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Review of Antibiotics Part

VIEWS: 18 PAGES: 81

									Review of Antibiotics - Part 2


Gary Skankey, MD, FACP, FIDSA
University of Nevada
School of Medicine
Quinolones
Quinolone Structure
             R3      O
    F    6       5       4       CO2 H
                             3
                     1
                             2
    R2   7   X       N
             8
                     R1
Nalidixic Acid
                 O
                     CO2 H


  CH3    N       N
 Norfloxacin
              O
                   CO2 H


CH3      N    N                    O
      Nalidixic Acid
                           F           CO2 H


                           N   C   N
          HN
      piperazine
CiprofloxacinO
     F             CO2 H



HN
     N   C   N                 O
     Norfloxacin
                       F                  CO2 H


                       N       N
     HN
                           cyclopropane
Levofloxacin
              Structure of Levofloxacin:
        The Levo-Rotatory Isomer of Ofloxacin
                                            O    O
                              F
                                                      OH

                              N             N         1/2   H2O
                       N                O       CH3
                 H3C
                                            H

  4-methyl piperazinyl group facilitates:        Oxazine ring facilitates:
     Increased oral absorption                      Increased gram-negative
     Increased activity against some                 coverage
      gram-negative bacilli                          Increased half-life
     Increased half-life
     Decreased GABA interactions
 Gatifloxacin   O
       F               CO2 H




 HN
       N        N                        O
       Ciprofloxacin       F                 CO2 H

CH 3
                           N             N
       HN                        OCH3
                               methoxy
Quinolone Generations
   1st Generation - gram neg. UTI only
    – Nalidixic acid
   2nd Generation - gram pos., better
    gram neg., systemic infections, fair
    atypical, BID dosing
    – Norfloxacin, Ciprofloxacin, Ofloxacin
   3rd Generation - better gram pos.
    (pneumococcus), gram neg.,
    anaerobes, better atypical., QD dosing
    – Levofloxacin, Gatifloxacin, Trovafloxacin,
      Sparfloxacin, Moxifloxacin
Fluoroquinolones: Mechanism of
Action
     Principal targets
       –Topoisomerase II (DNA gyrase)
       –Topoisomerase IV

     Primary targets differ among
      fluoroquinolones

 Boswell and Wise: Infect Dis Clin North Am 12:647-667, 1998.
 Fukuda and Hiramatsu: Antimicrob Agents Chemother 43:410-412, 1999.
Possible Adverse EventsWith Antibiotics
   CNS                                                            Prolonged QTc
     seizures & dizziness                                         interval
   (sparfloxacin, trovafloxacin)                                  (grepafloxacin, sparfloxacin,
                                                                  moxifloxacin)
   Taste perversion
   (clarithromycin, grepafloxacin)                                Phototoxicity
                                                                  (sparfloxacin)
   GI
      nausea/vomiting
   (levofloxacin, sparfloxacin,                                   Arthritis/
   trovafloxacin)                                                 Tendonitis
                                                                  (all quinolones)
   Idiosynchratic immune
   responses
   (temafloxacin, trovafloxacin, cephalosporins)
 Adapted from Fish: Clin Pharmacokinet 32:101-119,1997; Haria: Drugs 54:435-446,1997;
 Goa: Drugs 53:700-725,1997; Wagstaff: Drugs 53:817-824,1997; Avelox (moxifloxacin) package insert.
 Relationship of Quinolone Structure to
 Adverse Events and Drug Interactions
                                                                      O
                                                    R5           O
                                          F                           C     OH
Affects: CNS toxicity
   through GABA                                     X8           N
binding; NSAID and                       R7                           R2
    theophylline
interactions; genetic                                            R1
       toxicity                                                       Affects theophylline
                                              Affects                  interactions and
                                         phototoxicity and              genetic toxicity;
                                          genetic toxicity             difluorophenyl at
                                                                       R1 may relate to
                                                                         hepatotoxicity
  Adapted from Lipsky and Baker: Clin Infect Dis 28:352-364, 1999.
 In Vitro Activity of Key Antimicrobials:
 S. pneumoniae

