NEW ANTIBIOTICS, RESISTENT MICRORGANISMS, INFECTIOUS DISEASE, CRITICAL CARE, INTENSIVE CARE

1. AHMED MOHAMMED SARHANAHMED MOHAMMED SARHAN
MSMSCC CRITICAL CARECRITICAL CARE
Superbugs…Where’sSuperbugs…Where’s
The Hope?The Hope?
(2017)(2017)

2. The CASE SCENARIOThe CASE SCENARIO
68 ys old female admitted w respiratory failure,68 ys old female admitted w respiratory failure,
intubated, mechanically ventilated, failure tointubated, mechanically ventilated, failure to
wean, ICU course apart from reintubation,wean, ICU course apart from reintubation,
myocardial ischemia, labelled as failure tomyocardial ischemia, labelled as failure to
wean was almost nothing.wean was almost nothing.

3. SCOPE OF THE PROBLEMSCOPE OF THE PROBLEM

4. June 13, 2016, the Centers for Disease Control and Prevention issued, via the
Health Alert Network,
" Alert to U.S. Healthcare Facilities: First mcr-1 Gene in E. coli
Bacteria found in a Human in the United States ."

5. • A few months ago, a group of Chinese scientists found that many GNB
(Enterobacteriaceae) harbor the plasmid gene mcr-1.
• Before now, these plasmids were more commonly found in pigs and other
animals. (Colistin is often used to treat pigs in Southeast Asia and China).
• A number of publications followed, reporting the same colistin resistance
profile and gene in Europe, Africa, and throughout Southeast Asia. As a
commensal bacteria, it doesn't cause illness in humans [when residing in gut
flora or colonizing skin and mucosal surfaces].
• Mcr-1 colistin resistance has been found in non-ill nursing home residents in
Italy, and as far back as 2008, this resistance has been described in an isolate
of Shigella, which usually is a cause of dysentery, in Vietnam. So although just
reported, colistin resistance has been developing for some time, perhaps
silently, because such bacteria as E coli are rarely tested for colistin resistance.
• Having plasmid as a basis, these bacteria can spread to a whole host of
organisms. Everyone is waiting fearfully until mcr-1 is routinely found in acutely
ill hospitalized patients who are already resistant to other antibiotics.

7. By 2050, resistant bugs (or “superbugs”) are
projected to wipe out 10 million people annually worldwide.

8. The Evolution of Bacteria on a “Mega Plate” Petri Dish _ Harvard Medical School[1].mp4

9. • It has been 30 years since the discovery of a new class of antibiotic that hasIt has been 30 years since the discovery of a new class of antibiotic that has
hit the market. The longer an antibiotic is in use, the more time bacteriahit the market. The longer an antibiotic is in use, the more time bacteria
have to develop resistance to it.have to develop resistance to it.
• Thirty-seven antibiotics are currently undergoing clinical trials.Thirty-seven antibiotics are currently undergoing clinical trials.
Further, most new drugs target Gram-positive bacteria, that includesFurther, most new drugs target Gram-positive bacteria, that includes
superbug methicillin-resistant Staphylococcus aureus (MRSA). But recently,superbug methicillin-resistant Staphylococcus aureus (MRSA). But recently,
the main emerging threats have come from Gram negatives, which arethe main emerging threats have come from Gram negatives, which are
harder to treat.harder to treat.

