Aminoglycosides, Sulfonamides, Fluoroquinolones, Others

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1. Gentamicin
2. Tobramycin
3. Amikacin
4. Streptomycin

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Aminoglycosides

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can form a chemical complex and can be administered simultaneously but not in the same solution

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Aminoglycosides and beta-lactam antibiotics

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Preferred routes of administration for aminoglycosides

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IV or IM - poor absorption from GI tract

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30-60 minute IV infusion ; 2-3 equally divided doses per day or a once daily dosing regimen

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frequency of administration for aminoglycosides

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Where on the body do aminoglycosides not penetrate

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into the eye or into the CNS

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Diffuse through the porin channels in the outer membrane of gram negative bacteria

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how aminoglycosides get into bacterial cells

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Active transport across plasma membrane inhibited by

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1. low pH
2. anaerobic condition

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1. anaerobic bacteria
2. acidic environment of an abscess

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aminoglycosides are not effective against these

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enhance the transport of aminoglycosides into the bacterial cell.....have synergistic killing

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antibiotics that inhibit bacterial cell wall synthesis (penicillins, cephalosporins) with aminoglycosides

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Renal dosing is required

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Dosing changes for aminoglycosides

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MOA of Aminoglycosides

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inhibit bacterial protein synthesis by binding to the bacterial 30s ribosomal subunit - bactericidal

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3 actions after aminoglycoside binds to 30s ribosome

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1. block initiation of protein synthesis
2. block movement of ribosome - breaks up 70s ribosome into 50s and 30s subunites
3. misread the mRNA code leading to production of mutant proteins

*still works after drug level drops below MIC*

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1. Ototoxicity
2. Nephrotoxicity
3. Neuromuscular Block

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ADRs of aminoglycosides

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Auditory and vestibular toxicity with aminoglycosides

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1. tinnitus, loss of hearing
2. vertigo, ataxia, loss of balance

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use of other drugs that can cause ototoxicity with aminoglycosides

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1. Loop diuretics
2. Vancomycin

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Aminoglycosides that more commonly cause vestibular toxicity

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1. gentamicin
2. streptomycin
3. tobramycin

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Nephrotoxicity - Acute tubular necrosis with aminoglycosides

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1. rise in serum creatnine levels
2. SCr measured every 2-3 days
3. can be caused by higher doses more than 5 days
4. Gentamicin, Tobramycin, Neomycin

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Neuromuscular block with aminoglycosides

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*Rare - high doses*

1. muscle weakness and respiratory paralysis
2. inhibits release of acetylcholine - inhibit postsynaptic sensitivity to acetylcholine
3. Treat with IV calcium salt & Cholinesterase inhibitor

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30-60 minutes after IV or IM infusion - lets ya know if patient is achieving therapeutic levels

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Peak Concentration

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1. 30 minutes prior to next dose
2. hemodialysis can be used

Gentamicin - above 2ug/ml - toxicity

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Trough Concentration

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Mechanism for bacterial resistance to aminoglycosides

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1. production of bacterial enzymes that phosphorylate, adenylate, or acetylate the drug
2. metabolites formed - not capable of binding to 30s ribosome
3. cant inhibit protein synthesis

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Aminoglycoside more resistant to inactivating enzymes and may be more useful

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Amikacin

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Spectrum of activity for Aminoglycosides

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1. Staph aureus - do not use alone
2. Staph epidermidis - do not use alone
3. Proteus mirabilis
4. E. Coli
5. Klebsiella pneumoniae
6. Pseudomonas

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1. severe systemic infections (sepsis)
2. in combo with bacterial cell wall synthesis inhibitor for bacterial endocarditis

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Major clinical uses of aminoglycosides

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Streptomycin

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1. less activity against gram - enteric bacteria
2. used to treat bacterial endocarditis with penicillin
3. 2nd line treatment for TB

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Gentamicin

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1. used for serious gram negative infections (Pseudomonas, enterobacter, Klebsiella, Serratia, others)
2. used to treat complicated UTI with beta-lactam antibiotic, pneumonia caused by gram neg bacteria in a hospital, sepsis
*not recommended for community acquired pneumonia

