Antimicrobials Flashcards
Cell wall synthesis inhibitors
B-lactam antibiotics, vancomycin, daptomycin, bacitracin & fosfomycin
Protein synthesis inhibitors
tetracyclines, glycylcyclines, aminoglycosides, macrolides, chloramphenicol, clindamycin, streptogramins & linezolid
Drugs that affect nucleic acid synthesis
fluoroquinolones, sulfonamides & trimethoprim
Miscellaneous and urinary antiseptics
metronidazole & nitrofurantoin
Penicillins
• Inactive against organisms without peptidoglycan cell wall eg, mycoplasma, protozoa, fungi, viruses
Autolysin production
• Produced by bacteria and mediate cell lysis
• Penicillins activate autolysins to initiate cell death
• Bacteria eventually lyse due to activity of autolysins and inhibition of cell-wall assembly
Ability to ‘reach’ PBPs determined by:
• size
• charge
• hydrophobicity
Penicillin G
• Benzylpenicillin
Active against:
• Most Gram-positive cocci (NOT Staph)
• Gram-positive rods (eg, Listeria, C.perfringens)
• Gram-negative cocci (eg, Neisseria sp)
• Most anaerobes (NOT bacteroides)
• Susceptible to inactivation by B-lactamases
Drug of choice for:
• Syphilis (benzathine penicillin G)
• Strep infections (especially in prevention of rheumatic fever)
• Susceptible pneumococci
Repository penicillins
• Developed to prolong duration of penicillin G
Penicillin G procaine
• IM not IV (risk of procaine toxicity)
• t1/2 = 12-24h
• Seldom used (increased resistance)
Penicillin G benzathine
• IM
• t1/2 = 3-4 weeks
• DOC for syphilis, rheumatic fever
Penicillin V
- Similar antibacterial spectrum to penicillin G (LESS ACTIVE against Gram –ve bacteria)
- More acid stable than G (can give ORALLY)
Drug of choice for:
• Strep throat
• Employed mostly orally for mild-moderate infections eg, pharyngitis, tonsilitis, skin infections (caused by Strep)
Antistaphylococcal penicillins
- Methicillin, Nafcillin, Oxacillin, Dicloxacillin
- B-lactamase resistant
- Inactive against MRSA
- Restricted to treatment of B-lactamase-producing staphylococci
- Recommended as first-line treatment for staphylococci endocarditis in patients without artificial heart valves
Extended spectrum
- Ampicillin, Amoxicillin
- Similar to penicillin G (also have Gram-negative activity)
- Susceptible to B-lactamases
- Activity enhanced with B-lactamase inhibitor
- Amoxicillin has higher oral bioavailability than other penicillins (including ampicillin)
- Amoxicillin is a common antibiotic prescribed for children and in pregnancy
- Used for treatment of a number of infections: acute otitis media, streptococcal pharyngitis, pneumonia, skin infections, UTIs etc.
- Widely used to treat upper respiratory infections (H.influenzae & S.pneumoniae)
- Amoxicillin = standard regimen for endocarditis prophylaxis during dental or respiratory tract procedures
• Ampicillin is used in combination with aminoglycoside to treat Enterococci and Listeria infections
Antipseudomonal penicllins
- Carbenicillin, Ticarcillin, Piperacillin
- Effective against many Gram-negative bacilli
- Often combined with B-lactamase inhibitor
- Active against P.aeruginosa
- Commonly used to treat Pseudomonas aeruginosa
- Treatment of moderate-severe infections of susceptible organisms (eg, uncomplicated & complicated skin, gynecologic and intra-abdominal infections, febrile neutropenia)
Penicillin + aminoglycosides
- Synergistic
- Penicillins facilitate movement of aminoglycosides through cell wall
- Should never be placed in same infusion fluid (form inactive complex)
- Effective empiric treatment for infective endocarditis
Penicillin PK
Oral absorption
• Absorption impaired by food (except amoxicillin -> high oral bioavailability)
• Nafcillin = erratic (not suitable for oral admin.)
