosporin for penetrating
3. Enzymatic inactivation abdominal wounds
 Penetrates well into most tissues (except brain and More recommended that erythro
CSF) for endocarditis prophylaxis
 STREPTOGRAMINS
Quinopristin  Quinupristin-Dalfopristin - 30:70 ratio Treatment of infections caused by Arthralgia-myalgia syndrome
(streptogramin B)  Share ribosomal binding sites as macrolides and staph or by vancomycin-resistant
clindamycin strains of E. faecium
Dalfopristin  Rapidly bactericidal (except Enterococcus faecium)
(streptogramin A)  Given IV

CHLORAMPHENICOL
Cloramphenicol  Potent inhibitor of microbial protein synthesis Serious rickettsial infections GI disturbances and candidiasis Antagonizes bactericidal
 Binds reversibly to 50s subunit of bacterial ribosome Alternative to B-lactam antibiotics Dose-related reversible red cell drugs (penicillins and
and inhibits peptide bond formation (step 2) for bacterial meningitis suppression aminoglycosides)
 Inactivated by either conjugation with glucuronic acid Topically for eye infections Aplastic Anemia
or by reduction to inactive aryl amines Gray-baby syndrome (vomiting,
flaccidity, hypothermia, gray color,
shock, and vascular collapse)
OXAZOLIDINONES
Linezolid  Primarily bacteriostatic but bactericidal against strep Vancomycin resistant E. faecium Principal toxicity: hematologic (mild
 Inhibits protein synthesis by preventing formation of infections and reversible)
ribosome complex that initiates protein synthesis Nosocomial pneumonia Thrombocytopenia
 Also active to M. tb Community acquired pneumonia Anemia and neutropenia
 Binding site is 23s ribosomal RNA of the 50s subunit Optic and peripheral neuropathy
 100% bioavailability Off label use include treatment of Lactic acidosis
MDR tuberculosis and Nocardia Serotonin syndrome when
infections administered with SSRI (FDA
warning)
Tedizolid  Next-generation oxazolidinone Skin and soft tissue infection
 High potency against gram (+) including MRSA Health-care assoc peenumonia
SPECTINOMYCIN
Spectinomycin  Aminocyclitol antibiotic structurally related to Alternative treatment for drug- Nephrotoxic
aminoglycoside. resistant gonorrhea Anemia
 Mainly against gram (-)
 Lack amino sugar and glycosidic bonds.
 Rapidly absorbed after IM
 ANTIFOLATE DRUGS and DNA GYRASE INHIBITORS

Drugs Pharmacodynamics/Pharmacokinetics Clinical Use Adverse Effects Drug

Interactions
SULFONAMIDES  Inhibit dihydropteroate synthase and folate production
 Soluble at alkaline than at acid pH
 Inhibit both gram positive and negative bacteria
 Does not inhibit rickettsia but instead stimulate their growth
 Synergistic effect with dihydrofolate reductase inhibitor (trimethoprim or pyrimethamine)
 Resistance:
1. Overproduction of PABA
2. Production of folic acid-synthesizing enzyme that has low affinity to sulfonamides
3. Impaired permeability to the sulfonamide
 Adverse Effects:
1. Urinary Tract Disturbances (crystalluria, hematuria, obstruction)
2. Hematopoietic disturbances (hemolytic or aplastic anemia)
Oral Absorbable
Sulfisoxazole  Short to medium acting agents Urinary tract infections
Sulfamethoxazole
Sulfadiazine  Intermediate acting First line for acute toxoplasmosis Cystalluria
 Synergistic with pyrimethamine Bone marrow suppression
(minimized by giving folinic
acid)
Sulfadoxine  Only long acting sulfonamide Second line for malaria
 Coformulated with pyrimethamine as Fansidar
Oral Nonabsorbable
Sulfasalazine  Ulcerative colitis
Enteritis
Other inflammatory bowel disease
Topical
Sodium Bacterial conjunctivitis
sulfacetamide Adjunct for trachoma
Mafenide acetate  Inhibit carbonic anhydrase causing metabolic Burn wounds Metabolic acidosis
acidosis
Silver sulfadiazine  Less toxic topical sulfonamide Burn wounds
Trimethoprim and Trimethoprimsulfamethozole mixture
 Trimethoprim selectively inhibit bacterial Oral Trimethoprim: Acute UTI Megaloblastic anemia,
dihydrofolate reductase Oral TMP-SMZ leukopenia, granulocytopenia
 The mixture blocks sequential steps in folate 1. Pneumocystis jiroveci
synthesis resulting in marked enhancement of the 2. Prophylaxis in recurrent UTI in women
activity of both drugs IV TMP-SMX
 The combination id bactericidal, compared with 1. Agent of choice for moderately sever to
bacteriostatic actively of sulfonamide alone severe pneumocystis pneumonia
  Trimethoprim concentrates in prostatic fluid and Oral pyrimethamine with sulfonamide
vaginal fluid which are more acidic than plasma 1. Toxoplasmosis
2. F. malaria
FLUOROQUINOLONES  Synthetic fluorinated analog of nalidixic acid
 Quinolones block bacterial FNA synthesis by inhibiting bacterial topoisomerase II/DNA gyrase (preventing the
relaxation of positively supercoiled DNA required for normal transcription and replication) and topoisomerase IV
(interfering the separation of replicated chromosomal DNA)
 Excellent activity against gram negative aerobic bacteria; limited against gram positive
 Taken 2hrs before or 4hrs after any products with cations, absorption impaired by divalent and trivalent cations
 S/E: may damage growing cartilage and cause Arthropathy; Tendonitis; peripheral neuropathy
 Avoided in pregnancy
Norfloxacin  Least active flouroquinolones atypical pneumonia (mycoplasma and chlamydia)
 Active against both gram (+) and (-) another intracellular pathogen (listeria and some
Ciprofloxacin  Excellent gram negative activity, moderate-good mycobacteria) Lome and Pefloxacin:
Enoxacin activity against gram positive photosensitivity
Lomefloxacin  Ciprofloxacin: most active against gram(-) Respiratory flouroquinolones: Levo, Gati, Gemi, and
Levofloxacin  Levofloxacin: superior activity against gram positive moxifloxacin
Ofloxacin
Pefloxacin All (except moxifloxacin) effective for UTI
Gatifloxacin  Improved activity against gram positive All (except norfloxacin) for infections of soft tissues, Gatifloxacin: hyperglycemia in
Gemifloxacin  Gemifloxacin: active against ciprofloxacin-resistant bones and joints, and intra-abdominal and respiratory DM
Moxifloxacin S. pneumonia in vitro tract infections Prolongation of QT interval
 Moxifloxacin: modest activity against anaerobic
bacteria Ciprofloxacin: prophylaxis and treatment of anthrax

Cipro, Levo, or moxifloxacin: treatment of TB and

atypical mycobacterial infections;
:eradication of meningococci from carriers
:prophylaxis of infection in neutropenic
cancer patients