10. WHAT IF THIS IS AN INFECTIONWHAT IF THIS IS AN INFECTION
NOT A COLONIZATION ?NOT A COLONIZATION ?

13. • New AntimicrobialsNew Antimicrobials
• Here we outline some recent anti-infectives that are about to becomeHere we outline some recent anti-infectives that are about to become
available or are available for treatment and their potential uses in theavailable or are available for treatment and their potential uses in the
intensive care setting.intensive care setting.
1.1. New CephalosporinsNew Cephalosporins
 MRSA evades the antibacterial action of beta-lactams by producing aMRSA evades the antibacterial action of beta-lactams by producing a
modified PBPmodified PBP. Beta-lactams currently in use do not bind to PBP2a of. Beta-lactams currently in use do not bind to PBP2a of MRSA.MRSA.
However, two new cephalosporins have been developed that bypass thisHowever, two new cephalosporins have been developed that bypass this
obstruction by binding well to all PBPs: ceftaroline and ceftobiprole.obstruction by binding well to all PBPs: ceftaroline and ceftobiprole.
 Their pharmacokineticTheir pharmacokinetic (PK)/pharmacodynamic (PD) and adverse event(PK)/pharmacodynamic (PD) and adverse event
profiles resemble those of other cephalosporins that are in common clinicalprofiles resemble those of other cephalosporins that are in common clinical
use.use.

14. .
1-A Ceftaroline (ceftaroline fosamil)
 Broad in vitro activity against Gram-positive bacteria.
 It has similar efficacy to vancomycin for MRSA. It is active against penicillin-
resistant Streptococcus pneumonia, CONS and has some activity against
enterococci ( E. faecalis ), unlike other cephalosporins.
 It is inactive against Pseudomonas aeruginosa , Acinetobacter baumannii
and ESBL.
 Ceftaroline is administered twice daily and dose adjustment for renal failure
is required.
Ceftaroline has been evaluated in 2 RCT for skin/soft tissue infections against
vancomycin, demonstrating non-inferiority.
 Similarly, two trials were concluded comparing ceftaroline to ceftriaxone for
CAP, showing a slightly higher clinical cure rate.
 It has been recently approved by the FDA for these indications. The two
studies excluded patients admitted to the ICU.

15. 1-B Ceftobiprole1-B Ceftobiprole
 active against MRSA,active against MRSA, S. pneumoniae and E. faecalis . Its spectrum ofS. pneumoniae and E. faecalis . Its spectrum of
activity against Gram-negativeactivity against Gram-negative bacteria resembles ceftazidime and cefepimebacteria resembles ceftazidime and cefepime
(i.e. covering(i.e. covering P. aeruginosa ).P. aeruginosa ).
 2 RCT comparing ceftobiprole to vancomycin or vancomycin and2 RCT comparing ceftobiprole to vancomycin or vancomycin and
ceftazidime for skin/soft tissue infections showed comparable efficacy.ceftazidime for skin/soft tissue infections showed comparable efficacy.
 Ceftobiprole is approved in Canada and Switzerland for the treatment ofCeftobiprole is approved in Canada and Switzerland for the treatment of
skin/soft tissue infections, but has not received approval by Europeanskin/soft tissue infections, but has not received approval by European
Medicines Agency (EMA) or the Food and Drugs Agency (FDA) in the USAMedicines Agency (EMA) or the Food and Drugs Agency (FDA) in the USA
pending conduct of further randomized controlled trials.pending conduct of further randomized controlled trials.

16. 2- New lipoglycopeptides
 Include telavancin, dalbavancin and oritavancin. They are active against
Gram-positive bacteria, including MRSA, S. pneumoniae , vancomycin-
susceptible enterococci .
 Oritavancin has a broader spectrum of anti-Gram-positive activity,
covering VRSA. and C. difficile .
 All are highly protein-bound and only the free drug is active. Penetration
into the lungs is adequate for the treatment of pneumonia, while
cerebrospinal fluid (CSF) penetration is poor.
 The lipoglycopeptides are remarkable for their prolonged half-lives and
their activity is concentration dependant, compatible with infrequent
dosing.
• Oritavancin has the longest half life (393 h) and can thus be
administered as a single dose for a complete treatment course.
• Dalbavancin is administered once weekly
• Telavancin is once daily.

