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Skip to 0 minutes and 7 secondsWhich antibiotic would you use? In this case, Vincent has a ventilator-associated pneumonia caused by a multi-drug resistance, Pseudomonas aeruginosa. The antibiogram shows multi-drug resistance to fluoroquinolones, such as levofloxacin and ciprofloxacin, which is not shown. It's resistant to cephalosporins like cefepime, resistance to beta-lactams like piperacillin/tazobactam, is resistant to aztreonam meropenem, and it's only susceptible to tobramycin and polymyxins like colistin or polymyxin B. So what are our choices? The first choice that we would usually select to treat a pseudomonas pneumonia would be cefepime. However, in this case, this organism is resistant. Cefepime is an antibiotic that has a broad spectrum of antimicrobial therapy, including anti-pseudomonal activities. Unfortunately, not an option in Vincent's case.

Skip to 1 minute and 3 secondsThe next drug that we would typically use would be piperacillin/tazobactam. It has a similar antimicrobial spectrum to cefepime, but it also is active against anaerobes and enterococcus. Therefore, has a broader spectrum that we actually need in a ventilator-associated pneumonia case. However, in this case, the organism is also resistant. Carbapenems, such as meropenem, are drugs with a very broad spectrum of activity, including also anti-pseudomonal activity. Unfortunately, in this case, the organism is also resistant to meropenem. Therefore, not an option.

Skip to 1 minute and 44 secondsColistin and polymyxin. As part of the empirical treatment in severe infections in many countries, we have to select drugs that were repurposed-- that were created many decades ago and then were stocked on a shelf, such as colistin and polymyxin B. These drugs were reserved for the treatment of multi-drug-resistant organisms, such as pseudomonas, acinetobacter, and sometimes enterobacteriaceae. Colistin acts more like a detergent to wash off the cell membrane of the organisms, and most of the time we recommend using it in combination with another agent to avoid the development of resistance.

Skip to 2 minutes and 23 secondsThe dosing of colistin in critically ill patients is a loading dose of 9 milliunits followed by a maintenance dose of 4.5 MUs twice daily, if the creatinine clearance is greater than 50. If the patient has renal insufficiency, the dose has to be adjusted based on the creatinine clearance. The loading dose is not always indicated in non-critically ill patients because there isn't enough evidence. However, in clinical practice we do recommend, both in critically ill and non-critically ill, to consider using a loading dose based on the kinetics of the drug. The next agent that we could consider in some countries is fosfomycin. With fosfomycin, there is limited experience for the treatment of severe infections caused by carbapenem-resistant organisms and carbapenem-resistant pseudomonas.

Skip to 3 minutes and 19 secondsIt has no activity against acinetobacter, and its activity against pseudomonas is limited. Therefore, if you were to use this drug, it has to be used in combination with another effective agent and not as monotherapy. We recommend to consider using fosfomycin in patients with limited, very limited, or no therapeutic alternatives. And again, it should be used with one or two active agents. The dosing is 4 to 6 grammes intravenously four times a day, or 8 grammes intravenously three times daily. In some countries, this drug is yet only available as an oral option. You should never use it as monotherapy for complicated infections such as pneumonia, and the oral formulation is approved to treat uncomplicated urinary tract infections.

Skip to 4 minutes and 12 secondsIntravenous and oral formulations sometimes are used in serious cases with extreme drug-resistant organisms-- like in this case it's pneumonia, but also in osteomyelitis and bacteremia.

Skip to 4 minutes and 26 secondsSelecting antimicrobials to treat severe infections caused by other carbapenem-resistant organisms. If you were to choose a drug, you really need to think of what is the MIC or microbiological activity-- the minimum inhibitory concentration to kill this drug-- what is the toxicity profile, and what is the source of infection? And based on that, we recommend different priorities course, and it also need to consider the country where you live, where you practice, and the local antibiograms and susceptibilities in the population that you're treating. Treating a patient in the United Kingdom might differ completely from treating a patient in Spain, in the United States, or in a Latin American country.

Skip to 5 minutes and 10 secondsFor example, on the left side of this column, we have respiratory, intra-abdominal, urinary, or a catheter or primary bacteremias. And then on your right-hand side, we're going to see the regimens based on your first through your fifth priority according to their source of infection, and the area where you practice. In the case of respiratory infections, we would like to recommend that if you're dealing with a carbapenem-resistant organisms, you may want to choose a carbapenem in combination with another agent. In some countries, we already have the new cephalosporins with their carbapenem ACE inhibitors, and those would be excellent choices in the patients that have multi-drug resistant organisms.

Skip to 5 minutes and 54 secondsUnfortunately, not everywhere around the globe has the capacity to have access to these newer, highly effective, but very expensive agents. If you're dealing with an intra-abdominal source, you may also want to consider, instead of a carbapenem-- if you can use a carbapenem-sparing agent-- perhaps tigecycline in combination with another agent, if necessary. If the source is urinary, aminoglycosides might be an effective option-- always if the patient does not have renal insufficiency or a contraindication to the use of aminoglycoside. Fosfomycin could be an effective option in the case of uncomplicated urinary tract infections to spare the use of carbapenems and to spare the use of aminoglycosides or colistin.

Skip to 6 minutes and 37 secondsIf you looked at the fifth column in this slide, tigecycline is reserved as your last resort antibiotic for the treatment of urinary or a catheter-related bloodstream infection. The reason is that tigecycline has very poor concentration in urine and in blood or serum. Therefore, you should not use this agent as first-line therapy when dealing with primary bacteremias or urinary tract infections. Moving on to our next slide. There are some new antibiotics and antimicrobial combination therapies that are effective for the treatment of gram-negative bacterial infections. Some of the new antimicrobials include cephalosporins. We have ceftolozane/tazobactam. Ceftolozane looks like ceftazidime with a side chain. It has enhanced anti-pseudomonal activity, and it's eight times more potent and active than doripenem.

