Comprehensive summary on Managing MDR/XDR Gram-negative infections in ICU

1. DR. VITRAG H SHAH
MD Medicine, FNB Critical Care, EDIC-UK
(European Diploma in Critical Care)
Physician & Chief Intensivist
Velocity Hospital

3.  The organisms posing most danger have been
clubbed together under the term “ESKAPE,” i.e.,
Enterococcus faecium, Staphylococcus aureus,
Klebsiella pneumoniae, Acinetobacter baumanii,
Pseudomonas aeruginosa, and Enterobacter
species, as these have the ability to escape the
effect of antimicrobial drugs.
 The ones leading to increased mortality include
carbapenem-resistant Enterobacteriaceae (CRE),
P. aeruginosa, and A. baumannii, which have
acquired multiple mechanisms of resistance.

5.  MDR: non-susceptible to ≥1 agent in ≥3
antimicrobial categories
 XDR: non-susceptibility to at least 1 agent in
all but 2 or fewer antimicrobial categories (i.e.
bacterial isolates remain susceptible to only
one or two categories).
 PDR: non-susceptible to all antimicrobial
agents in all antimicrobial categories.

6.  Longer hospital stays
 Require treatment with drugs that may be:
Less effective
More toxic
More expensive

7. 1. Use nonstandard antibiotics for which resistance
has not yet occurred
2. Use the standard antibiotics with increased
doses, so PK/PD targets are still achieved
3. Use combination therapy with antibiotics from
options 1 and/or 2
 Distinguish colonization vs infection
 Use adjunctive therapies (surgery/source control,
reversal of immunosuppression)
 Know the exact molecular mechanism of
resistance and exact MIC

8.  Beta-lactamase (ESBL)
 Loss of porin channels
 Efflux pumps
 Aminoglycoside-modifying enzymes
 Topoisomerases modifications
(Fluoroquinolones)
 LipidA (LPS) modifications (Polymyxins)

9.  Heteroresistance
 Adaptive resistance
 Inoculum effect

12.  54 yr male, admitted with RTA-polytrauma
leading to Lt. leg # both bones, lung
contusions and Rt. Parietal ICH since 10 days.
 On IPPV since admission
 Having persistent fever since 3days
associated with increasingTLC s but is still
haemodynamically stable and static Fio2 and
ventilatory support

13.  Continuous fever 39°C
 No change in character of tracheal secretions
 No change in SOFA score
 CVC andArterial catheter insertion sites appear
free of infection

14.  Blood Central : GNBs sensitivity awaited
 Blood Peripheral : GPCs and FermentingGNBs
 TrachealGm Stain: Few GPCs+GNBs+ budding
yeast cells with few epithelial cells n few PMN
cells
 Tracheal culture : same as peripheral blood
 Urine culture: no significant growth but 20 pus
cells

15.  Inj Piperacillin +Tazobactam
 Inj Clindamycin
 Inj Eptoin
 Inj Mannitol (tapering doses)
 Mechanical DVT prophylaxis
 NG tube feed as per wt- tolerating well
 Microbiologist calls to tell GNBs are ESBL
producers

16.  Inj Meropenam 1gm iv tid
 InjTeicoplanin 400 mg stat and bd
 Inj Fluconazole 400 mg bd
 Pt’s relatives counseled and reassured that
cause of fever is sorted ????

17.  High grade spike of fever since 3 days
 All lines changed y’day n pan cultures were sent
 Mucopurulent tracheal secretions n culture
growing GNBs , blood culture sterile, urine has
candida..
 Microbiologist calls to tell that it’s MDR
pseudomonas sensitive to collistin only……

18.  Patient becoming haemodynamically unstable
and increasing FiO2
 Worsening metabolic acidosis with raising
creatinine
 Resusitation with fluid challenges+ vasopressors
but needed RRT
 Collistin 2mu i.v. tid added along with
echinochindin , family given a grave prognosis

19. Now My Patient is Dead
 Did we do enough?
 Did we do it right?
 Can we reflect what
went wrong and
WHEN?

20. NOT EVERY FEVER MEANS INFECTION….

21. More than antibiotics……

22.  Broader is better
 Failure to respond is failure to cover
 Response implies diagnosis
 When in doubt, change drugs (or add
another)
 Antibiotics are harmless
Kim JH. Am J Med. 1989; 87: 201-206

23.  Response to fever is an evaluation, not
changing antibiotics.
 Keep in mind non-infectious causes of fever
 Evaluate potential sources of infection
 Source control with least invasive method
earliest possible
 Get cultures from relevant sites before
starting/changing antibiotics
 Start empiric broad spectrum combination
therapy only if hemodynamically unstable