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Tobramycin

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1. better activity against Pseudomonas aeruginosa
2. used to treat bacteremia, osteomyelitis, pneumonia
3. inhalation forms treat bronchopulmonary infections caused by pseudomonas aeruginosa in cystic fibrosis

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Amikacin

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1. broadest antimicrobial spectrum
2. resistant to many of the bacterial enzymes that inactivate other aminoglycosides
3. treats serious nosocomial infection caused by gram negative aerobic bacilli in hospitals
4. less active against enterococci and should not be used to treat enterococcal infections

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Oral-Absorbable Sulfonamide

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Sulfamethoxazole

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Oral-Nonabsorbable Sulfonamide

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Sulfasalazine

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Topical Sulfonamides

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Silver Sulfadiazine cream

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Other Antifolate Drugs

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Trimethoprim

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Combination antifolate meds

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Sulfamethoxazole + Trimethoprim

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Bacteriostatic except in an environment that is deficient in thymine and amino acids

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Sulfonamides will be bactericidal

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MOA of antifolate drugs

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1. inhibit enzyme dihydropteroate synthetase in the biosynthetic pathway of tetrahydrofolic acid

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Enzyme dihydrofolate reductase in the biosynthetic pathway of tetrahydrofolic acid is inhibited by

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anti-folate drugs like trimethorpim inhibit

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Sulfonamides are chemically similar to

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PABA (p-aminobenzoic acid)

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decrease DNA synthesis

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ultimate effect of blocking dihydrofolic acid production

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Gram Positive Spectrum of activity for Sulfonamides and Trimethoprim

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*BROAD SPECTRUM*

1. Staph
2. Strep
3. Bacillus anthracis
4. Clostridium tetani
5. Clostridium perfringens
6. Nocardia

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Gram Negative Spectrum of Activity for Sulfonamides and Trimethoprim

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*BROAD SPECTRUM*

1. Enterobacter
2. E. Coli
3. Klebsiella
4. Proteus mirabilis/vulgaris
5. Salmonella
6. Shigella

**INCREASED RESISTANCE**

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Other Areas of Activity for coverage by Sulfonamides and Trimethoprim

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1. Chlamydia trachomatis
2. Toxoplasma gondii
3. Plasmodium

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Microorganisms that are resistant to Sulfonamides

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1. Spirochetes
2. Mycoplasma
3. Rickettsiae

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Bacterial Resistance to Sulfonamides and Trimethoprim

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*limits the use of these drugs as single agents*

1. Alterations in the enzyme dihydropteroate synthetase (chromasomal or spread by plasmids)
2. Overproduction of PABA
3. Chromosomal or plasmid mediated expression of mutated dihydrofolate reductase (over production)

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1. Bind to plasma proteins and can displace other drugs
2. displace bilirubin from protein binding sites leading to kernicterus

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Distribution of Sulfonamides

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N-acetylated metabolites and the parent compound in Sulfonamides

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are insoluble in teh acidic environment of the urine which can lead to crystalluria and renal damage

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ADRs of Sulfonamides

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1. Hypersensitivity and Skin reactions
2. Hematological Disorders (hemolytic anemia)
3. Renal Damage (crystalluria)
4. Clostridium difficile-associated psudomembranous colitis
5. Kernicterus

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Hypersensitivity and Skin Reactions associated with Sulfonamides

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1. cross sensitization between anti-infective sulfonamides and other drugs that contain a sulfonamide group
2. Allergy to sulfonamides can lead to SJS

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Sulfamethoxazole

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Used in combo with Trimethoprim

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90% of drug travels to colon where drug is cleaved by intestinal flora to form sulfapyridine and 5-aminosalicylic acid

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Sulfasalazine

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1. Ulcerative colitis (5-aminosaliclate treat IBS)
2. Rheumatoid Arthritis

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Sulfasalazine

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Silver Salt and Sulfadiazine in Silver Sulfadiazine has what kind of effect

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topical sulfonamide that effects the cell membrane and cell wall

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Clinical Uses of Silver Sulfadiazine topical cream

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1. adjunct therapy for infections associated with 2nd and 3rd degree burns