17.  Dose adjustment for renal failure
1.Telavancin elimination is renal, so dose adjustment is required.
2.Dalbavancin no dosage adjustment is necessary for renal failure, except for
(crcl <30 without hemodialysis).
3.Oritavancin no dosage adjustment is necessary for renal failure.
 EFFICACY
1.Telavancin is comparable to vancomycin for skin/soft tissue infections and
HAP. Patients with VAP have been included in the trials assessing pneumonia
(about 30 % of patients, 427 patients).
A few articles reviewing those two trials have been published over the last 2
years, re-emphasizing the concept that telavancin remains an alternative agent
for the treatment of MRSA nosocomial pneumonia.
Telavancin has not been evaluated for the treatment of CAP.

18. 2. Dalbavancin is comparable to (vancomycin, cefazolin, linezolid) in skin/soft
tissue infections and achieved higher clinical and microbiological cure rates
for catheter-related bloodstream infections caused by Gram-positive
bacteria in two once-weekly doses.
3. Oritavancin was comparable to vancomycin plus a first generation
cephalosporin for skin/soft tissue infections and to vancomycin for MRSA
bloodstream infection .
Of the three drugs, only telavancin is currently FDA-approved for clinical use.

19. 3- Lipopeptide (Daptomycin)3- Lipopeptide (Daptomycin)
 Daptomycin was discovered in the late 1980s, but development wasDaptomycin was discovered in the late 1980s, but development was
stopped when small studies in healthy volunteers showed a high rate ofstopped when small studies in healthy volunteers showed a high rate of
musculoskeletal system adverse events with accompanying increases inmusculoskeletal system adverse events with accompanying increases in
(CPK) levels.(CPK) levels.
 A decade or more later, a different pharmaceutical company discoveredA decade or more later, a different pharmaceutical company discovered
the simple fact that daptomycin toxicity was related to the frequency ofthe simple fact that daptomycin toxicity was related to the frequency of
administration. Once daily administration, even at high doses, wasadministration. Once daily administration, even at high doses, was
associated with a lower risk of CPK elevation. Following its approval inassociated with a lower risk of CPK elevation. Following its approval in
2003, daptomycin has been financially the most successful IV antibiotic in2003, daptomycin has been financially the most successful IV antibiotic in
US history.US history.
 Daptomycin is a cyclic lipopeptide, whose mode of action is probablyDaptomycin is a cyclic lipopeptide, whose mode of action is probably
related to bacterial membrane depolarization. Its activity is bactericidal,related to bacterial membrane depolarization. Its activity is bactericidal,
broad-spectrum of activity against Gram-positive bacteria including MRSA,broad-spectrum of activity against Gram-positive bacteria including MRSA,
E. faecium and VRE.E. faecium and VRE.
• skskin/soft tissue infectionsin/soft tissue infections
• bloodstream infection, including right-sided endocarditisbloodstream infection, including right-sided endocarditis

20. • Penetration into the lung parenchyma and CSF is poor, thus the drug is notPenetration into the lung parenchyma and CSF is poor, thus the drug is not
indicated for pneumonia and meningitis.indicated for pneumonia and meningitis.
• Daptomycin is approved for use at once daily dosing of 6 mg/kg forDaptomycin is approved for use at once daily dosing of 6 mg/kg for
bloodstream infection and 4 mg/kg for other infections.bloodstream infection and 4 mg/kg for other infections.
• It is eliminated mainly through the urine and dose adjustment for renalIt is eliminated mainly through the urine and dose adjustment for renal
failure is required.failure is required.
• Weekly CPK monitoring is recommended; post-marketing surveillance hasWeekly CPK monitoring is recommended; post-marketing surveillance has
shown a 2.5 % rate of CPK elevation.shown a 2.5 % rate of CPK elevation.