   MIC90 (mcg/mL) by Penicillin Susceptibility
                                         Category

                          Susceptible   Intermediate   Resistant
Antimicrobial              (N=2605)       (N=869)      (N=476)

Gatifloxacin                  0.5           0.5            0.5
Levofloxacin                  2.0           2.0            2.0
Clarithromycin               0.25          1.0          >32.0
Azithromycin                 0.12          2.0          >16.0
Cefuroxime                   0.06          4.0            8.0
Amoxicillin/clavulanate      0.06          1.0            8.0
Quinilones - Clinical Uses
   2nd Generation              3rd Generation
    (Cipro)                      (Leva.,Gati.,Moxi.)
    – UTI/Pyelonephritis         –   CAP
    – Gram negative              –   Sinusitis
      septicemia                 –   UTIs
    – Pseudomonal STI            –   Intraabd. Sepsis
    – Pseudomonal                –   STI
      pulmonary infections       –   Osteomyelitis
    – Atypical
      mycobacteria
Aminoglycosides
Aminoglycosides

   Streptomycin
   Gentamicin
   Tobramycin
   Amikacin
Aminoglycosides
   Bacterocidal in gram negatives
   Mechanism of action
     – act on cell wall
     – act on ribosomes, primarily 30s, to slow protein
       synthesis and cause production of defective
       proteins
   Post antibiotic effect in gram negatives
   Dose dependent killing
      Cephalosporin Killing Curve
                     3.5

                      3                                        cephal
                                                               ospori
                     2.5                                       n
   Bacterial killing 2
                     1.5

                      1
                     0.5

                      0
                            1         2          3         4
                 »         Increasing Drug Concentration -->
        Aminoglycoside Killing Curve
                      4.5
                       4
                      3.5
                       3
   Bacterial Killing 2.5
                       2
                      1.5                                         AG
                       1
                      0.5
                       0
                                 1         2         3        4
                  »         Increasing Drug Concentrations --->
Amikacin - Antibacterial
 Spectrum
   All gram-negatives except
     – Unreliable against Stenotrophomonas, B.
       cepacia
     – Legionella - poor intracellular levels
   MAI and other atypical mycobacteria
   Poor or no activity as solo therapy against
    gram positives, anaerobes, atypicals
Amikacin - Toxicity

   Ototoxicity
    –   can be irriversible
    –   related to dose and duration of therapy
    –   increased risk in concomitant vanco, loop diuretics
    –   decreased risk in once daily dosing
    –   gentamicin>tobramycin>amikacin
   Nephrotoxicity
    – requires several days of administration of drug
      before this develops
    – reversible
Aminoglycosides- Uses

   Rarely used as monotherapy (UTI)
   Synergistic combinations
    – + Ampicillin for Enterococcus
    – + Anti-pseudomonal beta-lactam for
      Pseudomonas
   Part of multi-drug empiric regimen for
    septic shock
Aminoglycosides - Pearls

   Poor CSF penetration
   Poor activity in pulmonary secretions
   Inactivated in pus - not good for
    abscesses
Macrolides
Macrolides

