Antimicrobials

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Antimicrobials

• Unit X

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Selective toxicity

• Injure target organism without affecting the host
• Can accomplish this by attacking processes that
  critical to microbial well-being, but that dont
  affect mammals
• Bacterial cell wall
• Inhibition of an enzyme unique to bacteria
• Disruption of bacterial protein synthesis

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classification

• Susceptible organism
• Narrow spectrum, broad spectrum
• Antibacterial
• Antiviral
• antifungal

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• Mechanism of action
• Cell wall
• Cell membrane permeability
• Lethal inhibition of bacterial protein synthesis
• Nonlethal inhibition of bacterial protein
  synthesis
• Drugs that inhibit bacterial synthesis of nucleic
  acids

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• Mechanism of action
• Antimetabolites
• Inhibitors of viral enzymes

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Microbial drug resistance

• Organisms staphylococcus aureus, enterococcus
  faecalis, enterococcus faecium, pseudomonas
  aeruginosa and mycobacterium tuberculosisi

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• Microbes may increase manufacture of
  drug-metabolizing enzymes (penicillins)
• Microbes may cease active uptake of certain drugs
  (tetracyclines)
• Changes in receptors which decrease antibiotic
  binding and action
• May synthesize compounds that antagonize drug
  actions

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• Antibiotic use promotes the emergence of
  drug-resistant microbes especially the use of
  broad-spectrum antibiotics
• The more the use the greater the chance

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Delaying the emergence of resistance

• Prescribed only when needed
• Narrow-spectrum
• Limit use of newer drugs
• Minimize giving antibiotics to livestock

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selection

• Identify the infecting organism
• Drug sensitivity of the infecting organism
• Host factors site of infection, host defenses,
  allergies, inability of drug of choice to
  penetrate the site of infection, unusual
  susceptibility of the patient to toxicity

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• Cultures must be obtained prior to initiation of
  therapy
• Drug sensitivity may or may not be done

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Antibiotic combinations

• Severe infection
• Mixed infections
• Prevention of resistance tuberculosis
• Decreased toxicity
• Enhanced antibacterial action

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Appropriate prophylactic use

• Surgery
• Bacterial endocarditis
• Neutropenia
• others

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Inappropriate uses

• Viruses
• Treat FUO
• Improper dosage
• Inadequate information
• Omission of surgical drainage

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Weaken bacterial cell wall

• Penicillins cause the bacterial wall to weaken
  and take up water and burst
• Mechanisms of resistance inability to reach
  targets and inactivation of penicillins by
  bacterial enzymes

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classification

• Narrow spectrum penicillinase sensitive
• Narrow spectrum penicillinase resistant
• Broad spectrum penicillins
• Extended-spectrum penicillins

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Penicillin G

• Against most gram positive, gram negative cocci
  and nonpenicillinase-producing strains of
  Neisseria gonorrhoeae, anaerobic bacterial and
  spirochetes

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• Sodium penicillin
• Potassium penicillin
• Procaine penicillin
• Benzathine penicillin highly sensitive
• Not given orally
• IM usually
• Only sodium and potassium given IV

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allergy

• Most common cause of drug allergy
• Prior exposure required but may not be known
• May have cross-sensitivity to cephalosporins

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Penicillinase-resistant penicillins

• Resistant to inactivation by beta-lactamases
• Naficillin
• Oxacillini
• Cloxavillin
• Dicloxacillin
• Methycillin resistant strains respond to
  vancomycin and/or rifampin

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Broad spectrum penicillins

• Ampicillin strep, pertussis, proteus, e.coli,
  salmonella, shigella and h influenzae
• Diarrhea and rash most common side effects

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• Amoxicillin more acid resistant
• Less diarrhea
• Amoxicillin with clavulanate augmentin
  (inhibits bacterial beta-lactamases)

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Extended spectrum penicillins

• Ticarcillin
• Carbenicillin indanyl
• Mezlocillin
• Pipercillin
• Pseudomonas, enterbacter, proteus, klebsiella
• Given with aminoglycoside for pseudomonas

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Drugs that weaken bacterial cell wall II

• Cephalosporins, imipenem, astreonam, vancomycin,
  teicoplanin, fosfomycin

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cephalosporins

• Most commonly used antibiotic
• Similar to penicillins
• Bactericidal
• First generation highly susceptible to
  beta-lactamases

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generations

• 1-4
• Increasing in activity against gram-negative
  bacterial and anaerobes
• Increasing resistance to destruction by
  beta-lactamases
• Increasing ability to reach cerebrospinal fluid

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• Most given parenterally
• Some can cause bleeding tendencies
• allergy

