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clinical approach to infectious diseases erysipelas by mikeholy

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                 community-acquired pneumonia
        parenteral antimicrobial therapy during hospitalization
Antimicrobial agent          USA (%)    Korea (No., %: N=235)
Macrolides (erythromycin)     41.1%       47 (9.1%)    
Ampicillin-sulbactam          16.4%       31 (6.0%)
Ticarcillin-clavulanate        4.0%
Penicillin G                  10.2%        4 (0.8%)    
Ampicillin                     9.2%
Piperacillin                   4.8%
Cloxacillin                    0.9%
Cefazolin                      9.0%       61 (11.9%)
Cefuroxime                    44.5%       87 (16.9%)   
Cefotetan                      1.1%
Ceftazidime                    5.3%       43 (8.4%)
Ceftriaxone                    3.2%
Ceftizoxime                    0.8%
Gentamicin                    28.1%      160 (31.1%)
Clindamycin                    8.0%       55 (10.7%)
Co-trimoxazole                 4.4%
Ciprofloxacin                  4.5%       17 (3.3%)
Vancomycin                     6.7%        3 (0.6%)
Aztreonam                      1.8%        4 (0.8%)        Am J Med 104:17-27, 1998
Other agents                   7.7%
                                                           Korean J Infect Dis 1997
No parenteral therapy          3.2%
• penicillin : crystalline penicillin - neurosyphilis
   benzathine penicillin : primary and secondary syphilis
                             streptococcus, rheumatic fever
   (oral form : penicillin v) - actinomycosis
• penicillinase-resistant penicillins (anti-staphylococcal penicillins)
                           methicillin, oxacillin, nafcillin, flucloxacillin
• aminopenicillins : ampicillin
                      (E. coli), streptococcus, enterococcus, Listeria
• anti-pseudomonal penicillins :
            carboxypenicillins, ureidopenicillin (piperacillin)
• amidinopenicillin : mecillinam/pivmecillinam
     bacteria for which penicillins are drugs of choice
organism                  drug of choice                alternative
Streptococcus pyogenes    penicillin G or V             macrolide, clinda, or vanco
Group B streptococcus     penicillin G or V             same as above
viridans streptococcus    penicillin G                  vancomycin
S. pneumoniae             penicillin G or v             macrolide, clindamycin, CM if
MSSA                      penicillinase-R penicillins   vancomycin
enterococcus              ampicillin                    vancomycin, teicoplanin
Neisseria meningitidis    penicillin G                  ceftriaxone
Bacillus anthracis        penicillin G                  erythromycin, tetracycline
Clostridium perfringens   penicillin G                  metronidazole, clindamycin
   C. tetani
Listeria monocytogenes    ampicillin                    TMP-SMX
Eikenella corrodens       ampicillin, amoxicillin       erythromycin, tetracyclin
Pasteurella multocida     penicillin G or V             tetracycline
Actinomyces               penicillin G                  tetracycline, erythromycin
Leptospira                penicillin G                  tetracycline
Treponema pallidum        penicillin G                  tetra, erythro, chlormaphenicol
Borrelia burdorferi       amoxicillin                   tetracycline, macrolides
      characteristics of penicillins
• bactericidal
• narrow spectrum
      advantage : low risk of superinfection
                    low potentiality of inducing resistance
• short half-life : usually less than 1 hour
                    every 4-6 hours or (continuous infusion)
• adverse reaction
      fatal anaphylaxis
      interstitial nephritis, cholestatic hepatitis
• high incidence of resistance
        combination with beta-lactamase inhibitors
oxacillin, cefazolin and vancomycin against S.
                             nafcillin   cefazolin   vancomycin
efficacy to MRSA        -                 -           +
       to streptococcus +/-               +           +
       to enterococcus -                  -           +
if methicillin-susceptible
   rapidity of cure          +3           +3          +1
   inoculum effect           -            +           -/+
   CSF/serum ratio           7%           <1%         7%
   cost                      +1 (>)       +1          +8
   side effects              +1           +1          +3
          nafcillin vs flucloxacillin
                  nafcillin                 flucloxacillin

Country           USA                       UK
Administration    IV                        PO and IV
BBB penetration   1-20% in meningitis       limited
Maximum dose      up to 16 g/day            8 g, up to 12 g/day
Adverse effects    interstitial nephritis   cholestatic hepatitis
Cost                10,000/g                2,000/g
                beta-lactamase inhibitors
                    Aerobic                 Aerobic         Anaerobes
                     G+C                     G-B
           MSSA/MRSA Strep Entero    E. coli Haemo Pseudo   G+C   G-B
* sulbactam as a monosubstance

amoxicillin-clavulanic acid/
                +     -     +   +      +         +    -     +     +
                +    -      +    -     ++        +    ++     +    +
ticarcillin-clavulanic acid      -
                +     -     +   +      ++        +    ++     +    +
which antibiotics is the choice in the following conditions?