Distribution
• All achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids & urine
• Nafcillin, ampicillin & piperacillin achieve high levels in bile
• Levels in prostate & eye = insufficient
• CSF penetration = poor (except in meningitis)
Excretion
• Most excreted primarily via kidney (beware in kidney failure)
• Nafcillin = exception as primarily excreted in bile
• Oxacillin & dicloxacillin = renal & biliary excretion
Penicillin SEs
Hypersensitivity
• Penicilloic acid = major antigenic determinant
• ~ 5 % patients claim to have some reaction
(maculopapular rash -> anaphylaxis)
• Cross-allergic reactions between B-lactam antibiotics can occur
- GI disturbances (eg, diarrhea)
- Pseudomembranous colitis (ampicillin)
- Maculopapular rash (ampicillin, amoxicillin)
- Interstitial nephritis (particularly methicillin)
- Neurotoxicity (epileptic patients at risk)
- Hematologic toxicities (ticarcillin)
- Neutropenia (nafcillin
- Hepatitis (oxacillin)
- Secondary infections (eg, vaginal candidiasis)
B-lactamase inhibitors
- Clavulanic acid, sulbactam, tazobactam
- Contain B-lactam ring but do not have sig. antibacterial activity
- Bind to and inactivate most B-lactamases
- Available only in fixed combinations with specific penicillins
Cephalosporins
- B-lactam antibiotics
- Bactericidal
- Same MOA as penicillins
- Affected by similar resistance mechanisms
- Classified into generations
• All cephalosporins are considered inactive against Enterococci, Listeria, Legionella, Chlamydia, Mycoplasma, and Acinetobacter species.
Cephalosporins first generation
- Cefazolin, Cephalexin
- Penicillin G substitutes
- Resistant to staphylococcal penicillinase
- Activity against Gram-positive cocci & P.mirabilis, E.coli, & K.pneumoniae
- Rarely DOC for any infections
- Cefazolin = DOC for surgical prophylaxis
Cephalosporins second generation
- Cefaclor, Cefoxitin, Cefotetan, Cefamandole
- Extended Gram-negative coverage
- Greater activity against H.influenzae, Enterobacter aerogenes and some Neisseria species
- Weaker activity against Gram-positive organisms
- Primarily used to treat sinusitis, otitis & lower respiratory tract infections
- Cefotetan & cefoxitin = prophylaxis & therapy of abdominal and pelvic cavity infections
Cephalosporins third generation
- Ceftriaxone, Cefoperazone, Cefotaxime, Ceftazidime, Cefixime
- Enhanced activity against Gram-negative cocci
- Highly active against enterobacteriacae, Neisseria, & H.influenzae
- Less active against most Gram-positive organisms
- Cefotaxime & ceftriaxone = usually active against pneumococci
Ceftriaxone
- Third generation cephalosporins
- DOC for gonorrhea
- DOC for meningitis due to ampicillin-resistant H.influenzae
- Prophylaxis of meningitis in exposed individuals
- Treatment of Lyme disease (CNS or joint infection)
Cefaperazone, Ceftazidime
- Third generation cephalosporins
* Activity against P.aeruginosa
Cephalosoprins fourth generation
- Cefipime
- Parenteral admin. Only
- Wide antibacterial spectrum
- Gram +ve activity of 1st generation + Gram -ve activity of 3rd generation
- eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa
• Treatment of infections with susceptible organisms eg, UTI’s, complicated intra-abdominal infections, febrile neutropenia
Cephalosporins fifth generation
- Ceftaroline
- Parenteral admin. Only
- Only cephalosporins with activity against MRSA
- Similar spectrum of activity to 3rd generation
- eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa
• Considering its spectrum of activity, including MRSA, ceftaroline is useful in the treatment of skin and soft tissue infection due to this pathogen, particularly if gram-negative pathogens are coinfecting.