24.  As ICU patients have multiple potential
source of infection, it is difficult to find out
source of infection many times
Infectious source Non-infectious source
ET /TTTube (VAP) Bed-ridden (DVT/PE)
Ryle’s tube (Sinusitis) Drugs
Foley’s Catheter (UTI) Acalculus cholecystitis
Central/Arterial line/HD Cath
(CRBSI)
Vasculitis
Drains Burns, Pancreatitis, Post-op
(SIRS)
Bedsore Central fever

26.  Perception of need: Is an antibiotic necessary?
 Choice of antibiotic:Which is the most
appropriate antibiotic?
 Choice of regimen :What dose, route, frequency
and duration are needed?
 Monitoring efficacy : Is the antibiotic effective?

27.  Right Drug
(Covering suspected pathogen and as per suseptibility
pattern, good penetration as suspected site of infection)
 RightTime
(Hit hard and hit fast)
 Right Dose
(Full loading dose irrespective of renal/hepatic function
and optimize maintainance dose as per Pk/Pd)
 Right Duration
(Deescalate earliest possible, combination to
monotherapy, broad spectrum to targeted therapy )

28. *Based on the 2005 ATS/IDSA guidelines for HAP/VAP/HCAP (Am J Respir Crit Care Med
2005;171:388–416), inappropriate would be the term used to refer to the inadequate
therapy noted on this slide.

29. Kumar et al. Crit Care Med 2006; 34:1589-1596

30. Intervention NNT
Antibiotics to prevent death in
sepsis
4
Thrombolysis to prevent
unfavourable outcomes in acute
ischemic stroke
17
Thrombolytics to prevent death in
STEMI
43
Aspirin to prevent death in STEMI 42
Statins for heart disease
prevention
83

31.  Spectrum
 Tissue penetration
 Antibiotic sensitivity (As per local
antibiogram)
 Safety profile
 Cost

32.  Gram Positives
 Streptococcus
 Pneumococcus
 S.Aureus
 Enterococcus
 Gram Negatives
 E.coli
 Klebsiella
 Pseudomonas
 Acinetobacter

33.  Above diaphragm
 Cover
 Pneumococci
 H.Influenza
 Streptococci
 S.Aureus
 Oral anaerobes
 Below diaphragm
 Cover
 E.coli
 Klebsiella
 Anaerobes

35. Gram negative coverage* Gram positive coverage
(MRSA/Enterococcus)
Ceftriaxone Vancomycin
BL-BLI :
 Piperacillin-tazobactam
 Cefoperazone-sulbactam
 Cefepime-Tazobactam
Teicoplanin
Daptomycin
Clindamycin
Carbapenems Linezolid
Aminoglycoside Tigecycline/Minocycline,
Fosfomycin(Both Gram
Negative & MRSA)
Colistin/Polymyxin B
*Piptaz & carbapenam covers anerobes as well as MSSA

36. BL-BLI Carbapenam
Variable in vitro activity
against ESBL producers
Excellent in vitro activity
against ESBL producers
In theory should inhibit
ESBLs
Not hydrolysed by ESBLs
But, many ESBL producers
also produce other beta lactamases /
Other resistance mechanism
Overuse leads to
carbapenem resistance
Inoculum effect Not subject to the
inoculum effect

37.  Carbapenems are the first-line choice for severe
ESBL infections
 The efficacy of BLBLI combinations has not been
adequately investigated in critically ill patients
with ESBL-PE infections: Piperacillin–
tazobactam can be used as a carbapenem-
sparing regimen for strains with low MICs (≤2
mg/L), using optimized administration (high
doses,extended or continuous infusion,
therapeutic drug monitoring)

38.  Post Hoc Analysis of Prospective Cohorts from Spain
 Mostly E. coli from urinary & biliary sources
 Mortality rates same for both empirical & definitive therapy
 “AMC or PTZ are suitable options for the definitive therapy of susceptible ESBL-EC strains
causing BSI, mainly in the urinary and biliary tracts, which could help prevent overuse of
carbapenems.”
 Re-analysed above data based on piperacillin MIC
 <2; 4-8; >8
 Mortality 41% for high MIC vs 0% for low MIC
 No deaths with urosepsis
 Retrospective analysis: mortality rate was 13% with BL/BLI & 24% with carbapenems
(But not statistically significant)
 A randomized controlled trial to compare piperacillin-tazobactam to meropenem for
the definitive treatment of bloodstream infection caused by ceftriaxone non-
susceptible E. coli and Klebsiella sp. (MERINO trial) - do not support using PTZ as a
carbapenem-sparing treatment option for same.
Clin Infect Dis 2012 54: 167-174
BMC Infectious Diseases 2012, 12:245
AntimicrobAgents Chemother 2013; 57:3402–4.

