One or Two Antibiotics for Pseudomonas? A Look at the Data.

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So, you are thinking about starting antibiotics to cover for pseudomonas? That is great. Piperacillin-tazobactam or cefepime are great choices. Perhaps ceftazidime is another one if you are feeling a bit wild. Piperacillin-tazobactam covers anaerobes while the other 2 do not, however metronidazole is a nice addition to the latter 2. Either way, these all will do the same job. Do you add another agent on top of that? I.e. Do you “double-cover” for pseudomonas?

Rationale:

The traditional teaching when covering gram-negative infections involves the use of beta-lactam and aminoglycoside, which allows you to 1) broaden empiric coverage in the event of high resistance pattern; 2) exploit synergy of two antibiotics; 3) prevent emergence of resistance (1). While there is some robust in-vitro data to suggests the synergistic activity of beta-lactam and aminoglycosides, the nephrotoxicity associated with the latter, as well as its more complicated dosing means that these are not quite frequently used as much (2). The use of the – relatively- safer fluoroquinolones has gained traction despite the lack of in-vitro data to suggest its synergy with beta-lactams (2) as a method to increase empiric coverage in places where you think anti-pseudomonal antibiotics may be resistant. Despite this rationale, however, one should keep in mind the risk of adverse events with combination antibiotics as, if you are talking about empiric coverage, you are also likely adding vancomycin into the mix. Add that to the risk of breeding resistance and the issue of “double pseudomonas coverage” becomes a bit more complex. I will not delve into the microbiological data here as I do not think it applies to most folks reading this and will focus on hard outcomes from clinical data, namely mortality. The thing to consider going forward in this post, however, is the lack of robust (read: randomized) data as well as the changes in the dosing of aminoglycosides, which may make the interpretation of the data difficult in our current practice. Further, most of the data tends to involve bacteremia since it is easier to obtain cultures here than for pneumonia. For all intents and purposes, most of the data here can be used for VAP/HAP, but with some caveats.

The idea of dual-therapy has been studied every since the 80s. In an early study (3), 282 patients treated with ceftazidime were compared to 268 treated with a combination of cephalothin, gentamicin, and carbenicillin for febrile neutropenia and found no difference in treatment results. An older study of pseudomonas bacteremia found that patients who received an antipseudomonal beta-lactam had higher cure rates (70%) compared to those who received aminoglycosides (29%), with no difference in those who received a combination of beta-lactam and aminoglycosides (72%), though a variety of antibiotics were used here (4). In another retrospective analysis of pseudomonas bacteremia (5), overall infection-related mortality was not statistically significant when comparing monotherapy with combination therapy:

Notably, however, the combination therapy involved either a carbapenem/beta-lactam OR fluoroquinolone with aminoglycoside which is not typically done nowadays. A large retrospective study of 2165 patients with gram-negative bacteremia (6) compared monotherapy with beta-lactam with combination therapy of beta-lactam and aminoglycoside and when logistic regression analysis was applied, combination therapy did not confer higher mortality risk when compared to monotherapy when used as empiric (OR 1.0, 95% CI 0.7-1.6) or definitive therapy (OR 0.9, 95% CI 0.5-1.8). Similar results were seen when looking only at pseudomonas infections (OR 1.4, 95% CI 0.9-2.1 for empiric therapy; OR 1.1, 95% CI 0.8-1.7 for definitive therapy). Indeed, it seems to be the appropriateness of therapy (i.e. if the antibiotic is susceptible to the bug) tends to be the main factor in these studies, as several of them use the more toxic aminoglycosides as a second antibiotic. Indeed, a retrospective study of 134 patients with Pseudomonas aeruginosa bacteremia compared combination therapy (beta-lactam + aminoglycoside and beta-lactam + ciprofloxacin) with monotherapy (7). While the numbers were quite small to draw any meaningful conclusions, it should be noted that the use of combination therapy yielded overall similar mortality results to that of antipseudomonal beta-lactam use while aminoglycoside therapy was associated with significantly higher mortality:

Of course, take into account that aminoglycoside was used predominantly in the first time period between 1976 to 1982 where medicine was practiced very differently from now. This means that it is more of the appropriateness of therapy rather than the dual nature that makes a difference. This was seen in a retrospective analysis of 115 episodes of Pseudomonas bacteremia, which found that in the early follow up (prior to receipt of susceptibility) found that both adequate combination and adequate monotherapy were associated with improved mortality when compared to inadequate therapy, however after susceptibility the risk of mortality was for adequate monotherapy after receipt of susceptibility report (8):

Despite this, there was no difference in mortality when looking at definitive therapy between adequate combination or adequate monotherapy when compared to inadequate therapy, suggesting that it is the susceptibility profile that makes the biggest difference here. More contemporary data suggests similar conclusions. A Greek retrospective cohort (9) from 2011 found that definitive treatment with combination therapy (beta-lactam alone or in combination with either aminoglycoside or quinolone) for Pseudomonas bacteremia was not associated with treatment success:

It should be noted that those who received combination therapy were generally sicker and younger, but numbers overall were fairly low in this study. In another retrospective analysis of 100 episodes of Pseudomonas pneumonia bacteremic episodes (10), 28-day mortality was significantly higher in the inadequate therapy group vs the adequate therapy group (69% vs 42%, p =0.01), with subgroup analysis of patients who received adequate therapy found that combination therapy was associated with reduced 28-day mortality (aOR 0.05, 95% CI 0.01-0.34), though it could be argued this was due to the higher likelihood of appropriate empiric therapy rather than anything to do with the combination itself. Indeed, more recent data leads one to a similar conclusion. For instance, a larger prospective cohort of 593 patients with pseudomonas bacteremia found that empiric combination therapy was not statistically different from monotherapy in terms of 30-day mortality when compared to inappropriate empiric therapy (11):

Further, by multivariate analysis, 30-day mortality risk was higher for the inappropriate therapy group in comparison to appropriate combination therapy (aHR 1.65, 95% CI 0.94-2.88), though it did not reach statistical significance. Another retrospective study of 292 episodes (12) of Pseudomonas bacteremia found that adequate empiric antipseudomonal therapy was associated with lower 30-day mortality (aOR 0.37, 95% CI 0.16-0.89), an association not found with any combination therapy (aOR 0.40, 95% CI 0.13-1.27). When looking at definitive therapy, however, combination with ciprofloxacin was associated with lower 30 day mortality (aOR 0.16, 95% CI 0.05-0.55), though adequate antipseudomonal therapy had similar results (aOR 0.17, 95% CI 0.05-0.62). 

Overall, it seems that adequate therapy trumps combination therapy, though in certain scenarios dual therapy may be appropriate (for instance, institutions where higher resistance to BL/BLI combinations or quinolones is seen for pseudomonas isolates, or those who have cystic fibrosis, it may be worth considering for a higher chance of appropriate coverage upfront).

Meta-Analysis:

There are a few things to consider when it comes to therapeutics targeting pseudomonas. First, it seems that appropriate therapy tends to be more important than the number of drugs you give someone. Second, a lot of these data hinges upon the use of aminoglycosides rather than the “friendlier” fluoroquinolones. This trend seems to hold with meta-analyses. For instance, in sepsis (13), combination therapy with aminoglycoside + beta-lactam had no advantage in terms of all cause mortality (RR 0.90, 95% CI 0.77 to 1.06) or treatment failure (RR 0.66 95% CI 0.72 to 1.02). One of the largest RCTs (14) evaluated 740 critically ill patients who had suspected VAP and randomized patients to either meropenem alone or meropenem plus ciprofloxacin. Primary outcome was 28-day all-cause mortality. Overall, relative risk for mortality in the combination group vs monotherapy was 1.05 (95% CI 0.78-1.42), although those who received combination therapy sere more likely to receive adequate initial therapy (93% vs 85%, p = 0.01). This was more pronounced in those patients who had MDRO isolated (84% vs 19%). Similarly a meta-analysis of 19 articles (15), totaling 8675 patients, found no difference in all-cause mortality between monotherapy with beta-lactams or combination with FQs or aminoglycoside + beta-lactam:

Similarly, there was no difference when looking at the empiric use rather than definitive:

Another meta-analysis of 10 studies (mostly retrospective, 16) found no difference between monotherapy with a beta-lactam or combination therapy in all-cause mortality (OR 0.89, 95% CI 0.57-1.40). Most monotherapy involved a beta-lactam with 4 studies also allowing the use of ciprofloxacin as well; combination therapy was similarly a beta-lactam with either a quinolone or an aminoglycoside. The only meta-analysis I was able to find to suggest a benefit of combination therapy involved all gram negative bacteremias. Here, 17 studies involving therapy for gram negative bacteremia found that combination therapy had a favorable outcome when it came to mortality (17):

It should be noted all were retrospective studies with different sources of bacteremia with combination therapy using either aminoglycoside (with no clear indication as to the dosing) or fluoroquinolone. 

Conclusions:

So there is little, if any, data to suggest benefit for combination-therapy in hospital acquired infections/pseudomonas. While the data does not apply broadly to VAP, I think we can generalize here. There is no randomized data we can  look at to make a decision, but it seems that above all appropriate therapy based on antibiograms is more important than the amount of antibiotics you give someone. If pseudomonas susceptibilities is such that piperacillin-tazobactam is 99% susceptible, then you are ok using monotherapy. If, however, your resistance profile is such that piperacillin-tazobactam susceptibility is like 70-80%, then adding a quinolone until cultures are back to broaden your coverage is actually reasonable. Another situation I can find this approach to work is in cystic fibrosis, where there are multiple pseudomonas isolates with weird resistance profiles. In all other cases, however, dual therapy for the sake of covering for pseudomonas does not pan out. 