Cephalosporlins PK
- Most administered parenterally (exceptions = cephalexin, cefaclor, cefixime)
- 3rd generation only reach adequate levels in CSF
- Mainly eliminated via kidneys (exceptions = ceftriaxone & cefoperazone excreted in bile)
Cephalosporins SEs
• Allergic reactions (cross-sensitivity with penicillins can occur)
However, minor penicillin allergic patients often treated successfully with a cephalosporin
• Pain at infection site (IM), thrombophlebitis (IV)
• Superinfections (eg, C.difficile)
- Cefamandole, cefoperazone & cefotetan contain methyl-thiotetrazole group, all can cause:
- hypoprothrombinemia (Vit. K1 admin can prevent) &
- disulfiram-like reactions (avoid alcohol)
Carbapenems
- Imipenem, Meropenem. Synthetic B-lactam antibiotics
- Resist hydrolysis by most B-lactamases
- Very broad spectrum of activity
- Active against penicillinase-producing Gram-positive & negative organisms; aerobes & anaerobes; P.aeruginosa
- Not active against carbapenemase producing organisms eg, carbapenem-resistant enterobacteriaceae, carbapenem-resistant klebsiella
- Not active against MRSA
Drugs of choice for
• enterobacter infections
• extended-spectrum B-lactamase producing Gram-negatives
Carbapenem PK and SEs
PK
• IV
• Imipenem forms potentially nephrotoxic metabolite. Combining with enzyme inhibitor Cilastatin prevents metabolism thus prevents toxicity & increases availability.
• Meropenem is not metabolized by same enzyme (no need for Cilastatin)
SEs
• GI distress (nausea, vomiting, diarrhea)
• High levels of imipenem can provoke seizures
• Allergic reactions (partial cross-reactivity with penicillins)
Monobactams
- Aztreonam
- Aerobic Gram-negative rods ONLY (including pseudomonas)
- No activity against Gram-positive bacteria or anaerobes
- Resistant to action of B-lactamases
• UTI’s, lower respiratory tract infections, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible Gram- negative bacteria
Monobactam PK and SE
- Mainly IV or IM
- Can be given by inhalation in CF patients
- Penetrates CSF when inflamed
- Excreted primarily via urine
SE
• Relatively nontoxic
• Little cross-hypersensitivity with other
Vancomycin
- Active against Gram-positive bacteria only
- Virtually all Gram-negative organisms are intrinsically resistant
- Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP)
- Binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
- Inhibits bacterial cell wall synthesis & peptidoglycan polymerization
RESISTANCE
• Plasmid-mediated changes in drug permeability
• Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)
Vancomycin clinical applications
- Treatment of serious infections caused by B-lactam resistant Gram +ve organisms eg, MRSA
- Treatment of Gram +ve infections in patients severely allergic to B-lactams
- In combination with an aminoglycoside for empirical treatment of infective endocarditis
- In combination with an aminoglycoside for treatment of enterococcal endocarditis or PRSP
- Given orally for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (C.difficile)
Vancomycin PK and SE
- Poor oral absorption
- Requires slow IV infusion (60-90 min)
- Penetrates CSF when inflamed
- 90-100% excreted via kidneys
SE
• Mostly minor eg, fever, chills, phlebitis at infusion site
• ‘Red man’ or ‘red neck’ syndrome (infusion-related flushing over face and upper torso)
• Ototoxicity (drug accumulation)
• Nephrotoxicity (drug accumulation)
Daptomycin
- Effective against resistant Gram-positive organisms (eg, MRSA (ORSA), enterococci, VRE & VRSA)
- Recommended for treatment of severe infections caused by MRSA or VRE
- Treatment of complicated skin/structure infections caused by susceptible S.aureus
- Inactive against Gram-negative bacteria
- Not effective in treatment of pneumonia
- Novel mechanism of action -> useful against multi-drug resistant bacteria
- Binds to cell membrane via calcium-dependent insertion of lipid tail
- Results in depolarization of cell membrane with K+ efflux -> cell death
