AHMED MOHAMMED SARHANAHMED MOHAMMED SARHAN

MSMSCC CRITICAL CARE CRITICAL CARE

Superbugs…Where’s Superbugs…Where’s The Hope?The Hope?

(2017)(2017)

The CASE SCENARIOThe CASE SCENARIO68 ys old female admitted w respiratory failure, 68 ys old female admitted w respiratory failure,

intubated, mechanically ventilated, failure to intubated, mechanically ventilated, failure to wean, ICU course apart from reintubation, wean, ICU course apart from reintubation, myocardial ischemia, labelled as failure to myocardial ischemia, labelled as failure to

wean was almost nothing.wean was almost nothing.

SCOPE OF THE PROBLEMSCOPE OF THE PROBLEM

 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. coliBacteria found in a Human in the United States ."

•           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.

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

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

• It has been 30 years since the discovery of a new class of antibiotic that has It 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 bacteria hit 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 includes Further, 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 are the main emerging threats have come from Gram negatives, which are harder to treat.harder to treat.

WHAT IF THIS IS AN INFECTION WHAT IF THIS IS AN INFECTION NOT A COLONIZATION ? NOT A COLONIZATION ?

• New AntimicrobialsNew Antimicrobials• Here we outline some recent anti-infectives that are about to become Here we outline some recent anti-infectives that are about to become

available or are available for treatment and their potential uses in the available 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 a MRSA 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 this However, 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 pharmacokinetic Their pharmacokinetic (PK)/pharmacodynamic (PD) and adverse event (PK)/pharmacodynamic (PD) and adverse event profiles resemble those of other cephalosporins that are in common clinical profiles resemble those of other cephalosporins that are in common clinical

use.use.

.

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.

1-B Ceftobiprole1-B Ceftobiprole

active against MRSA, active against MRSA, S. pneumoniae and E. faecalis . Its spectrum of S. pneumoniae and E. faecalis . Its spectrum of activity against Gram-negative activity against Gram-negative bacteria resembles ceftazidime and cefepime bacteria resembles ceftazidime and cefepime (i.e. covering (i.e. covering P. aeruginosa ). P. aeruginosa ).

2 RCT comparing ceftobiprole to vancomycin or vancomycin and 2 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 of Ceftobiprole is approved in Canada and Switzerland for the treatment of

skin/soft tissue infections, but has not received approval by European skin/soft tissue infections, but has not received approval by European Medicines Agency (EMA) or the Food and Drugs Agency (FDA) in the USA Medicines 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.

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.

Dose adjustment for renal failure1.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.

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.

3- Lipopeptide (Daptomycin)3- Lipopeptide (Daptomycin)

Daptomycin was discovered in the late 1980s, but development was Daptomycin was discovered in the late 1980s, but development was stopped when small studies in healthy volunteers showed a high rate of stopped when small studies in healthy volunteers showed a high rate of musculoskeletal system adverse events with accompanying increases in musculoskeletal system adverse events with accompanying increases in (CPK) levels.(CPK) levels.

A decade or more later, a different pharmaceutical company discovered A decade or more later, a different pharmaceutical company discovered the simple fact that daptomycin toxicity was related to the frequency of the simple fact that daptomycin toxicity was related to the frequency of administration. Once daily administration, even at high doses, was administration. Once daily administration, even at high doses, was associated with a lower risk of CPK elevation. Following its approval in associated with a lower risk of CPK elevation. Following its approval in 2003, daptomycin has been financially the most successful IV antibiotic in 2003, daptomycin has been financially the most successful IV antibiotic in US history.US history.

Daptomycin is a cyclic lipopeptide, whose mode of action is probably Daptomycin 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 infections in/soft tissue infections • bloodstream infection, including right-sided endocarditisbloodstream infection, including right-sided endocarditis

• Penetration into the lung parenchyma and CSF is poor, thus the drug is not Penetration 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 for Daptomycin 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 renal It 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 has Weekly CPK monitoring is recommended; post-marketing surveillance has shown a 2.5 % rate of CPK elevation.shown a 2.5 % rate of CPK elevation.

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, including Its antimicrobial spectrum includes most Gram-positive bacteria, including MRSA, with the notable exception of MRSA, with the notable exception of E. faecalis , E. faecium. E. faecalis , E. faecium.

It does not penetrate well into the CSF, peritoneal fluid and cardiac It does not penetrate well into the CSF, peritoneal fluid and cardiac vegetations, precluding its efficacy for these sites of infection. For vegetations, precluding its efficacy for these sites of infection. For pneumonia, clinical and microbiological efficacy has been poorer than pneumonia, 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 the The agents produce significant inhibition of cytochrome P-450 with the attendant effects on drugs metabolized through it. Its main adverse effects attendant 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 %).

GRAM NEGATIVE INFECTIONS

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.

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 with excretion 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 increased however, (FDA) has issued a warning regarding its use because of increased mortality with tigecycline. In 15 randomized controlled trials comparing mortality with tigecycline. In 15 randomized controlled trials comparing tigecycline to other antibiotics for a variety of infections (mainly complicated tigecycline to other antibiotics for a variety of infections (mainly complicated skin/soft tissue and intra-abdominal infections) all-cause mortality was skin/soft tissue and intra-abdominal infections) all-cause mortality was higher with tigecycline. Poor outcomes have also been observed with use of higher with tigecycline. Poor outcomes have also been observed with use of tigecycline for infections caused by MDR Gram-negative bacteria and tigecycline for infections caused by MDR Gram-negative bacteria and resistance development during therapy. Tigecycline should be reserved as resistance 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.

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.

AntifungalsAntifungalsAzolesAzolesprovide a safe treatment option for the prevention and treatment of provide a safe treatment option for the prevention and treatment of Candida Candida

spp. infections. spp. infections. • Fluconazole, is Fluconazole, is active against active against Candida sp. with the exception of C. crusei Candida sp. with the exception of C. crusei

and some C. glabrata and some C. glabrata Isolates. Isolates. • Voriconazole is activeagainst all Voriconazole is activeagainst all Candida spp. and Aspergillus Candida spp. and Aspergillus spp. spp. Both fluconazole and voriconazole are available as well-absorbed oral and Both fluconazole and voriconazole are available as well-absorbed oral and

intravenous formulations. The intravenous formulation of voriconazole is intravenous formulations. The intravenous formulation of voriconazole is complexed to a cyclodextrin molecule and is not recommended for use with complexed 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 of posaconazole, The newest azole entering clinical use whose spectrum of coverage includes coverage includes Candida spp., Aspergillus spp. and zygomycetes. It is Candida spp., Aspergillus spp. and zygomycetes. It is available only in an oral solution. Absorption is optimal when administered available 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 of Izavuconazole is currently being tested in phase 3 trials. It has a spectrum of coverage similar to or broader than that of posaconazole, with the coverage similar to or broader than that of posaconazole, with the advantage or both oral and intravenous formulations.advantage or both oral and intravenous formulations.

EchinocandinsEchinocandins

• Echinocandins target the fungal cell wall. They inhibit the synthesis of 1,3 Echinocandins 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 and The 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 are They are eliminated in bile eliminated in bile or hepatic metabolism. No dose adjustment for or 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, an Tissue 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. Combinations Little is currently known about antifungal drug combinations. Combinations used as salvage therapy include an echinocandin with either an azole or used 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.

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.

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).

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.

•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 actionTeixobactin is an inhibitor of cell wall synthesis that acts primarily by binding

to lipid II, a fatty molecule which is a precursor to peptidoglycan.

ActivityTeixobactin 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.

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.

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