References:

  1. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev. 2012 Jul;25(3):450-70. doi: 10.1128/CMR.05041-11. PMID: 22763634; PMCID: PMC3416487.
  2. Johnson SJ, Ernst EJ, Moores KG. Is double coverage of gram-negative organisms necessary? Am J Health Syst Pharm. 2011 Jan 15;68(2):119-24. doi: 10.2146/ajhp090360. PMID: 21200057.
  3. Pizzo PA, Hathorn JW, Hiemenz J, Browne M, Commers J, Cotton D, Gress J, Longo D, Marshall D, McKnight J, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med. 1986 Aug 28;315(9):552-8. doi: 10.1056/NEJM198608283150905. PMID: 3526155.
  4. Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med. 1985 Sep;145(9):1621-9. doi: 10.1001/archinte.145.9.1621. PMID: 3927867.
  5. Siegman-Igra Y, Ravona R, Primerman H, Giladi M. Pseudomonas aeruginosa bacteremia: an analysis of 123 episodes, with particular emphasis on the effect of antibiotic therapy. Int J Infect Dis. 1998 Apr-Jun;2(4):211-5. doi: 10.1016/s1201-9712(98)90055-8. PMID: 9763504.
  6. Leibovici L, Paul M, Poznanski O, Drucker M, Samra Z, Konigsberger H, Pitlik SD. Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrob Agents Chemother. 1997 May;41(5):1127-33. doi: 10.1128/AAC.41.5.1127. Erratum in: Antimicrob Agents Chemother 1997 Nov;41(11):2595. PMID: 9145881; PMCID: PMC163862.
  7. Kuikka A, Valtonen VV. Factors associated with improved outcome of Pseudomonas aeruginosa bacteremia in a Finnish university hospital. Eur J Clin Microbiol Infect Dis. 1998 Oct;17(10):701-8. doi: 10.1007/s100960050164. PMID: 9865983.
  8. Chamot E, Boffi El Amari E, Rohner P, Van Delden C. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother. 2003 Sep;47(9):2756-64. doi: 10.1128/AAC.47.9.2756-2764.2003. PMID: 12936970; PMCID: PMC182644.
  9. Bliziotis IA, Petrosillo N, Michalopoulos A, Samonis G, Falagas ME. Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia. PLoS One. 2011;6(10):e26470. doi: 10.1371/journal.pone.0026470. Epub 2011 Oct 26. PMID: 22046290; PMCID: PMC3202542.
  10. Park SY, Park HJ, Moon SM, Park KH, Chong YP, Kim MN, Kim SH, Lee SO, Kim YS, Woo JH, Choi SH. Impact of adequate empirical combination therapy on mortality from bacteremic Pseudomonas aeruginosa pneumonia. BMC Infect Dis. 2012 Nov 16;12:308. doi: 10.1186/1471-2334-12-308. PMID: 23157735; PMCID: PMC3519646.
  11. Peña C, Suarez C, Ocampo-Sosa A, Murillas J, Almirante B, Pomar V, Aguilar M, Granados A, Calbo E, Rodríguez-Baño J, Rodríguez F, Tubau F, Oliver A, Martínez-Martínez L; Spanish Network for Research in Infectious Diseases (REIPI). Effect of adequate single-drug vs combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections: a post Hoc analysis of a prospective cohort. Clin Infect Dis. 2013 Jul;57(2):208-16. doi: 10.1093/cid/cit223. Epub 2013 Apr 11. PMID: 23580739.
  12. Paulsson M, Granrot A, Ahl J, Tham J, Resman F, Riesbeck K, Månsson F. Antimicrobial combination treatment including ciprofloxacin decreased the mortality rate of Pseudomonas aeruginosa bacteraemia: a retrospective cohort study. Eur J Clin Microbiol Infect Dis. 2017 Jul;36(7):1187-1196. doi: 10.1007/s10096-017-2907-x. Epub 2017 Jan 21. PMID: 28110415; PMCID: PMC5495847.
  13. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ. 2004 Mar 20;328(7441):668. doi: 10.1136/bmj.38028.520995.63. Epub 2004 Mar 2. Erratum in: BMJ. 2004 Apr 10;328(7444):884. PMID: 14996699; PMCID: PMC381218.
  14. Heyland DK, Dodek P, Muscedere J, Day A, Cook D; Canadian Critical Care Trials Group. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008 Mar;36(3):737-44. doi: 10.1097/01.CCM.0B013E31816203D6. PMID: 18091545.
  15. Vardakas KZ, Tansarli GS, Bliziotis IA, Falagas ME. β-Lactam plus aminoglycoside or fluoroquinolone combination versus β-lactam monotherapy for Pseudomonas aeruginosa infections: a meta-analysis. Int J Antimicrob Agents. 2013 Apr;41(4):301-10. doi: 10.1016/j.ijantimicag.2012.12.006. Epub 2013 Feb 12. PMID: 23410791.
  16. Hu Y, Li L, Li W, Xu H, He P, Yan X, Dai H. Combination antibiotic therapy versus monotherapy for Pseudomonas aeruginosa bacteraemia: a meta-analysis of retrospective and prospective studies. Int J Antimicrob Agents. 2013 Dec;42(6):492-6. doi: 10.1016/j.ijantimicag.2013.09.002. Epub 2013 Oct 1. PMID: 24139926.

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