Marys Medicine

Clostridium difficile diagnostik

How to treat
multiresistant
bacterial
infections?
Reno Frei, M.D.
Klinische Mikrobiologie
Universitätsspital Basel
4031 Basel
[email protected]
www.labormedizin-uhbs.ch
Restricted Use in Children -1
 Fluoroquinolones (Cipro-, Levo-, Moxifloxacin)
• Not approved for children age <18 years
based on joint cartilage injury in immature animals
• Ciprofloxacin in special indications:
- P. aeruginosa in CF (each age)
- complicated UTI as drug of 3rd choice age >1 year
 Tetracycline, Doxycycline, Minocycline
• Only for children age >8 years
 Nitrofurantoin
• Contraindicated in infants age <3 months*
 Daptomycin (Cubicin™)
• Safety & efficacy in children <18 years not established
* risk of hemolytic anemia due to immaturity of enzyme activity Restricted Use in Children -2
 Tigecycline (Tygacil™)
• Not approved in children <18 years
• FDA warning: increased mortality in adult patients
 Ceftaroline Fosamil (Zinforo™)
• Safety and efficacy not established in children
• Not yet marketed in Switzerland
 Quinupristin-Dalfopristin (Synercid™)
• Not registered in Switzerland
• No data for pediatric use
 Phenotypic susceptibility testing is
based on the minimum inhibitory
concentration (MIC)
 The MIC is the reference for all other
phenotypic tests
 The MIC breakpoint is valid only in a
standardised method
G. Kahlmeter, ECCMID 2010

Routine Susceptibility Testing
in the Clinical Laboratory
 MIC measurements
• (Macrobroth dilution: reference) • Microbroth dilution: reference • Automated systems (Vitek®, Phoenix® etc.) • Gradient diffusion methods: Etest®  Disk diffusion test (Kirby-Bauer)

Interpretive Standards
Development
NCCLS
1975: Proposal for disk test
1980: Proposal for MIC test
2013: CLSI: 23rd update

EUCAST*
1997: founded
2010-2011: Clinical Breakpoint
Tables for MIC and disk test
2013: version 3.0
*European Committee on Antimicrobial Susceptibility Testing 6
 Breakpoints mainly based on MIC distributions,
PK-PD properties and clinical data
Mouton JW. Clin Microbiol Infect. 2012,18:E37-45
 Documents available for free
• Clinical Breakpoints
• Expert rules:
- intrinsic resistances - exceptional resistance phenotypes - interpretive rules Approach to MDR
 Question: intrinsic or acquired/mutational resistance
 or exceptional / unusual phenotype?
See Leclercq et al. Clin Microbiol Infect 2013,19:141–160
(EUCAST expert rules)
E.g. intrinsic resistance in non-fermentative Gram-negative bacteria
Intrinsic (inherent) Resistance
 Drug is clinically useless
 Antimicrobial susceptibility testing (AST) unnecessary
«susceptible» results: error in identification or AST,
even if confirmed: avoid the drug or use with caution
 Enterobacteriaceae
also intrinsically resistant to Benzylpenicillin,
glycopeptides, Fusidic acid, macrolides (with some
exceptions), Clindamycin, Rifampicin, Daptomycin,
and Linezolid
 Non-fermentative Gram-negative bacteria
additionally R to Cefuroxime and Cefamandole
Multidrug-Resistant Pathogens (MDR)
Pathogen
Resistance
E Enterococcus faecium
S Staphylococcus aureus
K Klebsiella pneumoniae
ESBL, KPC & others
A Acinetobacter baumannii Carbapenem-resistant
P Pseudomonas aeruginosa MDR
E Enterobacter Species
AmpC, ESBL, MDR
J Infect Dis 2009,48:1-12
General Rules
 Treatment of MDR microorganisms should be based
on in-vitro susceptibility testing results,
ideally on MICs (quantitative results)
 Testing of combinations of antimicrobial agents is
not feasible in the routine lab and still experimentally
in the research lab
 Combinations theoretically beneficial to prevent
further development of resistance
 Use only regimens (including combinations) that are
clinically proven (no «fantasy regimens»)
 Do not force the laboratory to test drugs lacking
established breakpoints for a certain microorganism
Enterococcus spp.
 E. faecalis: nearly all S to Amoxicillin, Imipenem
 E. faecium: mostly MDR → R to Amoxi →
R to all beta-lactam agents → Vancomycin
 Vancomyin-resistant enterococci = VRE*
Acquired: VanA, VanB; intrinsic: VanC  Alternatives
 Linezolid*, Teicoplanin,
 Nitrofurantoin (uncomplicated UTI and E. faecalis)
 TMP-SMX (in contrast to USA/CLSI)
 (Daptomycin*, Quinupristin/Dalfopristin, Tigecycline)
* Review: Whang DW. AAC 2013,57:5013-8
Enterococcus faecium
 Today E. faecium often MDR
 Primary: Vancomycin
 For UTI: Nitrofurantoin, TMP-SMX*
 For bactericidal action of Amoxicillin or Vancomycin
aminoglycoside is needed (e.g. in endocarditis) →
combination with Gentamicin or Streptomycin