Daptomycin PK and SE
- IV only
- Can accumulate in renal insufficiency
SE
• Constipation, nausea, headache, insomnia
• Elevated creatine phosphokinases (recommended to discontinue coadmin. of statins)
Bacitracin
- Unique mechanisms -> no cross resistance
- Interferes in late stage cell wall synthesis
- Effective against Gram-positive organisms
- Marked nephrotoxicity
Fosfomycin
- Inhibits cytoplasmic enzyme enolpyruvate transferase in early stage of cell wall synthesis
- Active against Gram-positive and negative organisms
- Oral
- Used for treatment of uncomplicated lower UTI’s
Protein synthesis inhibitors
- Tetracyclines
- Glycylcyclines
- Aminoglycosides
- Macrolides
- Chloramphenicol
- Clindamycin
- Streptogramins
- Linezolid
- Mupirocin
- Bind to and interfere with ribosomes
- Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome
- Mostly bacteriostatic
Tetracyclines
- Doxycycline, Minocycline, Tetracycline
- Broad-spectrum
- Bacteriostatic
- Activity against many aerobic and anaerobic Gram- positive & Gram-negative organisms
- Entry via passive diffusion & energy-dependent transport unique to bacterial inner cytoplasmic membrane
- Susceptible cells concentrate drug intracellularly
- Bind reversibly to 30S subunit of ribosome, preventing binding of aminoacyl tRNA
Tetracycline resistance
• Widespread resistance (usually plasmid mediated)
- 3 main mechanisms:
- Impaired influx or increased efflux by active protein pump
- Production of proteins that interfere with binding to ribosome
- Enzymatic inactivation
Tetracyclines
• Most common use = severe acne & rosacea
• Used in empiric therapy of community-acquired
pneumonia (outpatients)
• Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract, & intestines
• Syphilis (patients allergic to penicillin)
Drugs of choice for: • Chlamydia • Mycoplasma pneumoniae • Lyme disease • Cholera • Anthrax prophylaxis • Rickettsia (Rocky Mountain Spotted Fever, typhus)
Used in combination for:
• H.pylori eradication
• Malaria prophylaxis and treatment
• Treatment of plague, tularemia, brucellosis
Tetracycline PK and SE
- Variable oral absorption (decreased by divalent & trivalent cations)
- Doxycycline (lipid soluble) = preferred for parenteral admin. and good choice for STD’s and prostatitis
- Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)
- Concentrate in liver, kidney, spleen & skin
- Excreted primarily in urine except doxycycline (primarily via bile)
- TERATOGENIC – all cross placenta & are excreted into breast milk (FDA category D)
SE
• Gastric effects / superinfections (nausea, vomiting, diarrhea)
• Discoloration & hypoplasia of teeth, stunting of growth (generally avoided in pregnancy & not given in children under 8y)
• Fatal hepatotoxicity (in pregnancy, with high doses, patients with hepatic insufficiency)
• Exacerbation of existing renal dysfunction
• Photosensitization
• Dizziness, vertigo (esp. doxycycline & minocycline)
Glycylcyclines
- Tigecycline
- Structurally similar to tetracyclines
- Treatment of complicated skin, soft tissue and intra- abdominal infections
Antibacterial spectrum
• Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms
RESISTANCE
• Little resistance
• Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)
Glycylcyclines PK and SE
PK
• IV only
• Excellent tissue & intracellular penetration
• Primarily biliary/fecal elimination
SE • Well tolerated • AE similar to tetracyclines Contraindications • Pregnancy & children <8y
- Increased risk of mortality has been observed with tigecycline compared with other antibiotics when used to treat serious infections
- FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections
Aminoglycosides
- Amikacin, Gentamicin, Tobramycin, Streptomycin, Neomycin
- Bactericidal
- Associated with serious toxicities
- Largely replaced by safer antibiotics
- Most active against aerobic Gram-negative bacteria
- Anaerobes lack O2-dependent transport