39.  Adjusted risk of death: 1.9 times higher for patients
on piperacillin-tazobactam
 Piperacillin-tazobactam appears inferior to
carbapenems for ESBL bacteremia (331 patients)
Clin Infect Dis 2015 60: 1319-1325

40. Total of 13,091 Gram-negative bacteria
ESBL producers- 69%
P/T exhibited activity (81.37% organisms susceptible)
C/S (76.06% organisms susceptible).
Mohanty etal. Indian J Med Res 2005 ;122:425-428

42.  Local epidemiology (80% sensitivity rule) for empirical
therapy
 Definitive therapy as per sensitivity and MIC
 Clinical status & patient profile
 Affordability
 High dose of BL-BLI and optimize Pk-Pd
 Can be used urosepsis or biliary sepsis, rather than
pneumonia or CLABSI & E coli rather than Klebsiella

43.  S.Maltophilia –All Betalactam
 Pseudomonas –Tigecycline, Ertapenam,
TMP-SMZ, Chloramphenicol
 A.Baumannii – Ertapenam,Aztreonam,
Fosfomycin

45.  While monotherapy may be appropriate for patients with less
severe infections by susceptible isolates, patients with severe
infections and critically ill patients would likely benefit most from
rationally optimized combination therapy.
 Combination therapy for CR GNB is usually based on a cornerstone
antibiotic for which the organism presents in vitro susceptibility,
and an adjuvant drug to which the organism may be susceptible in
vitro or not.
 It needs to be emphasized that the concept of susceptibility test
refers to antibiotic monotherapy. An adjuvant drug, which may
cause no bacterial killing in monotherapy, can still be highly
beneficial to maximize bacterial killing or prevent resistance.
 The most frequently used adjuvant therapies for CRGNB
infections are carbapenems, tigecycline, fosfomycin,
aminoglycosides and rifampicin along with cornerstone drug
Polymyxins (Polymyxin B/ Colistin).

46. Advantages of Combination therapy Disadvantages
Broader coverage that includes
non-susceptible strains
Possible antagonism
Anti-bacterial synergy Possible superinfection
Prevents emergence of resistance May increase resistance & toxicity
Shorter duration & Less toxicity Increased cost
Avoid monotherapy of colistin,Tigecycline,Aminoglycoside, Fosfomycin & Avoid
monotherapy in any XDR infection

48.  Why meta-analysis fail to show benefit of
combination therapy?
 Why a particular combination works
effectively in one study but fails miserably in
other ?
 How to decide what combination is ideal in a
particular situation ?
 What’s the solution in Colistin Resistant/
Colistin only Sensitive isolates?

49.  These meta-analyses are fundamentally misleading.
They include a large number of heterogeneous studies
performed over a long period of time.The 2014
Cochrane Review, for instance, searched for studies
performed between 1966 and 2013 but the majority of
included studies were per- formed between 1980 and
2000.This was long before the emergence of CRE
 They did not analyze sub-groups with multidrug-
resistant organisms and, thus, do not address the
question of combination therapy in this group.

50.  Most virulent gram negative pathogen
 Main pathogen in neutropenic sepsis,
diabetic, structural lung disease patients
 High mortality (~30%) for bacteremia
 So need increased
dose/duration/combination therapy
 For empirical therapy: If it is sensitive as per
local data - Monotherapy, if MDR as per local
data, Combination therapy and deescalate as
per sensitivity and clinical profile

51.  Majority are XDR
 Typical strain are less virulent
 Frequently causes colonization of respiratory
tract
 Clinically significant infection in
compromised patients
 Source control (Remove lines, tube etc) is
more important with XDR than antibiotics

54.  First introduced 1959, known nephrotoxicity and
neurotoxicity
 May be actually less nephrotoxic than
aminoglycosides
 Surface active agents that disrupt cell membranes
 Resurgence in use since advent of carbapenem
resistant organisms
 Deficiency in knowledge about PK/PD
 Pk-Pd Profile : (AUC/MIC ratio) >> (Cmax > MIC)
 Concentration-dependent bactericidal drug
 Role in India : Extremely valuable drug in hospital
acquired infections in view of rising carbapenem
resistance

