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A. Overview [1,10,18]navigator

  1. Increasing Worldwide
    1. Risk factors for a variety of resistant organisms are similar
    2. Major organisms include Staphylococcus aureus, enterococci, gram negative baccili, Clostridium difficle, and Candida [1]
    3. Risks for infection with these organisms are similar
  2. Contributing Factors [1,22]
    1. Increased availability of prescription antibiotics
    2. Availability of non-prescription antibiotics worldwide
    3. Reduced threshold for treatment of "colds" with antibacterials
    4. Increasing incidence of aging and chronically ill persons
    5. Increasing incidence of chronically immunosuppressed persons
    6. Includes renal failure, liver failure, hematologic cancer, transplantation
    7. Long hospitalizations for very ill patients
    8. Use of multiple antibiotics in intensive care unit (ICU) settings [26]
    9. Cephalosporins and possibly fluoroquinolones are most often implicated [1]
    10. Macrolide use for streptococcal pharyngitis associated with increased carriage of macrolide resistant streptococcus [6]
    11. Long term use of antibiotics, particularly of low doses of agents
    12. Increasing use of antibiotics in animal feed worldwide
  3. Summary of Mechanisms of Resistance
    1. Mutations of bacterial gene targets which inhibit effects of antibacterials
    2. Reduction of cell wall/membrane permeability to antibacterials
    3. Transmission of novel genes which code for enzymes which inactivate antibacterials
    4. These novel genes may be coded on plasmids (episomes) or on bacterial chromosomes
    5. Active efflux (secretion) system operates in certain bacteria (such as Pseudomonas)
  4. Major Emerging Problems [15]
    1. Penicillin Resistant Pneumococci and other Streptococci
    2. Vancomycin Resistant Enterococci (VREF)
    3. Methicillin Resistant Staphylococci (MRSA) [2]
    4. Vancomycin Intermediate Staphylococci (VISA)
    5. Macrolide Resistant Streptococci [6]
    6. Aminoglycoside Resistant Enterococci
    7. ß-Lactam Resistant Gram Negative Organisms [5]
    8. Multidrug Resistant Gram Negative Organisms
    9. Quinolone Resistant Organisms
  5. Novel and Experimental Drugs for Resistant Organisms (see below)
    1. Pristinamycin (Quinupristin/Dalfopristin, Synercid®)
    2. Daptomycin (Cubicin®)
    3. Oxazolidinones (linezolid, Zyvox®)
    4. Everninomicin (Ziracin)
    5. Ketolides
    6. Anti-MRSA cephalosporins
    7. Glycylcyclines

B. Antibiotic Resistance in ICU [22]navigator

  1. Increasing problem in ICU with increased mortality and duration of hospital stay
  2. Ventilator associated pneumonia (VAP) and catheter-related infections main problems
  3. Major Organisms
    1. Methicillin resistant Staphylococcus aureus
    2. Pseudomonas aeruginosa
    3. Acinetobacter baumannii
    4. Stenotrophomonas (formerly Xanthomonas) maltophilia
  4. Risk Factors for VAP
    1. At least 7 days of mechanical ventilation
    2. Previous antibiotic use
    3. Use of broad-spectrum antibiotics
    4. Minor risk factors: prolonged length of hospital stay
  5. Strategies for Reducing Antibiotic Resistance in ICU [22]
    1. Limit unnecessary antibiotic administration
    2. Optimize antimicrobial effectiveness
    3. Antibiotics for VAP for 8 days as effective as 15 days with less antibiotic use and less development of resistance [27]
    4. Reduce length of mechanical ventilation (use noninvasive ventilation whenever possible)
    5. Increase vaccination of adults to pneumococcus, influenza virus, and H. influenzae
  6. Limiting Unnecessary Antibiotic Administration (Table 1 from [22])
    1. Develop hospital-based guideline for antibiotic use
    2. Create an antibiotic use quality improvement team (local, regional, national activities)
    3. Restrict hospital formulary (with increased infectious disease consult use)
    4. Use narrow-spectrum and older antibiotics
    5. Use quantitative cultures and qualititative assessments for nosocomial pneumonia
    6. Reduced use of vancomycin and 3rd generation cephalosporins associated with reduced incidence of vancomycin-resistant enterococci (VREF) [23]
    7. Reduce duration of antimicrobial therapy (8 days as effective as 15 days) [27]
  7. Optimize Antimicrobial Effectiveness (Table 1 from [22])
    1. Avoid inadqaute treatment by using automated quidelines
    2. Use combination antimicrobial treatment (mainly resistant GNR, see below)
    3. Consult with infectious disease specialist
    4. Antibiotic cycling and scheduled antibiotic changes
    5. Limit short-term antibiotic prophylaxis to clinically validated indications
    6. Avoid routine antimicrobial decontamination of the aerodigestive tract in ICU