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Absorption of Trimethoprim

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Completely absorbed after oral administration

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Spectrum of Activity for Trimethoprim

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1. Strep pneumoniae (Gram Pos)
2. Common Gram Negative agents that cause UTIs

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Uses of Trimethoprim

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1. UTIs (E. Coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter, Staph saprophyticus)

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1. Rash and pruritis (photosensitivity, SJS)
2. GI
3. Hematologic effects (folate depleted patients)
4. Teratogen

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ADRs of trimethoprim

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When should Trimethoprim be used in pregnancy

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only be used if the benefits justify the risk to the fetus

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1. UTIs (E Coli, Proteus, Klebsiella, Enterobacter) - empirical therapy
2. Pneumocystis Jiroveci pneumonia (AIDS)
3. GI infections
4. Otitis Media

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Uses of Sulfamethoxazole/Trimethoprim

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ADRs of Sulfamethoxazole/Trimethoprim

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*occurs in 80% of AIDS patients*

1. Hematological (folate depleted, malnourished, elderly)
*treated with folinic acid)

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1. life-threatening pneumonia in immunocompromised individuals (leading cause of death in AIDS patients)
2. fever, dermatological reactions, hematologic reactions
3. first classified as a protozoan but shares characteristics with fungi

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Pneumocystis jiroveci (carinii) - pneumocystosis

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Preferred drugs for Pneumocystis jiroveci (carinii)

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1. Sulfamethoxazole-Trimethoprim (IV, PO)
2. Pentamidine isethionate (IV)
3. Prednisone

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ADRs of Pentamidine isethionate

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1. Hypotension
2. Hypoglycemia (pancreatic islet necrosis)
3. Pulmonary (bronchospasm and cough)

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Fluoroquinolones

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1. Ciprofloxacin
2. Levofloxacin
3. Moxifloxacin

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Miscellaneous antibiotics

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1. Nitrofurantoin
2. Clindamycin
3. Vancomycin
4. Polymyxin B
5. Metronidazole
6. Bacitracin
7. Quinupristin/Dalfopristin
8. Linezolid
9. Daptomycin

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Oral absorption of fluoroquinolones

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1. impaired by divalent cations found in antacids
2. iron, zinc, calcium supplements decrease
3. patients should not take antacids containing these 4 hours before/2 hours after dosing

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Fluoroquinolone not excreted by kidney so it doesn't need renal dosing

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Moxifloxacin

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MOA of fluoroquinolones

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BACTERICIDAL

1. inhibit the bacterial enzymes DNA gyrase (topoisomerase II) and topoisomerase IV
2. this leads to inhibition of replication

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Mechanism of Resistance to fluoroquinolones

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INCREASING DEVELOPMENT - DEVELOPS QUICKLY!

1. mutation on DNA gyrase which prevents binding of the drug

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Spectrum of activity for Fluoroquinolones

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1. mostly gram negative (more than 90% of enterobacteriaceae)
2. Pseudomonas

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Fluoroquinolones with activity against Gram Positive

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Levofloxacin and Moxifloxacin

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Clinical Uses of fluoroquinolones

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1. Urinary tract infections (multi drug resistant bacteria)
2. Prostatitis
3. GI infection such as bacterial diarrhea (travellers diarrhea)
4. lower respiratory tract infections (community acquired pneumonia and bronchitis)

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Antibiotics used for prostatis

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1. Ciprofloxacin
2. Sulfamethoxazole-Trimethoprim

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ADRs of fluoroquinolones

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1. nausea, headache, dizziness - most common
2. CNS stimulation - convulsions, psychosis, hallucinations)
3. Sensitivity to light
4. damage to growing cartilage - not recommended in pregnancy and under 18 years of age
5. Adult tendonitis - rare
6. interfere with excretion of theophylline and caffeine
7. Superinfections

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Vancomycin

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1. poor oral absorption, should be administered IV
2. DOES penetrate CSF when meninges are inflamed
3. adjust dose with renal failure

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MOA of vancomycin

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*Bactericidal*

1. inhibits cell wall synthesis by binding to D-alanyl-D-alanine portion of peptidoglycan pentapeptide