55.  It is active against ESBL- and
carbapenemase-producing
Enterobacteriaceae (CPE), P. aeruginosa, and
A. baumannii, the most worrisome
pathogens.
 However, certain organisms such as tribe
Proteae, Burkholderia species, and Serratia
marcescens are intrinsically resistant to the
drug

57.  Colistin is administered as CMS, an inactive pro-drug
that needs to be converted in vivo to the active drug
colistin. However, only a small fraction (25-30%) of
CMS is converted to colistin in vivo and this
conversion is quite slow.Therefore, without loading
doses, therapeutic concentrations of colistin are only
reached after 48 h of CMS administration & loading
doses of CMS are required to reach therapeutic
concentrations of colistin in the first 12–24 h.
 In contrast, polymyxin B reaches higher serum
concentrations than Colistin after first dose, and these
polymyxin B concentrations are reached much more
quickly, even without a loading dose, which is
recommended but does not seem to be as essential as
for CMS.

58. Colistin and polymyxin B: peas in a pod, or chalk and cheese? 1. Clin Infect Dis. 2014 Jul
1;59(1):88-94

59.  CMS is predominantly cleared by the kidneys. CMS
concentrations increase as Cr Cl decreases, which
results in higher concentrations of CMS to be converted
to colistin.Therefore patients with impaired renal
function require dose adjustment of CMS. In contrast,
patients with normal, but especially those with
increased Cr Cl, e.g. initial phases of sepsis and septic
shock, will likely present low concentrations of colistin
in plasma with usually recommended doses.
 In contrast, the clearance of polymyxin B is not related
to Cr Cl; so dose adjustments are not required in renal
dysfunction.

60.  A potential advantage for CMS lies in the
treatment of urinary tract infections.As there
is substantial tubular reabsorption of
polymyxin B (and also colistin), very low
concentrations of polymyxin B or colistin are
found in urine . In contrast, CMS is highly
eliminated by the kidneys without tubular
reabsorption, and a large amount of CMS is
converted to colistin in urine leading to high
urinary concentrations of the latter.

62.  Polymyxin B would appear to have superior clinical
pharmacological characteristics for infections where it
is important to rapidly and reliably attain and
maintain plasma concentrations that are likely to be
efficacious, across a wide range of renal function. An
exception may be the treatment of urinary tract
infections where CMS/colistin may be the polymyxin
of choice.
 Because of smaller interindividual variability and lack
of impact of renal function on drug clearance, initial
dose selection and titration are simpler and more
predictable for polymyxin B.

63.  InhaledColistin for MDR/XDR GNB
In conjunction with IV Colistin
Delivery to lung tissue questionable
No mortality benefit (Clin Infect Dis 2010;51:1218)
but microbiological cure
Size effect : Bronchospasm (Rare)
 Intrathecal and intraventricular
administration for meningitis caused by
resistant GNB (Dose of intrathecal is quite
low, so cost effective as well)

64.  Conversions :
1mg CBA = 30,000 IU CBA
1 mg CBA = 2.4 mg CMS
1mg CMS = 12,500 IU CMS
or
(30 mg CBA = 80 mg CMS = 1 Million IU CMS)
1mg Polymyxin B = 10,000 IU Polymyxin B

65.  Colistin
 Loading dose: 9 million IU (or 4*IBW)
 Maintenance dose: 4.5 million IU every 12 hours
 Polymyxin B
 Loading dose : 25,000 U/Kg over 2 hour
 Maintainance dose : 15,000 U/Kg over 1 hour 12 hourly
 Concomitant IVAscorbic acid 1gm 6 hourly to reduce the
risk of nephrotoxicity
 Intrathecal dose
 Colistin : 3 lac unit CMS / day
 Polymyxin : 50,000 unit/day for 3-4 days f/b alternate day
 Inhalation dose (preferablyVibrating mesh nebulizer)
 1-3 MU CMS 3 times daily

66. CrCl (ml/min) As per PK Study group – divided bid US-FDA
(CBA,IBW)
CBA (mg/day) CMS (MIU/day)
>90 360 10.9 2.5-5mg/kg/day
divided bid-tid
80-90 340 10.3
70-80 300 9.00 2.5-3.8 mg/kg/day -
divided bid (4.5-7
MIU)
60-70 275 8.35
50-60 245 7.40
40-50 220 6.65 2.5 mg/kg /day -
divided bid
(4.5-5MIU CMS)
30-40 195 5.90
20-30 175 5.30 1.5 mg/kg q36h
(2.5-3MIU CMS
q36h)
10-20 160 4.85
5-10 145 4.40 Not recommended
<5 (ESRD) 130 3.95
Roger L. Nation et al; DosingGuidance for Intravenous Colistin in Critically Ill Patients, Clinical
Infectious Diseases,Volume 64, Issue 5, 1 March 2017, Pages 565–571