C. ß-Lactam Antibiotic Resistance [5,26] navigator

  1. Most commonly used antibiotics in USA and worldwide
  2. Overview of Mechanisms of ß-Lactam Resistance [14]
    1. Alterations in penicillin binding proteins (PBP)
    2. In gram-negative organisms, mutation of porins can reduce ß-lactam permeability
    3. Expression of one or more ß-lactamases
  3. Resistance by Alteration of PBPs
    1. Staphylococcus aureus (MRSA)
    2. Streptococcus pneumoniae
    3. Neisseria ssp
    4. Rare amongst Haemophilus influenzae
    5. Rare Proteus ssp resistant to imipenem
    6. Common in Pseudomonas auruginosa [14]
  4. Pneumococcal Resistance to Penicillins [20]
    1. About 25% of all isolates are now resistant to penicillin [4,20]
    2. Mutations in one or more PRPs which decrease affinity for ß-lactams
    3. ß-lactamases are not usually involved in pneumococcal resistance to penicillin
    4. Pneumococcal resistance to PCN is usually accompanied by multiple resistances
    5. These include 1st and 2nd generation cephalosporins, sulfa drugs, some macrolides
    6. Also resistant to extended range penicillins and ß-Lactamase inhibitors
    7. Resistance to vancomycin is exceedingly rare
    8. New conjugate vaccines cover most resistant serotypes [20]
  5. Changes in Bacterial Permeability to ß-Lactams
    1. Gram negative bacteria have an additional outer membrane which blocks antibiotic entry
    2. Pseudomonal resistance to imipenem by alteration of these porins
    3. Pseudomonas also has an active efflux system for secreting antibiotics
    4. Other serious gram negative organisms including Enterobacter and Serratia use this
    5. Double antibiotic coverage is often advocated to prevent this kind of resistance
  6. ß-Lactamases
    1. Most common mechanism of resistance amongst gram negative bacteria
    2. Often chromosomally coded and expressed at low levels constitutively
    3. Inducible ß-lactamases are always coded on chromosomes
    4. Clavulanic acid is a potent irreversible ß-lactamase inhibitor
    5. Classified into 4 groups based on effects of clavulanate sensitivity
  7. ß-Lactamase Classification [5]
    1. Group 1: Cephalosporinases not inhibited by clavulanate (example: AmpC)
    2. Group 2a: Penicillinases inhibited by clavulanate (example: PC1)
    3. Group 2b: Broad-spectrum enzymes inhibited by clavulanate (example: TEM-1)
    4. Group 2be: Extended broad-spectrum enzymes inhibited by clavulanate
    5. Group 2br: Broad-spectrum enzymes with reduced binding to clavulanate
    6. Group 2c: Carbenicillin-hydrolyzing enzymes inhibited by clavulanic acid
    7. Group 2d: Oxacillin (cloxacillin)-hydrolyzing enzymes inhibited by clavulanate
    8. Group 2e: Cephalosporinases inhibted by clavulanate
    9. Group 2f: Carbapenem-hydrolyzing nonmetallo-ß-lactamases
    10. Group 3: Metallo-ß-lactamases (such as L1 from Stenotrophomonas maltophilia)
    11. Group 4: Penicillinases resistant to clavulanate (Pseudomonas cepacia)
  8. Gram Negative Bacteria and Cephalosporin Resistance [5,14]
    1. The Group 1, AmpC, ß-lactamases are the most concerning
    2. Includes Enterobacter, Citrobacter, Providencia, Morganella, Serratia, Pseudomonas, Xanthomonas, Acenitobacter [34]
    3. AmpC expressing, ceftriaxone resistant Salmonella has been reported in USA [19]
    4. Resistance includes 1,2,3rd generation cephalosporins and aztreonam
    5. Enterobacter and Acenitobacter ssp are replacing Pseudomonas ssp as major resistant pathogens, particularly in-hospital [34]
    6. Carbapenems (imipenem, meropenem) or 4th generation cephalosporins may be effective
    7. Concurrent use of aminoglycosides does not prevent this kind of resistance
    8. Extended spectrum ß-lactamase (ceftazadime) resistance reported in nursing homes [16]
    9. Klebsiella increasing TEM-1 (Group 2b) expression [28]
  9. Multidrug Resistance Plague [7]
    1. Yersinia pestis resistant to certain aminoglycosides, ampicillin and tetracyclines
    2. Remains susceptible to gentamicin, trimethoprim, and cephalosporins
    3. Resistance carried on conjugative plasmid pIP1202
  10. Long term, low dose ß-lactams increase risk of ß-lactam-resistant pneumococcus [8]
  11. Agents for Resistant Gram Negative Bacteria
    1. Piperacillin-tazobactam (Zosyn®)
    2. Cefepime (Maxipine®)
    3. Carbapenams: imipenam-cilistatin or meropenam