21. 4- Quinupristin-Dalfopristin4- Quinupristin-Dalfopristin
 Combination of two streptograminsCombination of two streptogramins
 Mode of action is also protein synthesis inhibition,Mode of action is also protein synthesis inhibition,
 Its antimicrobial spectrum includes most Gram-positive bacteria, includingIts antimicrobial spectrum includes most Gram-positive bacteria, including
MRSA, with the notable exception ofMRSA, with the notable exception of E. faecalis , E. faecium.E. faecalis , E. faecium.
 It does not penetrate well into the CSF, peritoneal fluid and cardiacIt does not penetrate well into the CSF, peritoneal fluid and cardiac
vegetations, precluding its efficacy for these sites of infection. Forvegetations, precluding its efficacy for these sites of infection. For
pneumonia, clinical and microbiological efficacy has been poorer thanpneumonia, clinical and microbiological efficacy has been poorer than
comparator antibiotics in clinical trials.comparator antibiotics in clinical trials.
 The agents produce significant inhibition of cytochrome P-450 with theThe agents produce significant inhibition of cytochrome P-450 with the
attendant effects on drugs metabolized through it. Its main adverse effectsattendant effects on drugs metabolized through it. Its main adverse effects
are phlebitis if administered through a peripheral vein (>30 %).are phlebitis if administered through a peripheral vein (>30 %).

22. GRAM NEGATIVE INFECTIONS

23. 1. Doripenem
 Newest available carbapenem, similar to imipenem and meropenem in its
spectrum of activity.
 It has been tested in RCT for intra-abdominal infections, UTI, hospital-acquired
and VAP, showing non-inferiority vs. (levofloxacin, piperacillin-tazobactam,
meropenem and imipenem).
There is interest in its role in the treatment of patients with cystic fibrosis because it
has lower MICs than imipenem or meropenem for P. aeruginosa (and thus
enhanced potency), but clinical data are as yet lacking.
No data on penetration of doripenem into CSF, but penetration to other sites is similar
to that of other carbapenems.
Its adverse effects profile is also similar, but with a lower risk for seizures compared
with imipenem.
administered thrice daily as 1-h infusions with dosage adjustment required for renal
failure.

24. 2- Glycyclines (Tigecycline)2- Glycyclines (Tigecycline)
structurally related to tetracyclines and similarly act through inhibition of protein
synthesis and are bacteriostatic.
It has broad activity against Gram-positive bacteria (including MRSA and VRE),
atypical, MDR GNB (Acinetobacter baumannii and carbapenem-resistant K.
Pneumonia), Anaerobes.
Tigecycline is not active against Pseudomonas aeruginosa and Proteus sp.,
Providencia spp.).
Tigecycline is a lipophylic antibiotic with good tissue penetration. Thus,
antibiotic levels in the lung for example are higher than those found in blood
It is primarily eliminated by biliary excretion and clearance may be reduced withexcretion and clearance may be reduced with
cholestasis. No dose modifications are necessary for renal failure.cholestasis. No dose modifications are necessary for renal failure.
however, (FDA) has issued a warning regarding its use because of increasedhowever, (FDA) has issued a warning regarding its use because of increased
mortality with tigecycline. In 15 randomized controlled trials comparingmortality with tigecycline. In 15 randomized controlled trials comparing
tigecycline to other antibiotics for a variety of infections (mainly complicatedtigecycline to other antibiotics for a variety of infections (mainly complicated
skin/soft tissue and intra-abdominal infections) all-cause mortality wasskin/soft tissue and intra-abdominal infections) all-cause mortality was
higher with tigecycline. Poor outcomes have also been observed with use ofhigher with tigecycline. Poor outcomes have also been observed with use of
tigecycline for infections caused by MDR Gram-negative bacteria andtigecycline for infections caused by MDR Gram-negative bacteria and
resistance development during therapy. Tigecycline should be reserved asresistance development during therapy. Tigecycline should be reserved as
drug of last resort in the treatment of severe infections caused by GNB.drug of last resort in the treatment of severe infections caused by GNB.