67.  130mg CBA / day divided bid (3-4MIU CMS)
when not on dialysis andCrCl <5ml/min
 For IHD/SLED/CRRT, Add 10% of daily dose
per hour of dialysis
 Approx. dose with 10 hour SLED would be
130mg CBA twice daily (Total 260mg/day)
 Approx. dose with CRRT is 440mg CBA/day
(13MIU CMS/day, divided tid)

68. AntimicrobAgents Chemother. 2012 Aug; 56(8): 4241–4249

69.  Dalfino L, Puntillo F et al: High-dose, extended-interval colistin
administration in critically ill patients: is this the right dosing
strategy? A preliminary study. Clin Infect Dis 2012, 54:1720–1726.
 Garonzik SM, Li J, et al: Population pharmacokinetics of colistin
methanesulfonate and formed colistin in critically ill patients from a
multicenter study provide dosing suggestions for various categories
of patients. Antimicrob Agents Chemother 2011, 55:3284–3294.
 Plachouras D, Karvanen M et al: Population pharmacokinetic
analysis of colistin methanesulfonate and colistin after intravenous
administration in critically ill patients with infections caused by
gram-negative bacteria. Antimicrob Agents Chemother 2009,
53:3430–3436.
 Roberts JA, Lipman J: Editorial commentary: Closing the loop - a
colistin clinical study to confirm dosing recommendations from
PK/PD modeling. Clin Infect Dis 2012, 54:1727–1729.

70. Combination therapy for carbapenem-resistant Gram-negative bacteria. Expert Rev. Anti
Infect.Ther. 11(12), 1333–1353 (2013)

71.  Phosphonic acid derivative
 Broad spectrum Bactericidal drug
 Unique mechanism of action : Inhibition of first cytoplasmic step of
bacterial cell wall biosynthesis, formation of the peptidoglycan
precursor N-acetylmuramic acid.This inhibitory action takes place
at an earlier step than the action of β-lactams or glycopeptides.
 It reduces adherence of bacteria to urinary epithelial cells . In a
similar manner, fosfomycin suppresses platelet activator factor
receptors in respiratory epithelial cells, thus reducing adhesion of
Streptococcus pneumoniae and Haemophilus influenzae . It has
ability to penetrate into biofilms. Fosfomycin exerts
immunomodulatory effects by altering lymphocyte, monocyte and
neutrophil function.

72.  It is neither metabolized nor protein bound and
has a low molecular weight, thereby achieving
good penetration and concentration in tissues.
 Greater penetration into subcutaneous and
muscle tissue, followed by lung and bone. Good
distribution in CSF as well.
 Hemodialysis removes the drug completely;
therefore, the drug is readministered after the
procedure is over.
 Pregnancy : Category B

73.  Mainly used for CRE.
 It is considered active against Enterococcus spp. (including
Enterococcus faecalis and E. faecium irrespective of
vancomycin resistance), Staphylococcus aureus
(irrespective of methicillin resistance), and S. epidermidis.
 Fosfomycin is not active against anaerobes, such as
Bacteroides spp., but it is active against Peptococcus spp.
and Peptostreptococcus spp. Pseudomonas, Acinetobacter,
Stenotrophomonas maltophilia, Burkholderia cepacia,
Staphylococcus capitis, Staphylococcus saprophyticus, and
Mycobacterium tuberculosis are intrinsically resistant to
fosfomycin. Morganella morganii is also resistant to
fosfomycin

74.  Dose : 12-16 gm/day in 2-4 divided doses. However,
higher daily doses (up to 24 g) have been given to
patients with CNS or other severe infections .
Intravenous fosfomycin is administered as a slow
infusion after dilution in 100 ml.
 Used in combination with with other antibiotics, due
to its unique mechanism of action and its protective
effect against nephrotoxicity induced by
aminoglycosides or colistin.
 Adverse effect : Na & fluid overload, hypokalemia.
Every gram of IV Fosfomycin contains 0.32 g of
sodium. (1 L NS – 9 gm)

75.  Carbapenemase-producing Enterobacteriaceae isolates
present carbapenem MICs near to or even at the current
susceptibility breakpoints, that is, 1–4 mg/l; this occurs
especially for meropenem and doripenem. So higher
doses and optimal modes of administration, either by
extended or continuous infusion of the drugs , can lead to
an acceptable probability of attaining the PK/PD target
(i.e.,T/MIC >40%) for pathogens with carbapenem MICs
between 1 and 8 mg/l, even in critically ill patients.
 In contrast to Enterobacteriaceae, carbapenem MICs in CR
non-fermentative organisms are often very high (>32
mg/l), either because more potent carbapenemases are
involved or other resistance mechanisms are additionally
present.