   Erythromycin
   Clarithromycin - Biaxin
   Azithromycin - Zithromax
Macrolides

   Act on 50S ribosome to block protein
    synthesis
   Hepatic excretion - no dose adjustment
    for renal failure
   Bacterostatic for most bacteria
Macrolides
   Only erythromycin and azithromycin
    have IV formulations
   Erythromycin ethyl succinate
    – 45% oral absorption
   Clarithromycin
    – 50% oral absorption
   Azithromycin
    – 37% oral absorption, food decreases 50%
Macrolides - Spectrum of
Activity
   MSSA
   Lancfield group and viridans streptococcus
   H. influenzae (Azithromycin best)
   Mycoplasma pneumoniae
   Chlamydia spp.
   Legionella (Azithromycin best)
   Atypical mycobacteria (Clarithromycin and
    Azithromycin)
Erythromycin is Drug of 1st
Choice for:
   Mycoplasma pneumoniae infections
   Legionella pneumonia
   Diphtheria (plus antitoxin)
   Pertussis
   Campylobacter jejuni gastroenteritis
   Bacillary angiomatosis
   Secondary uses...
Erythromycin - Side effects
   GI: abd. Cramps, nausea, vomiting,
    diarrhea - IV or PO
   Cholestatic hepatitis
   Rash, fever, eosinophilia - sometimes
    accompanies hepatitis
   Transient hearing loss - more common
    with high doses in elderly or renal insuf.
Clarithromycin/Azithromycin -
Side effects
   Much less than erythromycin
   GI: nausea, vomiting, abd. Cramps
   Abnormal liver functions
   HA, dizziness
   Reversible hearing loss at high doses
Macrolides - Drug Interactions
   Inhibit drug metabolism through the
    cytochrome P450 system
   Increases drug levels
   Erythromycin>Clarithromycin>Azithro.
   Erythromycin can cause serious, life-
    threatening drug toxicity
   Azithromycin has almost no drug-drug
    effect
Drug Levels Increased by
Macrolides
   Carbamazepime      Theophylline
   cisapride          cyclosporin
   bromocryptine      rifampin
   colchicine         tacrolimus
   respiradone        quinidine
   digoxin            lovastatin
   dilantin           coumadin
Tetracyclines
Tetracyclines

   Tetracycline
   Doxycycline
   Minocycline
   Demeclocycline
Tetracyclines

   Bind to 30S ribosome to inhibit protein
    synthesis
   Bacterostatic against bacteria
   Resistance by blocking influx, or by
    eflux pumps
Mechanisms of Resistance
                                  Enzymatic
                                  inactivation




                        CH                               Reduced
Altered                  3                               permeabilit
binding                                                  y
                                             Efflux
  sites

                    Ribosomal
                    methylation
                                                      = drug
               DNA gyrase


          Nucleus
Tetracyclines - Spectrum
   S. aureus          Klebsiella
   S. pneumoniae      Shigella
   S. pyogenes        Campylobacter
   gp. B strep        Oral anaerobes
   Enterococcus       Actinomyces
   Neisseria          B. fragilis
   E. coli
   Enterobacter
Minocycline

   Used for MDR, hospital-acquired, gram
    negative infections
   Bacterostatic
   Many MDR gram negatives have low
    pathogenicity, so minocycline can
    handle
Tetracyclines - Drug of Choice :
   Borrelia - Lyme Dz, relapsing fever
   Chlamydia - psittacosis, STD, pneumonia
   Rickettsia - RMSF, typhus, Q fever
   Erlichia - HGE, HME
   Brucellosis
   Vibrio - cholera, V. vulnificus sepsis
   Mycoplasma/Ureaplasma
Tetracyclines - Pharmacology

   Short acting             Tetracycline
                              – 500mg PO QID
   Intermediate acting      Demeclocycline
                              – 300mg PO BID

   Long acting              Doxycycline
                              – 100mg PO BID, QD
                             Minocycline
                              – 100mg PO BID
Tetracyclines - Oral Absorption

   Tetracycline      77%

   Doxycycline       93%

   Minocycline       95%
Tetracyclines - Side Effects
   Skin - allergic rash, photosensitivity
   Teeth & Bones - yellow discoloration in kids
    – don’t use in pregnancy or kids <8 yrs.
   GI - N/V/D, esophageal ulcerations
    – decreased side effects with food, but food also
      decreases absorption
   Liver and kidney toxicity rare, but reported
   Minocycline - vertigo
 Tigecycline: First in a New Class of
     Antibiotics (Glycylcyclines)




The unique structure of tigecycline provides:
 1. Expanded broad spectrum of in vitro activity
 2. Avoidance of tetracycline-resistance mechanisms
                          Tigecycline In Vitro Activity:
                             Gram-positive Bacteria
                                                                                        % Susceptibility

                                                                                                        E. faecium   E. faecalis
   Antibiotic                         MSSA*†                  MRSA†                 S. agalactiae†         (VRE)        (VRE)
   Ceftriaxone                              89                    NA                            99         NA           NA
   Levofloxacin                             82                     17                           97          0            9
   Linezolid                               100                    100                          100         99           100
   Minocycline                              99                     97                           NA         62            36
   Tigecycline‡                            100                     99                          100         100          100
   Vancomycin                              100                    100                          100          0            0
Clinical efficacy has been demonstrated for susceptible strains in cIAI (*) and cSSSI (†).
The clinical significance of in vitro activity is unknown.
‡Breakpoint  for susceptibility is ≤0.5 μg/mL for Staphylococcus aureus and ≤0.25 for Streptococcus spp.
(other than S. pneumoniae) and Enterococcus faecalis (vancomycin–susceptible strains only).
NA=Not available.