- Used mostly in combination
- Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc
- Once organism is identified aminoglycosides are normally discontinued in favor of less toxic drugs
Drugs of choice for:
• Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin
• Streptomycin is the drug of choice for Plague (Y.Pestis)
- Passively diffuse across membranes of Gram-negative organisms
- Actively transported (O2-dependent) across cytoplasmic membrane
- Bind to 30S ribosomal subunit prior to ribosome formation leading to:
- misreading of mRNA, &
- inhibition of translocation
Aminoglycosides resistance
3 principal mechanisms:
• Plasmid-associated synthesis of enzymes that modify and inactivate drug
• Decreased accumulation of drug
• Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation
Oral Neomycin
• Used as adjunct in treatment for hepatic encephalopathy
Alternative treatment options for hepatic encephalopathy: • Lactulose • Oral vancomycin • Oral metronidazole • Rifaximin
Lactulose
Other Effects
• Prebiotic (suppression of urase producing organisms)
• Osmotically active laxative
Adverse Effects
• Osmotic diarrhea
• Flatulence
• Abdominal cramping
Aminoglycosides PK and SE
- Parenteral admin. only (except neomycin - topical)
- Once-daily admin.
- Well distributed (excluding CSF, bronchial secretions)
- High levels in renal cortex & inner ear
- 99% excreted in urine (reduce dose in renal insufficiency)
SE
Both time- and concentration-dependent
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade (myasthenia gravis = contraindicated)
• Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)
Macrolides
- Erythromycin, Clarithromycin, Azithromycin, Telithromycin
- Mainly used to treat Gram-positive infections
- Bacteriostatic (bactericidal at high conc.)
- Most active against Gram-positive bacteria (some activity against Gram-negatives)
- Spectrum is slightly wider than that of penicillins
- Azithromycin, clarithromycin & telithromycin have broader spectrum than erythromycin
- Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with B-lactam for inpatients)
- Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci)
- Erythromycin = DOC for whooping cough (B.pertussis)
- Common substitute for patients with penicillin allergy
- Reversibly bind to 50S subunit inhibiting translocation
- Binding site is identical or close to that for clindamycin & chloramphenicol
Macrolides resistance
3 main mechanisms (usually plasmid encoded):
• Reduced membrane permeability or active efflux
• Production of esterase that hydrolyze drugs (by enterobacteriaceae)
• Modification of ribosomal binding site (by chromosomal mutation or by a methylase)
• Complete cross-resistance between erythromycin, azithromycin, & clarithromycin
• Partial cross-resistance with clindamycin & streptogramins
Macrolides PK, SE, CI
- Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin
- Azithromycin & telithromycin = greater tissue penetration compared to other macrolides
- Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin)
SE
• GI irritation
• Hepatic abnormalities (erythromycin & azithromycin)
• QT prolongation
• Severe reactions are rare (anaphylaxis, colitis)
CI
• Statins (due to macrolides inhibiting CYP P450)
• Telithromycin – fatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances -> don’t use for minor illnesses
Chloramphenicol
- Potent inhibitor of protein synthesis
- Broad-spectrum (aerobic & anaerobic Gram-positive & - negative organisms)
- Bacteriostatic (usually)
- Toxicity limits use to life-threatening infections with no alternatives
- Very broad spectrum
- Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
- N.meningitidis, H.influenzae, Salmonella & bacteroides = highly susceptible
- Never given systemically for minor infections (due to adverse effects)
• Serious infections resistant to less toxic drugs
• When chloramphenicols penetrability to site of
infection is clinically superior to other drugs