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First generation

• Prophylaxis against infection in surgical
  patients
• Gram positive infection

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Second generation

• Some pneumonias
• Otitis, sinusitis, respiratory tract infections

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Third generation

• Menigitis
• Gram negative bacilli
• Gonorrhea, proteus, salmonella, klebsiella

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imipenem

• Broadest antimicrobial spectrum of any drug
  good for mixed infections always given in
  conjunction with cilastatin to inhibit
  destruction of imipenem by renal cells
• Carbapenems new class of beta-lactam
  antibiotics
• Only given IV, IM
• Nausea, vomiting, diarrhea, rash

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• Aztreonam monobactams
• Gram-negative aerobic bacteria
• IM, IV

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Vancomycin

• Pseudomembranous colitis
• MRSA
• Other serious infections
• Oral for GI infection
• Mostly given slow IV
• Ototoxicity, hypotension (with rapid IV
  infusion), thrombophlebitis

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Bacteriostatic inhibitors of protein synthesis

• Tetracyclines, macrolides, clindamycin,
  chloramphenicol, spectinomycin and
  dalflopristin/quinupristin
• Suppress bacterial growth and replication but do
  not kill
• Second-line agents

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tetracyclines

• Broad-spectrum
• Inhibit protein synthesis suppress bacterial
  growth
• Gram-positive and gram-negative bacterial
  rickettsia, spirochetes, brucella, chlamydia,
  myocoplasma, helicobacter pylori and vibrio
  cholerae

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• Due to use has increasing bacterial resistance
• Infectious diseases, acne, PUD, periodontal
  disease, rheumatoid arthritis

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Adverse effects

• GI
• Bones and teeth
• Suprainfection
• Hepatotoxicity
• Renal toxicity
• Photosensitivity
• Orally, IV, and IM

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macrolides

• Inhibit bacterial protein synthesis
• Azithromycin, erythromicin, clarithromycin,
  dirithromycin
• Effective against most gram-positive bacterial as
  well as some gram-negative bacterial
• May be good alternative to those allergic to PCN

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Therapeutic uses

• May be used as an alternative patients allergic
  to penicillins respiratory tract infections
• Legionella
• Pertussis
• Diphtheriae
• Mycoplasmic pneumoniae
• strep

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• Oral, IV
• Adverse effects - GI, Liver, suprainfection of
  the bowel, thrombophlebitis
• Clarithromycin not as much nausea (h. pylori),
  respiratory tract

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• Zithromax respiratory tract infections, others
• Not as much nausea

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clindamycin

• Cleocin given for specific conditions
• Causes pseudomembranous colitis
• Inhibits protein synthesis
• Anaerobic bacteria streptococci, some pelvic
  and abdominal infections
• Given orally, IV, IM

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• Adverse effects pseudomembranous colitis,
  diarrhea, rashes, hepatotoxicity

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aminoglycosides

• Bactericidal inhibitors of protein synthesis
• Narrow-spectrum aerobic gram-negative bacilli
• Gentamycin, tobramycin, amikacin

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• Amikacin least susceptible to resistance
• E.coli, Klebsiella pneum., serratia, proteurs
  mirabilis, pseudomonas
• Reserved for serious infections due to aerobic
  gram-negative bacilli
• Most given IM or IV

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• Binds tightly to renal tissue easily causes
  nephrotoxicity
• Ototoxicity
• Reduce dosage in patients with renal disease
• Narrow therapeutic range peak and trough levels
  (avoid high trough levels) not greater than
  2mcg/ml

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• Neomycin often given topically, eye, ear, skin
• Also given orally prior to surgeries of the
  bowel, suppress bowel flora

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Sulfonamides and trimethoprim

• Broad-spectrum disrupt synthesis of
  tetrahydrofolic acid inhibits synthesis of
  folic acid
• Doesnt hurt our cells because our cells take up
  folic acid from our diet
• Bacterial cells make their own and sulfonamides
  disrupt this process

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• Resistance prevalent
• Works on gram positive cocci, gram negative
  bacilli, actinomycetes, chlamydiae, some protozoa
• Primary usage urinary tract infections, mostly
  due to E. Coli
• Hypersensitivity, Stevens-Johnson syndrome,
  hemolytic anemia, kernicterus, renal damage

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• Sulfisoxazole (Gantrisin)good for urinary tract
  
• Trimethoprim given for urinary tract infections
• Azo-Sulfisoxazole (sulfonamide-phenzaopyridine)
  antibacterial agent with an analgesia combo

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Trimethoprim-sulfamethoxazole

• Trade names Bactrim, Cotrim and Septra
• Potentiation
• Urinary tract infections, pneumocystis carinii,
  otitis media, GI infections, bronchitis
• Oral, IV

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Urinary tract infections

• Community acquired usually E. coli
• Hospital acquired Klebsiella, proteus,
  pseudomonas, staph, enterobacter
• Acute cystitis single dose, short course,
  conventional therapy
• Acute urethral syndrome dysuria, frequency,
  urgency, pyuria chlamydia, gonorrhea,
  gardnerella