1. Tygacil® (tigecycline) Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals Inc. 2005.
2. Hoban DJ, et al. Diagn Microbiol Infect Dis. 2005;52:215-227.
                          Tigecycline In Vitro Activity:
                            Gram-negative Bacteria
                                                                                    % Susceptibility
                                                        Klebsiella                      Enterobacter       Serratia    Acinetobacter
Antibiotic                      E.    coli*†           pneumoniae*                        cloacae*        marcescens    baumannii
Amikacin                              99                         99                                  99      100            78
Amox/Clav                             79                         87                                  4        1             NA
Cefepime                              99                         98                                  95       97            40
Ceftriaxone                           97                         97                                  77       92            28
Imipenem                             100                         99                                  99       99            81
Levofloxacin                          79                         94                                  93       95            43
Minocycline                           84                         84                                  85       91            87
Pip/Tazo                              96                         94                                  82       95            68
Tigecycline‡                         100                         94                                  94       97            NA
Clinical efficacy has been demonstrated for susceptible strains in cIAI (*) and cSSSI (†).
The clinical significance of in vitro activity is unknown.
‡Breakpoint for susceptibility is ≤2 μg/mL, intermediate is 4 μg/mL, and resistant is >8 μg/mL for the

Enterobacteriaceae.
 NA=Not available.
Tygacil® (tigecycline) Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals Inc. 2005.
Hoban DJ, et al. Diagn Microbiol Infect Dis. 2005;52:215-227.
Data on File, Wyeth Pharmaceuticals Inc.
      Tigecycline: An Expanded Broad
        Spectrum of In Vitro Activity
                            TIGECYCLINE IN VITRO ACTIVITY
 Gram-positives              Yes    E. faecalis (vancomycin-susceptible isolates only)*†; S. aureus
                                    (MSSA)*†; S. agalactiae*; S. anginosus grp. (includes S. anginosus,
                                    S. intermedius, and S. constellatus)*†; S. pyogenes*; E. avium;
                                    E. casseliflavus; E. gallinarum; L. monocytogenes; S. epidermidis
                                    (MSSE); S. haemolyticus; E. faecium
 Gram-negatives              Yes    C. freundii †; E. cloacae†; E. coli*†; K. oxytoca†; K. pneumoniae†;
                                    A. hydrophila; C. koseri; E. aerogenes; P. multocida; S. marcescens
 Anaerobes                   Yes    B. fragilis*†; B. thetaiotaomicron†; B. uniformis†; B. vulgatus†;
                                    C. perfringens†; P. micros†; B. distasonis; B. ovatus;
                                    Peptostreptococcus spp.; Porphyromonas spp.; Prevotella spp.
 Resistant gram-positives    Yes    S. aureus (MRSA)*; S. epidermidis (MRSE); E. faecalis (VRE);
                                    E. faecium (VRE)
 Resistant gram-negatives    Yes    A. baumannii; S. maltophilia. TYGACIL is not affected by extended-
                                    spectrum beta-lactamases (ESBLs).
 Pseudomonas aeruginosa       No

Clinical efficacy has been demonstrated for susceptible isolates in cSSSI (*) and cIAI (†).

