Breakpoints to MICs Help Hone Pseudomonas aeruginosa Therapy

Selecting the most appropriate antibiotic therapy can be a challenge when it comes to empirical treatment for severe, multidrug-resistant infections, such as those caused byPseudomonas aeruginosa.

At the University of Pittsburgh Medical Center, clinical pharmacists bolstered the odds of success against likely P. aeruginosa infections by devising a combination antibiogram that applied pharmacodynamic (PD) breakpoints to minimum inhibitory concentration (MIC) distributions for a range of commonly used antibiotics.

Inclusion of PD breakpoints led to “substantial changes” in antibiotic treatment recommendations, according to the pharmacist-researchers, who presented the results of their investigation at the American College of Clinical Pharmacy annual meeting (abstract 135). The study was based on 376 P. aeruginosa isolates identified from blood or bronchoalveolar lavage cultures at three ICUs from January 2009 to December 2010.

“There were some striking findings,” said Brian A. Potoski, PharmD, BCPS (AQ-ID), associate director of the medical center’s Antibiotic Management Program and one of the authors. For example, he said, although cefepime has been used extensively as monotherapy at the medical center, “we found that we should probably not be [using] cefepime in the empiric setting, at least by itself, based on the PD breakpoint.”

Drawing on the medical center’s susceptibility and MIC data, the researchers also found that the optimal PD-based combination therapy for P. aeruginosa involved the use of a β-lactam antibiotic with an aminoglycoside. The top selection reported in their study was piperacillin-tazobactam plus tobramycin, followed closely by meropenem plus tobramycin. “We think that’s important,” Dr. Potoski said, “because there seems to be this reflex to use just a quinolone along with a β-lactam backbone. That doesn’t give you the best chance for appropriate therapy.”

Dr. Potoski noted that susceptibility patterns can vary greatly from institution to institution, even between those in the same locality. “It might be worthwhile,” he said, “for other institutions to take a look at using these methods because they might find something very different and yet very appropriate and important for their populations.”

The PD breakpoints recommended by the Pittsburgh researchers were at least 50% lower than those published by the Clinical and Laboratory Standards Institute (CLSI). “We know that there are certain MICs for particular antibiotics that are extremely unattractive,” Dr. Potoski explained, adding that outcomes at those MICs “are poorer” than those attained at lower MICs, even if the organism has been shown to be susceptible.

PD breakpoints recommended in the Pittsburgh P. aeruginosa antibiogram included cefepime no greater than 4 mcg/mL (vs. the CLSI standard of up to 8 mcg/mL); piperacillin-tazobactam no greater than 16 mcg/mL (vs. up to 64 mcg/mL); meropenem 2 mcg/mL or less (vs. 4 mcg/mL); and tobramycin 2 mcg/mL or less (vs. up to 4 mcg/mL).

Getting the Complete Picture

David P. Nicolau, PharmD, FCCP, FIDSA, director of the Center for Anti-Infective Research & Development at Hartford Hospital, Hartford, Conn., said, “Certainly we understand as a collective that there are some inadequacies from simply presenting susceptibility as defined by the laboratory. It works for a great many patients, but it doesn’t give the complete picture. So the [pharmacodynamic] approach is an opportunity to not only try to pick the right drug but also the right dose, dosing interval and infusion technique to optimize exposures.

“What these folks basically said was, ‘Hey, at the end of the day we can’t get there with one drug. So we’re going to take a PD-optimized drug A and ... PD-optimized drug B, and if we put them together, do we have a greater probability of success?’ And the answer is yes.”

Dr. Nicolau said the same approach could be used for other “drug–bug combinations, and we have done that both nationally and with international databases. We have a global program called Passport, [which] tries to take local resistances in South America, North America, Europe and the Asia-Pacific region and link them with drug exposures and dosing and optimization” (Int J Antimicrob Agent.)

The Pittsburgh researchers, he said, are taking the same concept and “bringing it home. What [they] have done is take their local Pseudomonas and asked, ‘What’s the best combination for our bugs?’ I think it makes a great deal of sense. It is something that could be done at many institutions if people took a little bit of time.”

Debra A. Goff, PharmD, FCCP, clinical associate professor at Ohio State University (OSU) College of Pharmacy and infectious disease specialist at the OSU Medical Center in Columbus, said the Pittsburgh Medical Center study was “an excellent example of how important pharmacodynamic modeling is in selecting optimal antibiograms. It also demonstrates how stewardship programs need to go beyond the antibiograms to make drug therapy selections for multidrug-resistant gram-negatives such as P. aeruginosa.”

The study, she added, “drives the point home with cefepime. We did a similar analysis at The Ohio State University Medical Center in partnership with Dr. Nicolau’s research lab. We found it necessary to increase the dose of cefepime to 2 g every eight hours infused over three hours to achieve the optimal pharmacodynamic target, despite the antibiogram reporting a 91% susceptibility. We are running out of options so we must learn how to get the most out of the agents we have. If we continue prescribing the same dose and the same drug to treat multidrug-resistant P. aeruginosa, we cannot expect a different response.”

by

Akshaya Srikanth

Pharm.D Internee

P.R.R.M.College of Pharmacy,

Kadapa