1. erysipelas :

2. cellulitis in a previously healthy patient :
                   diabetic patient :

3. staphylococcus bacteremia :
      with suspected infective endocarditis :
      with brain abscess :
• etiology of erysipelas
  : Group A beta-hemolytic streptococcus

• treatment:
   : penicillin
     (ampicillin, cephalosporins, vancomycin, EM)

cellulitis : etiology and treatment

• in healthy persons : S. aureus, GABH streptococcus

              nafcillin + penicillin
              (ampicillin-sulbactam, nosocomial - vancomycin)

• in diabetes : S. aureus, aerobic GNB, anaerobes

               amoxicillin-clavulanic acid
               cefazolin + aminoglycoside + metronidazole
               cefoxitin, if moderately severe
• S. aureus bacteremia, not likely endocarditis
    nafcillin 4-6 g/d
    cefazolin 3.0-4.0 g/d
    vancomycin 30 mg/kg/d
• S. aureus endocarditis
    nafcillin (12 g/d)
   cephalothin (12 g/d) >= cefazolin (6.0 g/d)
   (vancomycin 2-3 g/d: high treatment failure rate)
• S. aureus meningitis
   nafcillin 12 g/d
   vancomycin 30 mg/kg/d
Although they rarely are considered drugs
 of first choice for the therapy of bacterial

they are the most commonly prescribed
  agents for both ambulatory and
  hospitalized patients.
list of typical human pathogens and antibiotics of choice

       Pathogens               Antibiotics
    S. aureus
     penicillin-susceptible    penicillin
     methicillin-susceptible   oxacillin, nafcillin
     methicillin-resistant     vancomycin
     penicillin-susceptible    penicillin
     penicillin-insensitive    cefotaxime, vancomycin
     ampicillin-susceptible    ampicillin (+ aminoglycoside)
     ampicillin-resistant      teicoplanin/vancomycin
list of typical human pathogens and antibiotics of choice

   Pathogens                   Antibiotics

   Listeria monocytogenes        ampicillin (+ aminoglycoside)
   Escherichia coli, Klebsiella, Proteus
                                 cefotaxime +/- an aminoglycoside
   Pseudomonas aeruginosa ceftazidime + an aminoglycoside
     Peptostreptococcus          penicillin
     Bacteroides group           metronidazole
List of cephalosporins according to the generation
1st generation Cephalothin                    Cephalexin
                      Cefazolin Cephapirin    Cephradine
                      Ceftezole Cephradine    Cefadroxil
2nd generation
 w/o anaerobic        Cefuroxime              Cefuroxime axetil
                      Cefamandole             Cefaclor
                      Cefonicid               Cefprozil
                      Cefotiam   Ceforanide   Loracarbef*
 with antianaerobic
                      Cefoxitin  Cefminox
3rd generation
 w/o anti-pseudomonal
                  Cefotaxime Cefminoxime Cefixime
                  Ceftizoxime              Cefpodoxime
                  Ceftriaxone              Ceftibuten
 with anti-pseudomonal
                  Cefoperazone Cefpimizole
                  Ceftazidime  Cefsulodin
4th generation Cefepime, cefpirome
• 1st generation : cephalothin, cefazolin
• 2nd generation :
    w/o anaerobic : cefuroxime, cefamandole
    with antianaerobic : cephamycin (cefoxitin, cefotetan)
• 3rd generation :
     w/o anti-pseudomonal :
        cefotaxime, ceftizoxime, ceftriaxone
     with anti-pseudomonal activity :
         cefoperazone, ceftazidime, cefpiramide
• 4th generation : cefepime, cefpirome
     structure-function relationships
 activity               pharmacokinetic &
                        adverse effects