76.  Double-carbapenem combination therapy can be used for
KPC producing Enterobacteriaceae.
 Specifically, the rationale is using a carbapenem with
increased affinity for KPC, that is, ertapenem, to act as a
‘suicidal’ drug in order to improve the action of another
carbapenem, especially doripenem/meropenam, with
increased stability against the hydrolyzing activity of KPC.
 However, non-carbapenemase mediated resistance to
carbapenems also occurs among CR GNB and combining
carbapenems is expected to be ineffective against such
isolates.
 1 g ertapenem 24 hourly followed 1 hour later by
meropenem (2 g) every 8 hours in an infusion that is to be
carried out over 3-4 hours duration .

77.  Monobactam, similar MOA to betalactam.
 The monobactam class is ‘unique’ among the
clinically available b-lactams in its capacity of not
being hydrolyzed by metallo-b-lactamases; thus,
aztreonam is an important therapeutic option
against metallo-b-lactamase-producing CR GNB.
 Dose : 1-2gm 8 hourly
 Can be used in patients with penicillin allergy
 No activity against anaerobes and Gram positive
bacteria

78.  Tigecycline is a minocycline derivative belonging to the
new class of antimicrobials known as glycylcyclines.
 It is a broad-spectrum antimicrobial with activity against
many Grampositive, Gram-negative and anaerobic
pathogens and has been frequently prescribed as a part
of combination schemes against CR Enterobacteriaceae
and also CR A. baumannii. Proteus and Pseudomonas are
intrinsically resistant toTigecycline.
 Approved by US FDA for complicated intra-abdominal
infections (cIAIs) and skin-soft tissue infections (SSTI)
and community-acquired pneumonia (CAP).
 It is bacteriostatic drug with high volume of distribution
& Low levels are found in blood, epithelial lining fluid,
and urinary tract. It is not recommended for use in
primary blood stream infections.

79.  Dose : 100 mg loading dose followed by 50mg
BD, 150-200 mg loading dose followed by 75-
100 mg BD in severe MDR/XDR infections/ if
MIC >2
 Valuable drug for
Carbapenemase producing Enterobacteriaceae
(CRE)
Combination regimens for Acinetobacter
Empiric therapy for nosocomial infections in
combination with an anti-pseudomonal agent

80.  Semisynthetic tetracycline derivative
 Active against many MDR strains of Acinetobacter
 CLSI susceptibility breakpoints for minocycline and
Acinetobacter exist, ≤4 µg/mL for susceptible, 8
µg/mL for intermediate, and ≥16 µg/mL for
resistance
 US FDA approved for the treatment of infections
caused by Acinetobacter
 Usual dose 200 mg intravenous load, followed by
100 mg intravenous every 12 h (not to exceed 400
mg in 24 h).
 Renal dosing not required
CID 2014:59 (Suppl 6) • S374

81.  They act at the 30S subunit of the ribosome, interfering
with bacterial protein synthesis.This effect likely
contributes to prevention of emergence of resistance in
combination regimens, as inhibition of protein
synthesis will prevent the over-expression of resistance
mechanisms that depend on protein synthesis.
 Aminoglycosides cause concentration dependent
bacterial killing and have a prolonged post-antibiotic
effect.
 To minimize the impact of adaptive resistance, longer
dosing intervals (i.e., 24 h) are suggested for
aminoglycosides. (IV: 15 mg/kg, higher for MIC >8-16)

82.  Sulbactam clearly has intrinsic activity against
A. baumannii isolates by binding to penicillin-
binding proteins and contributes the major
part of the activity in the combinations with
ampicillin or cefoperazone.
 fT>MIC is the PK/PD index of Sulbactam.
 Dose : 3 g sulbactam every 8 h as 4 h infusion
is recommended over 1gm every 6 hour over
30 min.