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Recurrent UTIs

• Reinfection often with females 1-2 per year
  will be treated as separate infection
• More frequently long term prophylaxis with
  lower doses of certain drugs
• Relapse recolonization may also require long
  term therapy, may need surgical procedure
  depending on cause

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Acute pyelonephritis

• Infection of the kidney patient will be
  sicker
• Mild moderate infection will be treated on
  outpatient with oral agents
• Severe infection hospital and IV antibiotics

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Acute bacterial prostatitis

• Bacterial infection of the prostate
• Usually E.coli from indwelling catheter, surgical
  manipulation, instruments

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nitrofurantoin

• Macrodantin urinary tract antiseptic
  broad-spectrum antimicrobial
• Staph, strep, e.coli
• Lower urinary tract only
• Orally GI, pulmonary reactions, hematologic,
  peripheral neuropathy

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Antimycobacterial agents

• Slow growing microbes, therapy needs to be
  prolonged
• Tuberculosis epidemic proportions due to
  resistant strains, AIDS
• People may harbor the organism but may have no
  symptoms (inactive)
• May be in lungs only may be disseminated
  throughout body

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• Transmitted by inhalation of sputum particles
  (coughing, sneezing)
• Rapid response by immune system (phagocytes)
  keeps most individuals from developing obvious
  signs and symptoms
• Necrosis of lung tissue can be result if
  patient develops clinical disease

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• Screening very important especially in high-risk
  populations
• PPD, CXR, sputum evaluations cultures best but
  take longer
• Drug resistance is becoming more concerning
  highest multi-drug resistance in New York City

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treatment

• Must always consist of two or more drugs to which
  the organism is sensitive
• Decrease the incidence of resistance
• Decrease the incidence of relapse
• Usually starts with daily therapy four drugs
  isoniazid, rifampin, pyrazinamide, ethambutol (2
  months)

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treatment

• Then after, four months of isoniazid and rifampin
• Multidrug-resistant tubercle bacilli treatment
  may start with as many as seven drugs treatment
  will last longer
• Special considerations in those with HIV infection

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• Directly observed therapy to promote compliance
• Continuing evaluation of treatment cultures,
  CXR, symptoms
• Prophylaxis therapy patients who have had
  recent known exposure, HIV, patients with known
  exposure and immunosuppression

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isoniazid

• First line primary agent
• Suppresses bacterial growth by inhibiting
  synthesis of mycolic acid (component of cell
  wall)
• Oral and IM
• Peripheral neuropathy, hepatoxicity, anemia, GI
  distress

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rifampin

• Broad-spectrum antibiotic
• Inhibits protein synthesis
• Always given in conjunction with other
  antituberculosis drug
• Can cause hepatoxicity
• Discoloration of body fluids, GI, rash, flu-like
  syndrome

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pyrazinamide

• May be used with rifampin, isoniazid, and
  ethambutol initially
• Hepatotoxic GI, arthralgia,rash

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ethambutol

• Bacteriostatic most strains are sensitive
• Optic neuritis blurred vision and lack of color
  discrimination
• Allergic reactions, GI disturbances, elevated
  uric acid levels

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Fluoroquinolones

• Ciprofloxacin bactericidal inhibits bacterial
  DNA replication
• Administered orally or IV
• Respiratory tract infections, GI, bones, joints,
  etc.
• Not useful against infections caused by anaerobes

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• Adverse effects GI, dizziness, h/a restlessness
• Candida infections
• Tendon rupture not for children under 18 yrs.
• Should not be taken with milk or food
• Watch for bleeding elevates warfarin levels

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Others

• Norfloxacin
• Lomefloxacin
• Enoxacin
• Levofloxacin

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metronidazole

• Protozoal infections
• Anaerobic organisms
• C. difficile
• Patient should not have alcohol

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Antifungal

• Amphotericin B drug for systemic fungal
  infections
• Given IV for very serious infections
• Causing leakage of intracellular cations in
  fungal cells
• Must be given for several months

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Adverse effects

• Infusion reactions pretreat locally change IV
  sites
• Nephrotoxicity almost all patients will have
  some degree
• Lipid-based formulas cause less nephrotoxicty
  (much more expensive)
• May be given with flucytosine can reduce dose
  of Ampho decrease side effects

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Acyclovir

• Infections caused by herpes simplex viruses and
  varicella zoster virus
• Suppresses synthesis of viral DNA inhibits
  viral replication

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Therapeutic use

• Genital herpes topical and oral for recurrent
• Mucocutaneous herpes simplex infections face
  and oropharynx
• Varicella-zoster shingles and chickenpox

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Adverse effects

• Typically well-tolerated
• Oral GI, rash dizziness
• IV phlebitis, inflammation, reversible
  nephrotoxicity

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