• Active against many VRE
• Topical treatment of eye infections (mainly outside US)
- Enters cells via active transport process
- Binds reversibly to 50S ribosomal subunit (site adjacent to site of action of macrolides & clindamycin)
- Can inhibit protein synthesis in mitochondrial ribosomes -> bone marrow toxicity
RESISTANCE
• Presence of factor that codes for chloramphenicol acetyltransferase (inactivates drug)
• Changes in membrane permeability
Chloramphenicol PK and SE
- Oral, IV or topical
- Wide distribution (readily enters CSF)
- Inhibits hepatic oxidases (3A4 & 2C9)
SE • GI distress • Bone marrow depression: • dose-related reversible depression • severe irreversible aplastic anemia • Gray baby syndrome (cyanosis), due to drug accumulation
Clindamycin
- MOA = same as macrolides (binds to 50S subunit)
- Mainly bacteriostatic
- Primarily used against Gram-positive anaerobic bacteria (including bacteroides)
- Anaerobic infections (eg, bacteroides infections, abscesses, abdominal infections)
- Skin and soft tissue infections (streptococci and staphylococci, and some MRSA)
- In combination with primaquine as an alternative in PCP
- In combination with pyrimethamine as an alternative in toxoplasmosis of brain
- Prophylaxis of endocarditis in valvular patients allergic to penicillin
RESISTANCE Due to: • mutation of ribosomal receptor site • modification of the receptor • enzymatic inactivation of drug • Most Gram-negative aerobes & enterococci are intrinsically resistant • Cross-resistant with macrolides
Clindamycin PK and SE
- Oral or IV
- Good penetration (including abscesses and bones)
SE
• GI irritation (~ 20% people experience diarrhea)
• Potentially fatal pseudomembranous colitis
(superinfection of C.difficile)
• Skin rashes (~10 %)
• Neutropenia & impaired liver function
Streptogramins
- Quinupristin, Dalfopristin
- Given as a combination (act synergistically to have bactericidal action)
- Long postantibiotic effect
- Gram-positive cocci
- Multi-drug resistant bacteria (streptococci, PRSP, MRSA, E.faecium)
- Restricted to treatment of infections caused by drug- resistant Staphylococci or VRE
Mechanism of action
• Bind to separate sites on 50S bacterial ribosome • Resistance is uncommon
Streptogramins PK
- IV only
- Penetrates macrophages & polymorphonucleocytes
- Inhibitors of CYP 3A4
SE
• Infusion related (venous irritation, arthralgia & myalgia)
• GI effects
• CNS effects (headache, pain)
Linezolid
- Bacteriostatic (cidal against streptococci & Clostridium perfringens)
- Most Gram-positive organisms (staphylococci, streptococci, enterococci, Corynebacterium, Listeria monocytogenes)
- Moderate activity against mycobacterium tuberculosis
- Treatment of multi-drug resistant infections
Mechanism of action
• Inhibits formation of 70S initiation complex
• Binds to unique site on 23S ribosomal RNA of 50S subunit
RESISTANCE
• Decreased binding to target site
• No cross-resistance with other drug classes
Linezolid PK, SE, CI
- Oral (100% bioavailable) & IV
- Widely distributed (including CSF)
- Weak reversible inhibitor of MAO
SE
• Well tolerated for short admin. (GI, nausea, diarrhea, headaches, rash)
Long-term admin. can cause:
• Reversible myelosuppression
• Optic & peripheral neuropathy, & lactic acidosis
CI
• Reversible, nonselective inhibitor of MAO -> potential to interact with adrenergic and serotonergic drugs
Fidaxomicin
• Narrow spectrum macrocyclic antibiotic
• Activity against Gram-positive aerobes and
anaerobes especially Clostridia
• No activity against Gram-negative bacteria
• Treatment of C.difficile colitis (in adults)
• Inhibits bacterial protein synthesis by binding to RNA polymerase
PK
• When administered orally, systemic absorption is negligible but fecal concentrations are high
SE
• Main effects appear to be gastrointestinal disorders
• The safety and effectiveness of fidaxomicin in patients < 18 years of age have not been established.