83. Ceftazidime+Avibactam
Colistin Aztreonam

86.  New drug approved by FDA , Combination of
cephalosporin and new nonbeta-lactam beta-lactamase
inhibitor
 The addition of avibactam (a novel nonbeta-lactam
beta-lactamase inhibitor) to ceftazidime protects it
fromTEM, SHV, CTX-M, KPC, AmpC, and some OXA-
producing bacteria. It has limited activity in case of
metallo-beta-lactamases.
 The recommended dosage of the drug is 2.5 g iv (2 g/0.5
g) 8 hourly via intravenous infusion over 2 hours for 7
days in cUTI and 4–14 days in cIAIs. Both the
components of the drug are excreted through the
kidney, thereby demanding dose adjustment in renal
insufficiency cases.

87.  It is novel Antibiotic Adjuvant Entity containing a
beta-lactam antibiotic - Ceftriaxone, a beta-
lactamase inhibitor - Sulbactam and an
Antibiotic Resistance Breaker -Disodium EDTA-
37mg.
 It restores the in vitro activity ofCeftriaxone
against ESBL/MBL producing gram-negative
bacteria, including enzyme families that belong
to Ambler class A (TEM, SHV, CTX-M), class B
(NDM,VIM, IMP), class C (some variants of
AmpC), and class D (OXA ESBLs).

89.  Combination of rifampin with colistin and
meropenem/doripenem has demonstrated
synergistic effects against MDR Pseudomonas
spp., Acinetobacter spp., and CRE.
 But it should not be used routinely, specifically
in India in view of high prevalence ofTB.

91.  Colistin / Polymyxin B +Tigecycline
 Use carbapenam with least MIC & highest
possible dose, in prolonged infusion
 Evaluation of following drugs in combination
therapy:
Minocycline
Fosfomycin
Aminoglycoside
Fluroquinolone
Chloramphenicol
Cotrimoxazole

92. MDR Infections
Polymyxins
MIC < 2mg/l MIC > 2mg/l
Polymyxins based Tx
Doripenem/Meropenem
MIC < 8mg/l
MIC > 8mg/l MIC < 4mg/l
If Acinetobacter
Sulbactam
Carbepenem based Tx
Add Doripenem/Meropenem
Tigecycline
MIC < 8mg/l
MIC > 8mg/l
MIC > 1mg/l MIC < 1mg/l
Add Tigecycline
Fosphomycin
MIC > 32mg/l MIC < 32mg/l
Aminoglycoside
Amikacin > 4mg/l
Rifampicin
Add Fosphomycin
MIC < 4mg/l
Doripenem/Meropenem
MIC > 4mg/l
Tigecycline
Add Ampi/Sul or Cefo/Sul

93. Flowchart for selecting mainstream and adjuvant therapy against Gram-negative bacteria.
Expert Rev. Anti Infect.Ther. 11(12), 1333–1353 (2013)

94.  Decisions about duration of antibiotic therapy need to be
individualized, taking into account different variables regarding the
patient (e.g., severity of illness, clinical response), the type of infection
(e.g., source control, deep seated infection [e.g., bone infection], MDR
pathogens) and the availability of diagnostic tools (e.g., clinical/
laboratory scores, biomarker-PCT).
 Longer antibiotic courses are associated with MDR pathogen selection
and spread, increased risks of toxicity, and higher costs, but courses
that are too short risk inadequate bacterial eradication and relapse.
 An 8-day course will likely be more than sufficient in most ICU
patients, and shorter courses may be considered when the source is
controlled. Current guidelines advise a 7–10 day course, unless poor
prognosis predictors are present (e.g., initial clinical failure,
undrainable foci of infection).
 Infections caused by Staphylococcus aureus or Pseudomonas
aeruginosa may require longer courses.

95.  There is no clear PCT cut-off value to decide when to
stop antibiotics, although high values (>1 ng/mL) are
strongly suggestive of active bacterial infection.
 A value <0.5 ng/mL or a decrease >80 % from the
initial value may be used as a threshold value to stop
antibiotics in stable patients.
 This approach has been evaluated in several RCTs. In
the PRORATA trial , which included 621 ICU patients
half of whom had septic shock, patients in whom
antibiotics were started or stopped according to PCT
concentrations had significantly more days without
antibiotics than controls (14.3 versus 11.6, p < 0.001),
without apparent harm.

96.  Rationale: Higher drug concentrations at the site of
the infection while avoiding or minimizing systemic
toxicity & reduced pressure for selection of resistant
organisms
 Technical problems : Large droplets (>5 μm) are more
likely to be trapped in the circuit, whereas smaller
particles (<0.5 μm) are more likely to be expulsed
during expiration, so that the size of the particles
generated should optimally be between 1 and 3 μm.
 Optimizing delivery : HighTidal volume, LongTi &
reduced inspiratory flow. Remove HME during
nebulization.