            N-methylthiotetrazole (MTT)
• moxalactam         cefoperazone
  cefotiam           cefonicid         cefmetazole      cefamandole
  cefotetan          cefminox
• cause hypoprothrombinemia and possibly bleeding
       monitoring of PT or weekly administration of vitamin K
• risk factors for beta-lactam associated hypoprothrombinemia
  - impaired intestinal absorption of vitamin K
      insufficient bile acids : gastric suctioning
      impaired intestinal transport : ileus, peritonitis, obstruction
      damage to intestinal microvilli : cytotoxic chemotherapy
  - nonintestinal factors
      malnutrition with vitamin K depletion
      renal failure : excessive MTT concentration
4th generation
• cefepime, cefpirome, cefaclidine, cefozoporan
• zwitterion structure
     can easily penetrate the outer cell membrane porins of GNB
• enhanced stability against beta-lactamase
  : [chromosomal type-1 beta-lactamases (>ceftazidime),
      extended spectrum beta-lactamase (variable)]
      has an activity against P. aeruginosa,
                              ESBL-producing Enterobacteriaceae
      similar to cefotaxime against S. aureus, Streptococcus

  antimicrobial spectrum of cephalosporins

                 Aerobic                Aerobic         Anaerobes
                  G+C                    G-B
          MSSA/MRSA Strep Entero E. coli Haemo Pseudo   G+C G-B

cefazolin     +3/-      +2/3   -   +2     -    -        +1    -
cefuroxime    +2/-      +2     -   +3     +3    -       +2    -
cefoxitin     +1/-      +1     -   +2     +1   -        +2    +3
cefotaxime    +1/-      +3     -   +3     +3    -       +1    +1
ceftazidime   -/-       +1     -   +2/3   +3   +2       -      -
cefpirome     +2/+(?)   +3     -   +3 *   +3   +2        -      -
cephems are inactive against the following
  penicillin high-level resistant S. pneumoniae
  Stenotrophomonas maltophila, B. cepacia
  Clostridium difficile
  intracellular organisms/absence of cell wall
      Listeria monocytogenes, legionella,
      (mycoplasma), rickettsia, Brucella,
     salmonella (3rd generation cephems-effective)
infusion of
after a loading dose
of 12 mg/kg, 6 g/day

JAC 43:309-311, 1999
 clinical use of 1st generation cephalosporin

1) surgical prophylaxis
    clean surgery : cefazolin
    clean-contaminated (I.e., operation entering mucosal surface)
         duration of op. < 2 hr : cefoxitin
                         > 2 hrs : cefotetan
2) skin and soft tissue infection
    S. aureus, Streptococcus pyogenes : cefazolin
    in diabetes : polymicrobial, includuing S. aureus : cefoxitin
3) osteomyelitis, septic arthritis
   S. aureus, streptococcus : cefazolin
   a child younger than 5 years - S. aureus, H. influenzae : cefuroxime
4) acute infective endocarditis
     S. aureus (viridans streptococcus) : nafcillin (cephalothin. cefazolin)
comparison of cefamandole and cefuroxime
                                cefamandole cefuroxime
inoculum effect                 yes           no
MTT side chain                  present       absent
CNS penetration                 inadequate    borderline
dose interval (hr)              4             8

activity against Haemophilus    +1            +3
activity against penicillin-
   intermediate S. pneumoniae   -             +
inducing beta-lactamase         +             no
dose                            1 g q 4-6 h   0.75-1.5g q8h
        clinical use of cefuroxime
active against S. aureus,
               penicillin-susceptible S. pneumoniae,
               beta-lactamase producing H. influenzae
• community-acquired pneumonia, moderate severity
• post-influenza pneumonia
• complicated sinusitis and epiglottis
• severe bacterial bronchitis
• problem :
  emergence of penicillin-resistant S. pneumoniae and beta-
  lactamase negative ampicillin resistance in H. influenzae
     decreasing role of cefuroxime in the near future
        comparison of cefoxitin and cefotetan
                           cefoxitin           cefotetan

half-life (hr)             1                   3-4.5
dosing interval            4-6 hrs             12 hrs
                                           cost-effective replacement of cefoxitin

MTT side chain                absent           present
activity against S. aureus +2-4                1
activity against GNB          1                 superior (= 3rd )
activity against Bacteroides most potent        inferior
(resistance rate B. fragilis    6%                22%)
      non-fragilis Bacteroides 5-33%               43-100%)
   clinical use of cefoxitin-cefotetan
1) mild to moderate skin and soft tissue infection caused by
   aerobic-anaerobic infection : diabetes, pressure ulcer
2) mild to moderate intra-abdominal, pelvic infection
   - PID (? cefoxitin-resistant N. gonorrheae)
3) surgical prophylaxis involving anaerobes