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Resistance to Vancomycin

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bacterial enzymes that can induce alteration in the cell wall precursors so that vanco can't bind as wel

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Spectrum of activity for Vanco

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1. Gram + : methicillin resistant and methicillin susceptible Staph aureus, Staph epidermidis, Strept, C. difficile

2. Gram - : NO USE

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Clinical uses of Vanco

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1. Serious Staph infections (sepsis, endocarditis)
2. Gram + infections in patients allergic to penicillins and cephs - (enterococcal endocarditis - with aminoglycoside)
3. Diarrhea caused by C. difficile

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ADRs, Toxicity, C/I of Vanco

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1. Ototoxicity (rare) - more common when given with other ototoxic drugs
2. Nephrotoxicity (rare)
3. Red Man or "Red Neck" syndrome - flushing of face, neck, torso

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Clindamycin

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1. well absorbed after oral administration
2. excreted mainly in the bile - doses adjusted with HEPATIC failure
3. does not penetrate well into the CNS even with inflammation of the meninges
4. good penetration into abscesses

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MOA of Clindamycin

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*Bacteriostatic*

1. binds to 50s ribosomal subunit
2. inhibits bacterial protein synthesis

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Mechanism of Resistance to Clindamycin

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1. Mutations in the 50s ribosomal subunit prevents binding
2. enzyme methylase prevents binding

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Spectrum of Activity for Clindamycin

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1. Gram + : most Staph aureus strains
2. Gram - : not useful
3. Anaerobes: active against both gram + and gram - including B. fragilis and C. perfringens.

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Clinical Uses of Clindamycin

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1. treat anaerobic infections (abscesses but not in the brain)
2. prophylaxis against endocarditis in patients with valvular heart disease who are having dental procedures done
3. alternative to penicillins and cephs if allergic

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ADRs of Clindamycin

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1. diarrhea, nausea, skin rash
2. Pseudomembranous colitis caused by C. difficile

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Nitrofurantoin

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1. excretion of drug is VERY rapid - no systemic effects seen
2. not to be used with renal failure
3. Used to treat UTIs (prophylactically and treatment)
4. ADR: Gi Upset (anorexia, nausea, vomiting)

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Polymyxin B sulfate

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used topically due to toxicity that is associated with parenteral administration

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MOA of polymyxins

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Interact with cell membrane phospholipids - disrupt cell membrane permeability, and cause leakage of intracellular components

**This killing effect can cause serious ADRs**

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Spectrum of Activity for Polymyxins

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1. restricted to Gram negative bacteria
2. Pseudomonas aeuroginosa

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Clinical Uses of Polymyxins

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1. topical treatment of infections of hte eye, skin, mucous membranes, ears, wounds, burns
2. indwelling catheters

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ADRs of parenteral polymyxins

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1. Nephrotoxicity
2. Neurotoxicity

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Metronidazole

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1. good absorption after oral admin....also by IV, rectal suppos, vaginal gel
2. widely distributed, including the CNS and brain abscesses

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MOA of Metronidazole

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**Bactericidal**

reduction of the drug to compounds that bind to intracellular macromolecules

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Spectrum of Activity and Clinical Uses of Metronidazole

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ACTIVITY: anaerobes including B. fragilis and C. difficile

USES: soft tissue infection, intra-abdominal infections, pelvic infections, brain abscesses, pseudomembranous colitis, PUD caused by helicobacter pylori

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ADRs of metronidazole

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1. Carcinogenic potential
2. disulfiram-like interaction with alcohol
3. peripheral neuropathy with chronic use`

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Bacitracin

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1. used opthalmically and dermatologically
2. not used parenterally

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MOA of bacitracin

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inhibits cell wall formation by interfering with the lipid that carries peptidoglycan subunits to the site of cell wall formation

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Spectrum of Activity and Clinical Uses of Bacitracin

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ACTIVITY: similar to penicillin

USES: topically for open wounds to eradicate mixed microorganisms, eye infections

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ADRs of Bacitracin

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1. serious nephrotoxicity (parenteral use)
2. Renal failure (tubular and glomerular necrosis)