99.  Combination therapy over monotherapy for sicker patients
(Septic shock/ MODS)
 Carbapenem* based combination therapy if meropenam MIC
<8-16 (*High dose, extended infusion), Else Colistin as
cornerstone drug
 Klebsiella/E.Coli:
 High dose Meropenam+Colistin/Polymyxin+-
Tigecycline/Fosfomycin
 Acinatobacter:
 Colistin/Polymyxin +- Tigecycline/Minocycline + high dose
Sulbactam
 Add Inhaled Colistin 1-2 MUTDS (IfVAP)
 Pseudomonas:
 High dose Meropenam/Aztreonam+Amikacin/Quinolone/Colistin/
Polymyxin
 Add Inhaled Colistin /Tobramycin 300mg BD (IfVAP)
 Add anything else found sensitive (e.g. septran /
Chloramphenicol) in XDR

100.  The set of activities and policies to improve the
rational use of antibiotics.

101.  Infection control
 Source control
 Early & Better Diagnosis (Clinical & Lab)
 Combination therapy
 Antibiotic stewardship : Antibiotics at the
Right choice, Right dose, Right time, Right
duration
Empirical therapy as per local antibiogram
OptimizeTargeted therapy as per Pk-Pd and MIC
De-escalation

102.  Getting MDR/XDR bugs in culture report
doesn’t necessary mean to change/escalate
antibiotic.
 Always correlate clinically (Check colony
count; ForVAP - check xray, fever, secretion
etc; For UTI - check if culture was sent from
old foley’s – likely colonizer)

103.  Treat patient, not onlyTLC/Fever
 Find out source of fever
 Distinguish colonization vs infection
 Send relevant cultures only
 Use your Local Antibiogram
 Treat as per suspected pathogen
 Loading dose irrespective of renal function & optimize
maintainance dosing as per Pk-Pd & MIC
 Use of biomarkers for deescalation
 Cefo-Sulb & Pip-Taz are good empirical antibiotics for
HAIs. Carbapenam for community acquired infections
with septic shock
 Consider combination of drugs carbapenem +
polymyxins+/- tigecycline/minocycline) in empirical
therapy of health care associated sepsis with mods

104.  “Penicillin should only be
used if there is a properly
diagnosed reason
&
if it needs to be used,
use the highest possible
dose for the shortest
time
necessary
Otherwise antibiotic
resistance will develop”

105.  Zavascki, A. P et al. (2013). Combination therapy for carbapenem-resistant Gram-negative bacteria.
Expert review of anti-infective therapy, 11(12), 1333-1353.
 Morrill, Haley J., et al. "Treatment options for carbapenem-resistant Enterobacteriaceae infections."
Open forum infectious diseases. Vol. 2. No. 2. Oxford University Press, 2015.
 Vincent, Jean-Louis, et al. "Advances in antibiotic therapy in the critically ill." Critical Care 20.1 (2016):
133.
 Taneja N, Kaur H. Insights into Newer Antimicrobial Agents Against Gram-negative Bacteria.
Microbiology Insights. 2016;9:9-19. doi:10.4137/MBI.S29459.
 Yamamoto, M., & Pop-Vicas, A. E. (2014).Treatment for infections with carbapenem-resistant
Enterobacteriaceae: what options do we still have? Critical Care, 18(3), 229.
http://doi.org/10.1186/cc13949
 Ruppé, É., Woerther, P.-L., & Barbier, F. (2015). Mechanisms of antimicrobial resistance in Gram-
negative bacilli. Annals of Intensive Care, 5, 21. http://doi.org/10.1186/s13613-015-0061-0
 Nation, R. L., Velkov,T., & Li, J. (2014). Colistin and polymyxin B: peas in a pod, or chalk and cheese?.
Clinical Infectious Diseases, 59(1), 88-94.
 Falagas ME et al. 2016. Fosfomycin. Clin Microbiol Rev 29:321–347
 Michalopoulos, A. S. et al. (2011).The revival of fosfomycin. International journal of infectious
diseases, 15(11), e732-e739.
 Sanford Guide to Antimicrobial Therapy & Johns Hopkins ABX (Antibiotic) Guide
 Apps : Lexicomp, MedScape, Epocrates
 LIFTL : https://lifeinthefastlane.com/
 UpToDate : www.uptodate.com

107. THANK YOU