Mupirocin
• Antibiotic belonging to monoxycarbolic acid class
• Activity against most Gram-positive cocci, including MRSA and most streptococci (but not enterococci)
• Only topical/intranasal agent with activity against MRSA
• Intranasal:
• Eradication of nasal colonization with MRSA in
adult patients and healthcare workers • Topically:
• Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes
• Binds to bacterial isoleucyl transfer-RNA synthetase resulting in the inhibition of protein synthesis
SE
• Resistance develops if used for long periods of time
• Mainly local and dermatologic effects (eg, burning, edema, tenderness, dry skin, pruritus)
Fluoroquinolones
- Broad spectrum, bactericidal drugs
- Enter bacterium via porins
- Inhibit bacterial DNA replication via interference with topoisomerase II (DNA gyrase) & IV
- Classified into generations
- Lower generations have excellent Gram-negative activity
- Higher generations have improved activity against Gram- positives
RESISTANCE
• Emerged rapidly in 2nd generation (esp. C.jejuni, gonococci, Gram-positive cocci, P.aeruginosa & serratia).
• Due to chromosomal mutations that:
• encode subunits of DNA gyrase (eg, gonococci resistance) and topo IV
• regulate expression of efflux pumps (eg, S.aureus, S.pneumonia, M.tuberculosis)
• Cross-resistance between drugs occurs
Fluroquinolones generations
1st - Nalidixic acid
• Moderate Gram -ve activity
• Uncomplicated UTI’s
2nd - Ciprofloxacin
•Expanded Gram -ve activity
• Some activity against Gram +ve and atypical organisms
• Synergistic with B-lactams
•Travelers diarrhea (E.coli)
• P.aeruginosa (CF patients)
• Prophylaxis against meningitis (alternative to ceftriaxone & rifampin)
3rd - Levofloxacin
• Expanded Gram -ve activity
• Improved activity against Gram +ve and atypical organisms
• Excellent activity against S.pneumoniae
• Prostatitis (E.coli)
• STD’s (not syphilis)
• Skin infections
• Acute sinusitis, bronchitis, TB Community acquired pneumonia
4th - Gemifloxacin, Moxifloxacin
• Improved Gram +ve activity and anaerobic activity
• Community acquired pneumonia
Respiratory fluoroquinolones
Levofloxacin, moxifloxacin & gemifloxacin (excellent activity against S.pneumoniae, H.influenzae & M.catarrhalis) Used in treatment of pneumonia when: • First-line agents have failed • In the presence of comorbidities • Patient is an inpatient
Fluoroquinolones PK and SE
- Good oral bioavailability
- Well distributed into all tissues and fluids (including bones)
- Iron, zinc, calcium (divalent cations) interfere with absorption
- Dosage adjustments required in renal dysfunction (except moxifloxacin)
SE
• GI distress
• CNS, rash, photosensitivity
• Connective tissue problems (avoid in pregnancy, nursing mother, under 18’s)
• QT prolongation (moxifloxacin, gemifloxacin, levofloxacin)
• High risk of causing superinfections (C.difficile, C albicans, streptococci)
Fluoroquinolones interactions and CI
- Theophylline, NSAIDs & corticosteroids = enhance toxicity of fluoroquinolones
- 3rd & 4th generation = raise serum levels of warfarin, caffeine & cyclosporine
- Pregnancy & nursing mothers
- Children < 18y (unless benefits outweigh risks)
Sulfonamides
- Sulfamethoxazole, Sulfadiazine, Sulfasalazine
- Structural analogs of p-aminobenzoic acid (PABA)
- Bacteriostatic against Gram-positive & Gram-negative organisms
- Infrequently used as single agents (resistance)
- Topical agents (ocular, burn infections)
- Oral agents (simple UTI’s)
- Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD
- Inhibit bacterial folic acid synthesis
- Synthetic analogs of PABA (p-amino-benzoic acid)