 Vancomycin-resistant enterococci (VRE):
Linezolid, (Tigecycline), possibly Teicoplanin (if S)

* Trimethoprim-Sulfamethoxazole, Cotrimoxazole Enterococcus spp. Combination with Aminoglycoside
 Penicillins and glycopeptides show bacteriostatic
rather than bactericidal activity
 Enterococci are intrinsically resistant to aminoglyco-
sides and aminoglycoside monotherapy is ineffective
 There is likely to be synergy between aminoglyco-
sides and penicillins or glycopeptides against E.
without acquired high-level resistance (HLR)
 Test for Gentamicin HLR (MIC >128 mg/L):
If negative → assume synergy / bactericidal activity
 If positive: avoid Gentamicin and other aminoglycos.
→ test for Streptomycin HLR (MIC >512 mg/L)
 Methicillin-/Oxacillin-resistant S. aureus →
crossresistant to all beta-lactam agents (except Ceftaroline)
 IDSA guidelines for adults and children:
Clin Infect Dis 2011,52:e18-55  Primary: Vancomycin (esp. for severe infections)
 Alternatives if strain is susceptible:
 Linezolid (esp. for pneumonia)
 TMP-SMX, Clindamycin, Minocycline, Doxicycline
 Only in combination: Rifampicin, Fusidic acid
 (Teicoplanin, Daptomycin, Ceftaroline)
S. aureus / MRSA
Clindamycin
 If resistant to macrolides → MLSB* induction test
 If positive → resistant mutants can be selected by
clindamycin → clinical failure may occur
 If negative → clindamycin may be used
D-Zone Test
* macrolides, lincosamides and streptogramins B
Clin Infect Dis 2005, 40:280-5
S. aureus, MRSA VISA, VRSA
 Vancomycin S: MIC ≤2 mg/l
 Vancomycin-intermediate VISA: 4-8 mg/L: very rare
 Vanco-resistant VRSA: >8 mg/L: <20 strains reported
 High failure rates with vancomycin in MRSA found
 particulary in isolates with MIC 2.0 mg/l (>1 mg/L)
in bacteremia (BSI)
van Hal SJ. CID 2012, 54:755-71
 Reasons unclear
Holmes NE. J Infect Dis 2011, 204:340-7  Best treatment unknown
 Target trough levels of 15-20 mg/L recommended
Severe Infections due to K. pneumoniae ESBL Failure of Cephalosporin Treatment
% failure
MIC (mg/l)
J Clin Microbiol 39:2206, 2001 Susceptibility Testing Paradigm Change
 After lowering the breakpoints 2011 
 Both EUCAST and CLSI: Report as tested irrespective
of resistance mechanisms  Treat as reported
 However, doubts on the efficacy of e.g.
- cephaloporins or Amoxi/clav. against ESBL
- carbapenems against carbapenemase-producers
 Controversial issue
Livermore DM et al. JAC 2012, 67:1569-77 Are susceptibility tests enough, or should laboratories still seek ESBLs and carbapenemases directly?  In Switzerland: Labs continue to identify important
resistance mechanisms at least in the next 2 years
AmpC β-Lactamase
 In Enterobacter spp., Citrobacter freundii,
Serratia spp. and Morganella morganii (and others):
 If susceptible in vitro to Ceftriaxone or Ceftazidime
do not use these drugs in monotherapy
 Selection of AmpC-derepressed cephalosporin-
resistant mutants may occur during therapy
 Combination with an aminoglycoside may also lead
to failure (in contrast to quinolones)
 Selection risk absent or much diminished for cefepime
Tamma PD et al. Clin Infect Dis 2013, 57:781-8  Piperacillin-Tazobactam: conflicting data
Chow JW et al. Ann Intern Med 1991,115: 585–90 20 Leclercq R et al. Clin Microbiol Infect 2013,19:141–160  Primary: Meropenem, Imipenem, Ertapenem
 For uncomplicated UTI: Fosfomycin oral,
Nitrofurantoin (E. coli)
 If susceptible: TMP-SMX, quinolones
 Often categorized as susceptible to combinations
of a penicillin and a β-lactamase inhibitor
 If susceptible to Amoxycillin–clavulanate or
Piperacillin–tazobactam or 3rd/4th generation
cephalosporin → uncertain therapeutic outcome
for infections other than UTIs