D. Resistant Staphylococci [12] navigator

  1. S. aureus are nearly always penicillin resistant due to PC1 enzyme (ß-lactamase)
  2. Oxacillin, cloxacillin, methicillin, dicloxacillin are resistant to PC1
  3. Methacillin Resistant Staphylococcus aureus (MRSA) [2]
    1. Most oxacillin (methicillin) resistant organisms are also resistant to cephalosporins
  4. Antitiobic Resistant Staph aureus [31]
    1. Nearly all Staph aureus carry ß-lactamase, making them penicillin resistant
    2. MRSA originates from introduction of the large (~20-55kb) genetic element SCCmec
    3. SCCmec (staphylococcal cassette chromosome mec) transfer into sensitive staph renders them resistant to methicillin and related antibiotics through mec gene
    4. SCCmec is integrated into Staph aureus chromosome at specific location
    5. Mec codes for altered penicillin binding protein (PBP) 2A
    6. Mec gene mutations responsible for many cases of MRSA
    7. Altered PBP 2A prevents methicillin (and other anti-staphylococcal penicillins), as well as most cephalosporins and carbapenams from inhibiting bacterial cell wall synthesis
    8. Five types of SCCmec identified; type 4 usually community acquired
    9. Oxa1 (bla) is sometimes present and is inhibited by clavulanic acid
    10. Mutations in fem (factors essential for methicillin resistance) also reported
    11. MRSA is now the most common cause of skin and soft-tissue infections in some emergency rooms in USA [32]
    12. Both community acquired and (more commonly) hospital acquired MRSA are significant proportions of staphylococcal infections
    13. Community acquired MRSA usually more sensitive to other antibiotics than hospital MRSA [2,15]
  5. Treatment of MRSA
    1. Vancomycin is the agent of choice for most infections
    2. MRSA organisms are typically sensitive to sulfa agents, but these are third line
    3. Agents effective in VISA and VRSA are very effective in MRSA (see below)
  6. Vancomycin Resistant Staph aureus
    1. Vancomycin intermediate-resistant (VISA) isolates reported very uncommon
    2. Highly vancomycin resistant Staph aureus (VRSA) reported but usually sensitive to newer antibiotics (see below) intermediate Staph aureus (VISA) are occasionally reported
  7. Treatment of Vancomycin Resistant (and MRSA) Infections
    1. Pristinamycin (Synercid®) is bactericidal for gram positive organisms [29]
    2. Oxazolidinones (eperezolid and linezolid) inhibit protein synthesis
    3. Linezolid (Zyvox®) resistance has been reported in critically ill patients [24]
    4. Daptomycin (Cubicin®) good activity against various resistant gram positives [3,30]
    5. Everninomicins - alternatives to vancomycin
    6. Additional agents are discussed above