The clinical significance of in vitro activity is unknown.
                Tigecycline Dosing

• Standard dose
  – Initial dose of 100 mg IV
    followed by 50 mg IV q12h
  – Indicated in patients ≥18 years of age
  – PK not altered by age, sex, or race
• Renal impairment
  – No dosage adjustment necessary
  – Not dialyzable
• Hepatic impairment
  – No dosage adjustment necessary
    in patients with mild to moderate impairment
  – In patients with severe hepatic impairment (Child Pugh C),
    the initial dose is 100 mg IV followed by 25 mg IV q12h
Metronidazole

   Converted to toxic metabolite within
    bacterial cell by reduction of nitro group
   Bacterocidal
   Almost complete oral absorption
Metronidazole - Spectrum
   Bacteroides, Prevotella spp.
   Fusobacterium
   Clostridium
   Capnocytophaga
   Anaerobic gram negatives and gram
    positives
    – poor activity vs. peptostreptococcus
Metronidazole - Indications
   Amebiasis                  750 mg PO/IV TID
   Susceptible anaerobic      500 mg PO/IV Q8 hrs.
    infections
   Bacterial vaginosis -      500 mg PO BID x 7 days
    Gardenerella
   Trichomonas vaginitis      1.5 to 2 gm PO x1
   Giardiasis                 250 mg PO BID or TID x7d
   C. difficile colitis       250 mg PO QID or 500 mg
                                PO TID (IV less effective)
Metronidazole - Side Effects
   Most common: GI intolerance
   Metalic taste
   Leukopenia
   Rare, but serious:
    – Seizures
    – Encephalopathy
    – Neuropathy
Clindamycin

   Binds to 50S ribosome inhibiting protein
    synthesis
   Slowly bacterocidal vs MSSA, S.
    pyogenes, and pneumococcus
   Inhibits synthesis of proteinaceous
    virulence factors in S. pyogenes
Clindamycin

   90% oral absorption
   Poor CSF penetration
   Excellent bone and soft tissue
    penetration
   Metabolized by liver - no dose
    adjustment for renal failure
Clindamycin - Spectrum

   MSSA
   Lancfield group Streptococci
   Viridans group Streptococci
   All oral anaerobes
   GI anaerobes except “DOT”
Clindamycin - Uses

   Staph/Strep osteomyelitis
   Staph/Strep cellulitis
   gp A Streptococcal necrotizing fasciitis
   Head and neck infections
   Aspiriation pneumonia
   Intraabdominal infections
Clindamycin - Other Uses

   Toxoplasmosis (+ pyrimethamine)
   Pneumocystis (+ primaquin)
   Malaria (+ quinine)
Clindamycin - Side Effects

   Diarrhea
    – Antibiotic-related in up to 20%
    – C. difficile-related in up to 10%
   Mild, reversible transaminase elevation
   Otherwise, minimal side effects
Monobactams

   Aztreonam
   Gram negatives, except…
    – Stenotrophomonas
    – B. cepacia
   No gram positive or anaerobic coverage
   Low cephalosporin cross-allergenicity
Aztreonam - Uses

   Any gram negative infection in a
    cephalosporin-allergic patient
    – Pneumonia
    – Meningitis
    – UTI
    – Septic shock
    – etc.,
Chloramphenicol

   Released in 1949
   Binds to 50S ribosome to inhibit protein
    synthesis
   Only bacterocidal vs H. influenzae, S.
    pneumoniae, N. meningitidis, otherwise
    bacterostatic
Chloramphenicol - Spectrum

   Gram positives except S, aureus and
    Enterococcus
   Gram negatives except Enterobacter,
    Pseudomonas, Proteus
   Anaerobes
Chloramphenicol - Toxicity

   Reversible bone marrow suppression
    – Common
    – Dose-related
    – Due to inhibition of mitochondrial protein
      synthesis
Chloramphenicol - Toxicity
   Indiosyncratic aplastic anemia
    – Usually fatal
    – Occurs 1 in 24,500 to 40,800 patients
    – Not dose related
    – Occurs during therapy only 22% of time,
      more commonly occurs weeks to months
      after therapy
    – More common after oral administration…
      now only IV form available in USA
Colistin