25. 3- Colistin
 a revival of several old antibiotics, including polymyxins.
mechanism of action is on the bacterial cell membrane, leadin (bactericidal).
 pro-drug (colistimethate sodium) that is converted in-vivo to active colistin.
 Colistin is active against Gram-negative bacteria, except Proteus spp.,
Providencia spp., and Serratia spp. It has no activity against GP bacteria.
 Emerging PK/PD data indicate that doses above 9 MIU/day are needed to
achieve serum levels above 2 mg/L, which is the MIC breakpoint for
Acinetobacter spp., and Enterobacteriaceae.
It might also take up to 60 h for colistin to reach this level in critically-ill
patients. Therefore, a loading dose equivalent to the total daily dose is
recommended in critically-ill patients.
CSF penetration is poor and intra-thecal administration is possible in case of
MDR gram-negative meningitis.
Colistin should be reserved for the treatment of carbapenem-resistant
bacteria where no other treatment options exist.

26. AntifungalsAntifungals
AzolesAzoles
provide a safe treatment option for the prevention and treatment ofprovide a safe treatment option for the prevention and treatment of CandidaCandida
spp. infections.spp. infections.
• Fluconazole, isFluconazole, is active againstactive against Candida sp. with the exception of C. cruseiCandida sp. with the exception of C. crusei
and some C. glabrataand some C. glabrata Isolates.Isolates.
• Voriconazole is activeagainst allVoriconazole is activeagainst all Candida spp. and AspergillusCandida spp. and Aspergillus spp.spp.
Both fluconazole and voriconazole are available as well-absorbed oral andBoth fluconazole and voriconazole are available as well-absorbed oral and
intravenous formulations. The intravenous formulation of voriconazole isintravenous formulations. The intravenous formulation of voriconazole is
complexed to a cyclodextrin molecule and is not recommended for use withcomplexed to a cyclodextrin molecule and is not recommended for use with
creatinine clearance <50 mL/ min due to accumulation of cyclodextrin.creatinine clearance <50 mL/ min due to accumulation of cyclodextrin.
• posaconazole, The newest azole entering clinical use whose spectrum ofposaconazole, The newest azole entering clinical use whose spectrum of
coverage includescoverage includes Candida spp., Aspergillus spp. and zygomycetes. It isCandida spp., Aspergillus spp. and zygomycetes. It is
available only in an oral solution. Absorption is optimal when administeredavailable only in an oral solution. Absorption is optimal when administered
during or after a meal and with acidic gastric pH.during or after a meal and with acidic gastric pH.
• Izavuconazole is currently being tested in phase 3 trials. It has a spectrum ofIzavuconazole is currently being tested in phase 3 trials. It has a spectrum of
coverage similar to or broader than that of posaconazole, with thecoverage similar to or broader than that of posaconazole, with the
advantage or both oral and intravenous formulations.advantage or both oral and intravenous formulations.

27. EchinocandinsEchinocandins
• Echinocandins target the fungal cell wall. They inhibit the synthesis of 1,3Echinocandins target the fungal cell wall. They inhibit the synthesis of 1,3
beta D-glucan, leading to cell rupture and death.beta D-glucan, leading to cell rupture and death.
• They are active against all Candida sppThey are active against all Candida spp. and are not active against. and are not active against
mucormycosis.mucormycosis.
• The 3 echinocandins currently available are caspofungin, anidulafungin andThe 3 echinocandins currently available are caspofungin, anidulafungin and
micafungin.micafungin.
• administration through a central line is required to prevent thrombophlebitis.administration through a central line is required to prevent thrombophlebitis.
They areThey are eliminated in bileeliminated in bile or hepatic metabolism. No dose adjustment foror hepatic metabolism. No dose adjustment for
renal failure and only caspofungin requires adjustment with liver dysfunction.renal failure and only caspofungin requires adjustment with liver dysfunction.
• Tissue penetration is generally good, except for the CNS and the eye, anTissue penetration is generally good, except for the CNS and the eye, an
important issue to remember with candida retinitis.important issue to remember with candida retinitis.
• Little is currently known about antifungal drug combinations. CombinationsLittle is currently known about antifungal drug combinations. Combinations
used as salvage therapy include an echinocandin with either an azole orused as salvage therapy include an echinocandin with either an azole or
amphotericin, given the different targets of these drug classes.amphotericin, given the different targets of these drug classes.