E. Vancomycin Resistant Enterococci (VREF) navigator

  1. Three phenotypes: A, B and C; ~8% of all isolates (varies by area)
  2. Van A
    1. High level resistance to vancomycin and teicoplanin
    2. No bactericidal regimen is available
    3. Usually accompanied by high level aminoglycoside resistance
    4. May be sensitive to doxycycline, chloramphenicol, streptogramins, combinations
    5. Increasing high-level aminoglycoside resistance (HLAR) reduces efficacy of aminoglycosides in E. faecalis endocarditis
    6. In HLAR E. faecalis endocarditis, high dose ampicillin (2gm q4 hours) and ceftriaxone (2gm q12 hours) IV for 6 weeks showed reasonable efficacy [33]
    7. Vancomycin binds D-ALA-D-ALA on bacterial cell walls
    8. Van A contains genes which allow change to D-ALA-D-Lactate
  3. Van B
    1. Moderate level resistance in strains which do not express plasmid efficiently
    2. Majority of VanB strains are sensitive to teicoplanin
    3. Some strains have become vancomycin "dependent", require drug for growth
  4. Van C - low level resistance
  5. Resistance carried on plasmids or chromosome
  6. Infection Containment
    1. Restriction of iv and po vancomycin use
    2. Isolation of carriers
  7. Aminoglycoside resistance coexists in about 50% of isolates; may be high level [33]
  8. Pristinamycin (Synercid®) [17,29]
    1. Bactericidal against streptococci and staphylococci
    2. Bacteriostatic against Enterococcus faecium
    3. Nearly 70% of vancomycin resistant E. faecium (VREF) had clinical responses
    4. E. faecalis is intrinsically resistant to pristinamycin
    5. Active against methicillin (and vancomycin) resistant Staph aureus (MRSA, VISA)
    6. Dose is typically 5mg/kg iv q12 hours
  9. Daptomycin (Cubicin®) [3,30]
    1. Bactericidal membrane agent against resistant gram positives
    2. Excellent killing of MRSA, VREF, penicillin-resistant Strep pneumoniae
  10. Linezolid (Zyvox®) [13]
    1. Oxazolidinone which inhibits protein synthesis by bacterial ribosome
    2. Activity against all gram positive organisms and many anaerobes
    3. Cytostatic activity against both E. faceium AND E. faecalis
    4. Oral and IV available, usual dose is 600mg twice daily
    5. Clinical cure rates in VRE infections 67% (range 50-85%)
  11. Treatment with antianaerobic antibiotics leads to increases in VREF levels in stool [21]
  12. Reduced use of vancomycin and 3rd generation cephalosporins reduces VREF [23]

G. Quinolone Resistance [9] navigator

  1. Chromosomal mutations that modify DNA gyrase or DNA topoisomerase IV
  2. Plasmid mediated resistance reported for Klebisiella and E. coli
  3. Fluoroquinolone resistant Salmonella has been reported in the UK
  4. Levofloxacin resistant pneumococcal pneumonia has been described [25]
    1. Acquired resistance during standard (10 day) treatment
    2. Primary resistant pneumococcus also demonstrated

H. Multidrug Resistant Gram Negative Rods (GNR) [14] navigator

  1. Increasing problem in intensive care units [22]
  2. Acinetobacter and Stenotrophomonas have most highly resistant profiles
  3. Enterobacter and Klebsiella [28] are increasingly resistant to multiple agents
  4. Pseudomonas remains a major problem
  5. Antibiotic Resistance Patterns
    1. Quinolones
    2. Ceftazidime
    3. Ceftriaxone
    4. Piperacillin and Piperacillin-Tazobactam
    5. Some resistance to imipenam
  6. Use of "older" narrow spectrum antibiotics may reduce emergence
  7. Combination antibiotics may have some utility

I. Multidrug Resistance Salmonella [11] navigator

  1. Increasing antibacterial drug resistance in USA
  2. Mainly due to increased use of antibiotics for farm animals
  3. Multidrug resistant S. typhimurium DT104 isolated
  4. Resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline
  5. These resistant strains from USA are sensitive to ciprofloxacin

References navigator

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  10. Choice of Antibacterial Drugs. 2001. Med Let. 43(1111):69
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  13. Linezolid. 2000. Med Let. 42(1079):45 abstract
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  15. Moellering RC. 1999. Ann Intern Med. 130(2):155 abstract
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  30. Quinupristin / Dalfopristin. 1999. Med Let. 41(1066):109 abstract
  31. Daptomycin. 2004. Med Let. 46(1175):11 abstract
  32. Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. 2006. Lancet. 368(9538):874 abstract
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