- Competitive inhibitors (& substrate) of dihydropteroate synthase
Sulfonamides resistance
Plasmid transfers / random mutations that:
• Altered dihydropteroate synthase
• Decreased cellular permeability
• Enhanced PABA production
• Decreased intracellular drug accumulation
Sulfonamides PK and SE
- Oral or topical
- Can accumulate in renal failure
- Acetylated in liver. Can precipitate at neutral or acidic pH -> kidney damage
SE
• GI distress, fever, rashes, photosensitivity are common
• Crystalluria (nephrotoxicity)
• Hypersensitivity reactions
• Hematopoietic disturbances (esp. patients with G6PD deficiency)
• Kernicterus (in newborns and infants <2 months)
Sulfonamides interactions and CI
• Warfarin, phenytoin and methotrexate can lead to increased plasma levels
SE
• Newborns & infants < 2 months (kernicterus) – drugs compete with bilirubin for binding sites on albumin
Trimethoprim
- Structurally similar to folic acid
- Bacteriostatic against Gram-positive & Gram-negative organisms
- UTI’s
- Bacterial prostatitis
- Bacterial vaginitis
- Potent inhibitor of bacterial dihydrofolate reductase
- Inhibits purine, pyrimidine & amino acid synthesis
PK
• Mostly (80-90%) excreted unchanged through kidney
• Reaches high concentrations in prostatic & vaginal fluids
SE
• Antifolate effects (contraindicated in pregnancy)
• Skin rash, pruritus
Cotrimoxazole
- Combination of trimethoprim & sulfamethoxazole
- Bactericidal
- Uncomplicated UTI’s (drug of choice) • PCP (drug of choice)
- Nocardiosis (drug of choice)
- Toxoplasmosis (alternative drug)
- Respiratory, ear, sinus infections (H.influenzae, M.catarrhalis)
Mechanism of action
• Synergistic: inhibition of sequential steps in tetrahydrofolic acid synthesis
Cotrimoxazole PK and SE
- Oral admin. generally (can be given IV)
- Well distributed (including CSF)
SE • Dermatologic (common) • GI • Hematologic (hemolytic anemia) • AIDS patients = higher incidence • Contraindicated in pregnancy (esp. 1st trimester)
Metronidazole
• Antimicrobial, amebicide & antiprotozoal
• Activity against anaerobic bacteria (including
bacteroides & Clostridium)
• Bactericidal
- Anaerobic conditions are vital for optimal activity
- Undergoes reductive bioactivation of its nitro group by ferredoxin
- Forms cytotoxic products that interfere with nucleic acid synthesis
- C.difficile infections (drug of choice)
- Anaerobic or mixed intra-abdominal infections
- Vaginitis (trichomonas & bacterial vaginosis, G.vaginalis) • Brain abscesses
- H.pylori eradication (in combination)
Metronidazole PK and SE
- Oral, IV, rectal or topical
- Wide distribution (including CSF)
- Elimination = hepatic metabolism
SE
• GI irritation, stomatitis, peripheral neuropathy (prolonged use)
• Headache, dark coloration of urine
• Leukopenia, dizziness, ataxia (rarer)
• Opportunistic fungal infections
• Disulfiram-like effect (avoid alcohol)
• Use generally not advised in 1st trimester
Nitrofurantoin
- Urinary antiseptics. Oral agents with antibacterial activity in urine but little or no systemic effect
- Use is limited to prophylaxis and treatment of lower UTI’s
- Bacteriostatic & bactericidal
- Active against many Gram-positive and Gram-negative bacteria
- Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA
- Slow emergence of resistance and no cross-resistance
Nitrofurantoin PK, SE, CI
Pharmacokinetics
• Rapid elimination (only achieves adequate concentrations in urine)
Adverse Effects
• Anorexia, nausea & vomiting.
•Neuropathies, hemolytic anemia (G6PD deficient patients)
CI
• Significant renal insufficiency
• Pregnancy at term (38-42 weeks)
• Infants <1 month (risk of hemolytic anemia)