Pseudomonas aeruginosa
 Primary: Ceftazidime, Pip-Tazo, Cefepime,
Meropenem, Tobramycin° (in combination)
 Alternative: Imipenem, Aztreonam°, Ciprofloxacin,
(Levofloxacin), in combination Gentamicin or
Amikacin
 For MDR: Colistin° + carbapenem or Rifampicin
 Combination therapy: frequently recommended for
empiric therapy in severe infections esp. for MDR
 For directed therapy: conflicting study results →
still unsettled and controversial *

° = also nebulized for inhalation * Review: Tamma PD. Clin Microbiol Rev 2012, 25:450-70
Stenotrophomonas maltophilia
 EUCAST: «For Stenotrophomonas maltophilia the
only drug with clinical correlation between MICs and
clinical outcome is Trimethoprim-Sulfamethoxazole"
 TMP-SMX: therapy of choice
 "It may be that in the future one or two more drugs
may receive breakpoints, but current literature does
not clearly indicate another drug for which it is
reasonable to determine breakpoints."
 CLSI: breakpoints also for Ceftazidime, Levofloxacin,
Minocycline, (Chloramphenicol, Ticarcillin-clav. acid)
Acinetobacter baumannii
 In many countries MDR strains
including carbapenem-R, possibly panresistant
 EUCAST: no breakpoints for penicillins and
cephalosporins defined
 Primary: Meropenem, Imipenem (± Ciprofloxacin)
 For MDR: Colistin  combine with a carbapenem
even if the isolate is resistant in vitro1
 If susceptible: Cefepime (tested according to CLSI),
Ciprofloxacin, Levofloxacin, Minocycline,
(TMP-SMX), and aminoglycosides in combination
General review: Fishbain J. CID 2010,51:79-84 24
1) Zusman O. AAC 2013, 57:5104-11
Conclusions
 For MDR gram-positive bacteria:
Vancomycin
 For MDR gram-negative bacteria:
Meropenem, Ertapenem or Imipenem
 For extensively MDR gram-negative bacteria:
Colistin*
possibly combined with a carbapenem
 In severe infections, consider to use
cominations for empiric therapy, e.g.
• Vancomycin + Flucloxacillin in S. aureus • Vancomycin + Ceftriaxone in meningitis * Kapoor K. Pediatr Crit Care Med 2013,14:e268-72

Source: http://www.pigs.ch/pigs/04-meetings/doc2013/frei.pdf