• not recommended because cefoxitin is a potent inducer of
  inducible or depressible chromosomal beta-lactamase of
  Enterobacter, Serratia, Citrobacter
      comparison of cefotaxime, ceftizoxime and
                       cefotaxime ceftizoxime   ceftriaxone
dosing interval (hr)     6          8           24 for systemic infection
                                                12 for meningitis
excretion               renal       renal       renal (50%) &
                                                  biliary (40%)
adverse effects                                 pseudocholecystitis
                                                GI side effects
indications             pregnancy               home IV therapy
                        neonate                 gonorrhea
usual dose              1g                      1-2 g
comparison of ceftazidime and cefoperazone
                                  ceftazidime     cefoperazone
activity against P. aeruginosa    +++             ++
              (MIC ug/ml          4-8             32-64)
development of resistance
     during treatment             ++              +++
activity against Enterobacteriaceae
                                  ++              +++
MTT side chain                    -               +
excretion                         renal           biliary (70%)
penetration to CNS                +               low
dosage                            1-2 g q 8 hrs   2 g q 8-12 hrs
clinical use of 3rd generation cephalosporins
 1) empiric therapy of community-acquired meningitis (cf: 4th cephem)
 2) empiric therapy of community-acquired sepsis of
      unknown primary site, UTI, pneumonia
 3) SBP
 4) viridans streptococcal infective endocarditis

 P. aeruginosa infection (with an aminoglycoside)
   : nosocomial pneumonia, nosocomial UTI, meningitis,
     cystic fibrosis, malignant otitis media
third generation cephalosporins is not
             indicated for:

1) surgical prophylaxis
2) single-agent therapy in severe Pseudomonas aeruginosa
3) empiric single-agent therapy in hospital acquired sepsis or
   unknown etiology
4) severe infections due to Enterobacter cloacae and
   Acinetobacter baumannii
5) enterococcal infections
6) severe intraabdominal infections
  clinical use of 4th generation cephalosporin

: similar to the third generation cephalosporins
• monotherapy
 community-acquired CNS infections
 community-acquired pneumonia in patients with underlying lung
  diseases : likelihood of P. aeruginosa infection
 urinary tract infection
• combination therapy
 an empirical regimen for nosocomial GNB infections - in endemic
   areas of ESBL-producing GNB infections
    - pneumonia
    - with an aminoglycoside
 intraabdominal infections : with anti-anaerobic agents
 febrile neutropenia
   adverse effects of cephalosporins and other
             beta-lactam antibiotics

Hypersensitivity reactions (in 1-5%;cephalosporins may cross-react with
                          penicillins, but little or no cross-reaction with aztreonam)
 Severe hypersensitivity is rare : anaphylaxis, angioedema
 Maculopapular rash
 Drug fever, with or without organ dysfunction
 Serum sickness (cefaclor)
Bleeding complication
 Moxalactam,      Cefoperazone,       Cefamandole,         (Cefmenoxime,      cefotetan),
Disulfiram-like reaction (if alcohol is ingested)
   Moxalactam, Cefoperazone, Cefamandole, (Cefmenoxime, cefotetan)
Diarrhea (in 5-10%; Clostridium difficile enterocolitis may occur with any agent)
  Cefoperazone, Ceftriaxone, Imipenem,
adverse effects of cephalosporins and other beta-
                lactam antibiotics
Superinfection (in 5-10% of recipients of any third-generation
   cephalosporin; especially enterococcus, pseudomonas, candida)
Seizure : Imipenem
Nausea (may be accompanied by hypotension, dizziness, and sweating) :
Rare complications with any cephalosporin
 Coombs test positive (3%) (hemolysis is rare)
 eosinophilia (1-7%), neutropenia (<1%)
 thrombocytopenia, thrombocytosis (5%)
 hepatic dysfunction
    mild elevation of transaminase/alkaline phosphatase
    biliary sludge (ceftriaxone)
 interstitial nephritis (rare)
Phlebitis (1-5%)
             oral cephalosporins
first gen      second generation third generation
cephalexin     cefaclor            cefixime cefpodoxime
cephradine     cefprozil           ceftibuten cefdinir
cefadroxil     cefuroxime axetil              cefteram
               loracarbef                     cefditoren*

S. aureus      H. influenzae       H. infl    H. influenzae
PS S. pn       PS S. pneumo        E. coli    E. coli
(E. coli)      S. aureus           PSSP       PISP
                                              S. aureus
* effective against PISP and non-BL-producing H. influenzae

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