   Last chance antibiotic
   Highly nephrotoxic
   IV and aerosolized (for CF patients)
   Peptide cationic detergent which
    disrupts bacterial cell wall
Antifungals
   Amphotericin
     – molecules orient themselves in cell membrane perpendicularly, bound to sterols,
       and form pores increasing permeability of membrane ->-> loss of potassium and
       other cell components.
          • Same thing happens to mammalian cells, hence it’s toxicity
     – highly lipophilic - accumulates in fatty tissue, then slowly releases into serum
          • Serum levels detectable up to seven weeks after end of therapy
     – main toxicities : renal failure, potassium, magnesium, and bicarbonate wasting,
       infusion reactions (fever, chills, tachycardia)
Amphotericin Lipid Complexes
   No difference in efficacy demonstrated
    as yet when compared to Ampho
   Abelecet - lipid complex
   Ambisome - liposomal ampho
   Amphotec - colloidal dispersion
   Dose 4 to 5 mg/kg IV QD
   30 - 60 x more expensive than Ampho B
Triazoles
   Ketoconazole, Fluconazole, Itraconazole,
    voriconazole, posaconazole
   Inhibit C-14alpha demethylation of lanosterol
    by binding to a P450 cytochrome ->->
    decreases ergosterol production
   Decreases synthesis of testosterone and
    cortisol in humans
   Less effect than ampho on human cell
    membrane sterols…lower side effects
   Ketoconazole
    –   variable absorption - depends on gastric pH…achlorhydria inhibits absorption
    –   effective vs coccidioides, but less so than fluconazole
    –   poor CNS penetration
    –   drug-drug interactions -
         • rifampin and INH lower ketoconazole serum levels
         • ketoconazole increases cyclosporin, phenytoin, and coumadin levels
    – side effects are common- nausea, anorexia, dose-dependent depression in serum
      testosterone and ACTH-stimulated cortisol response (doses >400 mg/day)
   Fluconazole
     – reliable PO absorption (80% bioavailability) - independent of acidity
     – excellent CNS penetration (70% of serum levels)
     – drug-drug interactions -
          • rifampin lowers fluconazole serum levels by 25%
          • fluconazole increases levels of phenytoin, glipizide, glyburide, tolbutamide, coumadin,
            rifabutin, cyclosporin.
     – Side effects uncommon - headache, hair loss, anorexia, rare increased LFTs
          • less effect on hormone synthesis than ketoconazole
– Itraconazole
    • PO form has variable absorption
         – AIDS patients absorb poorly
         – Suspension better absorbed
    • IV form contraindicated in renal failure
    • Drug-drug interactions (cyclosporin, oral hypoglycemics, digoxin,
      antihistamines, protease inhibitors, etc.)
    • Probably not as effective as amphotericin vs. aspergillus
    • Possibly slightly more effective against non-CNS cocci than fluconazole
Voriconazole
   Similar spectrum as fluconazole, and covers
    aspergillus, scedosporium, histoplasma
   Mild side effects - blurred vision, skin rash,
    elevated LFTs
   Drug-drug interactions a problem
   IV and PO - 80% oral absorption
   Dosed Q12 hrs
Posaconazole

   Similar spectrum to voriconazole
   Some activity against zygomycetes
   Only comes in PO suspension
   Dose with food, increases absorption
   Minimal drug-drug interactions
   Prophylactic dose – 200 mr TID
   Treatment dose – 400 mg BID
Echinocandins

   Caspofungin (Cancidas)
   Micofungin (Micamine)
   Anidulofungin (Eraxis)
Caspofungin (Cancidas)
   An echinocandin - new class
   Very low toxicity
   No adjustment for renal failure
   IV only: 70 mg load, then 50 mg IV QD
   Few, if any, drug-drug interactions
    (cyclosporin?)
   Inhibits cell wall synthesis by blocking beta
    1,3 glucan synthase
Caspofungin (Cancidas) -
Spectrum of Activity
   FDA approved for invasive aspergillosis
   Candidiasis - effective against all
    species
   Not effective against cryptococcus
   Dimorphic fungi ?
    – Early data not promising for hostoplasma
    – Insufficient data on coccidioides
Antifungal Activity
        Asperg Cocci   Histo   Crypto C. alb   Non-   C. lus
                                               alb
Ampho
          +     ++      ++      ++ +++ +++               -
Fluc
          -      +        -      +      ++       +      +
Itra
          +      +       +       +      ++       +      +
Caspo
          +      ?        -      -     +++ +++ +++

								
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