28. Continuous Versus Bolus Antibiotic Administration
The pharmacodynamic properties of an antibiotic determine whether its
principal mode of activity is
1.concentration-dependent (where greater inhibition of bacteria occur with
higher antibiotic concentrations) or
2.time-dependent (where inhibition of bacteria mandates antibiotic levels above
the minimal inhibitory concentration of the antibiotic, but improved killing is not
achieved with higher concentrations)
The measure of antibiotic efficacy for concentration-dependent antibiotic is the
ratio between (C max /MIC),
while for time-dependent antibiotics, it is the time above MIC.

30. In addition, a drug may have post-antibiotic effects (PAE), where the inhibitory
effect on bacteria persists after antibiotic concentrations have fallen below
the MIC. PAE is characteristic of antibiotics whose mode of activity is
primarily concentration-dependent (aminoglycosides, quinolones).

31. Concentration-dependent activity and long PAEs support bolus antibiotic
administration of high doses with extended intervals. Continuous antibiotic
administration might be beneficial when antibiotic activity is primarily time
dependent.
Observational studies suggest an association between continuous intravenous
beta-lactam (classically time-dependent antibiotics) administration and
improved survival. Randomized controlled trials have not shown improvement
in cure rates or survival with continuous intravenous infusion of beta-lactams,
but nearly all existent trials used lower antibiotics doses in the continuous
infusion arm compared to the bolus arm.
Once-daily dosing of aminoglycosides is supported by their concentration
dependent activity and PAE. Several systematic reviews have assessed the
efficacy and toxicity of once-daily aminoglycoside dosing compared with
multiple-daily dosing. Generally, the findings indicate similar or higher rates of
clinical success, similar or lower rates of nephrotoxicity and no significant
differences with regard to microbiological failure and morality.
However, current guidelines recommend multiple-daily aminoglycoside dosing
for staphylococcal endocarditis.

32. •ANTIBIOTICS UNDER TRIALS
•Teixobactin
In January 2015, a collaboration of 4 institutes in the US and Germany reported
that they had isolated a new antibiotic, killing "without detectable resistance.
Represent a new class of antibiotics, raising hopes that the new isolation
techniques employed could lead to further antibiotic discoveries.
Mechanism of action
Teixobactin is an inhibitor of cell wall synthesis that acts primarily by binding
to lipid II, a fatty molecule which is a precursor to peptidoglycan.
Activity
Teixobactin was reported to be potent in vitro against all
gram-positive bacteria tested, including Staphylococcus aureus and
enterococci, with Clostridium difficile. It also killed Mycobacterium TB.

33. It is not active against bacteria with an outer membrane such as gram negative
pathogens, particularly carbapenem resistant enterobacteriaceae.
Induction of resistance
No resistant strain of S. aureus or M. tuberculosis was generated in vitro when
administering sublethal doses, for as long as 27 days.
It is postulated that teixobactin is more robust against mutation of the target
pathogens, because of its unusual antibiotic mechanism of binding to less
mutable fatty molecules rather than binding to relatively mutable proteins in the
bacterial cell.
However, several scientists caution that it is too early to conclude that
teixobactin resistance would not develop in the clinical setting. Similar claims
were made for vancomycin, yet resistance emerged soon after large-scale use
in the 1980s. It is possible that genes encoding resistance to teixobactin are
already present in soil bacteria. Resistance could also arise by mutation after
prolonged use in patients.
In early 2015, human clinical trials of teixobactin were predicted to be at least
two years away.

34. THANKTHANK
YOUYOU