Skip to 7 minutes and 27 secondsIt has activity against extended spectrum beta-lactamases and AmpC metallo-lactamases. Therefore, this is an excellent option for multi-drug-resistant organisms. We recommend to prioritise the use of ceftolozane/tazobactam for the use of pseudomonas resistant to carbapenems and leaving it as a second choice for enterobacteriaceae. It's important to remember that it has no activity against the class B carbapenemases. Currently in phase 3 on 4 trials, it's superior to levofloxacin for complicated catheter-associated urinary tract infections, and non-inferior to meropenem plus metronidazole for complicated intra-abdominal infections. Ceftolozane/tazobactam has no anaerobic activity. Therefore, if you're going to use this agent to treat anaerobes in combination with a carbapenem-resistant organism such as pseudomonas, remember to add anaerobic activity.

Skip to 8 minutes and 23 secondsIn the case of Vincent, which we presented before, you do not need anti-anaerobic activity. This drug was approved by the FDA in the United States in December 2014, and it's available for use. Other new antimicrobials include beta-lactamase inhibitors, such as ceftazidime/avibactam, or TAZ-AVI. Ceftazidime/avibactam combines a combination of ceftazidime with a potent beta-lactamase inhibitor, which is avibactam. This drug has activity against ESBLs, AmpCs, KPCs, and OXA-48. It is non-inferior in the treatment of complicated UTIs and complicated intra-abdominal infections, and was approved by the FDA in the United States in 2015. And it's available in Europe as of March of this year, at least in the United Kingdom. It may vary by country.

Skip to 9 minutes and 14 secondsIt is not active against the metallo-beta-lactamases, and it's extremely important to remember that if you're treating a New Delhi metallo- lactamase-- an NDM-- this drug will not be active by itself. The next agent that is coming up but it's not yet available is ceftaroline plus avibactam. Ceftaroline is a drug that has a very potent spectrum of activities, such ceftriaxone, but also has activity against MRSA. The combination with avibactam even provides further spectrum of activity against ESBLs, AmpC, KPCs, and maybe OXA-48s. It is not active against non-fermenters, such as pseudomonas and Acinetobacter baumannii. Therefore, this drug will not be suitable for our patient, Vincent. This drug is yet not available, and it's in phase 3 clinical trials.

Skip to 10 minutes and 7 secondsThe last drug that we are going to talk about today is aztreonam plus avibactam. This drug will have activity against KPCs and some of the class D OXA-48s. But it's hydrolyzed by the class A ESBLs and AmpC. It's also in phase 2 and phase 3 clinical trials. It may have activity against pseudomonas. Back to the case. So the treatment options that we have in the case like Vincent are becoming a major challenge globally. Intravenous aminoglycoside or colistin in combination with a beta-lactam antibiotic could be an option. And in this case, we would prefer to use the new beta-lactamase inhibitors.

Skip to 10 minutes and 49 secondsThe microbiology lab should test susceptibilities to ceftolozane/tazobactam as it could be the most effective option in combination with either the aminoglycoside or colistin or polymyxin. If ceftolozane/tazobactam is not available, then we would recommend to use agents like fosfomycin or ceftazidime/avibactam, which could be combined and considered if susceptible, in combination, perhaps, with other agents, such as colistin or aminoglycosides. What if you don't have any of these drugs available? Well, then you're in trouble. So you may want to use colistin in combination with a carbapenem. And again, it would all depend of what is the minimum inhibitory concentration of the carbapenem.

Skip to 11 minutes and 31 secondsIf the MIC is less than 8, you can probably continue to use a carbapenem in combination with colistin or an aminoglycoside and try to overcome that resistant by doing extended or continuous infusion of the carbapenem. If the carbapenem has MIC greater than 8, it is unlikely that you will be able to overcome that mechanism of resistant. Yet it might be better than using colistin monotherapy.

Choosing an antibiotic for Vincent

In this video Dr Lilian Abbo discusses the antibiotic treatment options for Vincent.

Please watch the video and then consider the duration of therapy for Vincent:

  1. 3 days
  2. 5 days
  3. 8 days
  4. 14 days
  5. 21 days

There are no standardised studies on the duration of treatment for VAP for carbapenem resistant pseudomonas, but clinically we extrapolate from studies with more susceptible bacteria.

An article by Chastre:

 Graph with x axis "Probability of survival 0 - 1.0, y axis "Days after bronchoscopy" 0 -60.  Two tracked lines of data representing antibiotic regimen of 8 days or 15 days.  Data shows slightly better survival with 8 day regimen

provides this data:

Alt text

  • Same probability of survival after 60 days

  • Mortality: 18.8 vs. 17.2% at 28 days

  • Relapse: 29% vs. 26% (higher with non-fermenting gram negative bacteria 41% vs. 25%)

  • In the short length arm there was a lower risk of multi drug resistant bacteria 42% vs. 61% in patients treated with longer course of antibiotics on the first episode.

  • In most cases 8 days is effective to treat VAP. Less is more.

You may also like to read Brad Spellberg’s paper “The New Antibiotic Mantra: - “Shorter the better”, 2016 which discusses the evidence for the duration of antibiotic therapy.

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This video is from the free online course:

Challenges in Antibiotic Resistance: Gram Negative Bacteria

The British Society for Antimicrobial Chemotherapy