“it is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgement with respect to particular patients or special clinical situations.”
-IDSA/ATS Guidelines 2016
A 73 year old man is admitted from a nursing home for an NSTEMI and is treated on the telemetry floor. Three days into his hospitalization he becomes febrile with a rising white blood cell count, productive cough and evolving right middle lobe infiltrate. You fortunately work in a hospital with a MRSA prevalence of < 5%. The patient is well-appearing, with no underlying structural lung disease and has not had antibiotics in a number of years. You reach for piperacillin-tazobactam as monotherapy, but are challenged by one of your colleagues. Should you add a second anti-pseudomonal? Vancomycin? You turn to the recent IDSA guidelines for help.
Healthcare Associated Pneumonia
The last IDSA guidelines for the management of hospital-acquired and ventilator-associated pneumonia were published in 2005. As many of us who have been practicing within the last decade have known, the entity of healthcare-associated pneumonia [HCAP] necessitated similar empiric therapy to that of hospital-acquired pneumonia [HAP] and ventilator-associated pneumonia [VAP]. HCAP risk factors for multi-drug resistant organisms [MDROs] included:
- hospitalization for more than 48 hours in the last 90 days
- residence in a nursing home or extended care facility
- home infusion therapy
- chronic dialysis within one month
- home wound care
- a family member with a multi-drug resistant organism.
In any patient who met any of the aforementioned criteria, or in those who had received antimicrobial therapy in the preceding 90 days, had been hospitalized for more than 5 days, who came from a place of high frequency of MDROs in the community or in those with immunosuppression, then MRSA coverage plus two anti-pseudomonal antimicrobials [of different classes] were recommended.
In the most recent update, however, HCAP has been scrapped – at least for now. A meta-analysis of 24 studies including more than 20,000 patients found that HCAP was associated with MDROs [e.g. MRSA, pseudomonas], however, the aforementioned HCAP risk factors were neither sensitive nor specific to identify at-risk patients. The poor clinical outcome noted with HCAP patients was felt to be related more strongly with age and comorbidities rather than MDROs per se. Further, there was a large publication bias suspected. The panel unanimously decided that HCAP should not be included in the HAP & VAP guidelines.
However, as a separate entity, HCAP – or some modification thereof – may be included in a forthcoming revision of the community-acquired pneumonia [CAP] guidelines.
While the current guidelines discuss a number of issues germane to HAP and VAP including: microbiological evaluation, ventilator-associated tracheobronchitis, the use of biomarkers and clinical prediction scores, inhaled antibiotics, etc. this post will focus on standard, empiric therapy as this is a common clinical quandary [see figure 1].
Firstly, some definitions are required. HAP is a pneumonia that develops at least 48 hours following hospitalization while VAP is a pneumonia that develops at least 48 hours after intubation. The panel for the current guidelines performed their own systematic reviews and meta-analyses of additional data since the 2005 publication and found that for VAP, the risk of MDROs was greatest for those who had received intravenous antibiotics within the previous 90 days [odds ratio [OR] of 12.3]. Additional VAP-MDRO risk factors included: ARDS prior to VAP [OR 3.01], renal replacement therapy prior to VAP [OR 2.5], septic shock at the time of VAP or more than 5 days of hospitalization prior to the VAP [OR 2.01]. Euros
Interestingly, with regards to HAP-MDRO risk factors, only prior intravenous antibiotic use carried an increased risk [OR 5.17]. When looking at case-control studies for MDR pseudomonas species, the authors found an increased risk [not quantified] in those having “received prior antibiotics, mechanical ventilation and a history of chronic obstructive pulmonary disease.” They go on to note that patients with bronchiectasis are also at increased risk for pseudomonas colonization.
From the above, the recommendations for aggressive anti-pseudomonal coverage in HAP – somewhat confusingly – becomes those: with septic shock, requiring ventilator support, who have received intravenous antibiotics in the last 90 days, have bronchiectasis and have pseudomonas with a > 10% resistance to a potential monotherapy. There was conflicting data regarding the duration of hospitalization [e.g. more or less than 5 days] and the risk of MDRO in the HAP population; therefore, unlike VAP, this is not factored into broad spectrum antimicrobial selection.
The contentious issue of double anti-pseudomonal coverage is also addressed in the current guidelines. While the authors do note multiple VAP trials showing no difference in clinical outcome between monotherapy and dual-therapy for pseudomonas, they criticize these trials for excluding patients known to have resistant pathogens as well as excluding patients with “medical comorbidities.” They also note that data for dual anti-pseudomonal coverage is exceptionally sparse in the HAP population. They therefore continue to recommend dual anti-pseudomonal empiric therapy until speciation/susceptibility testing is available. When therapy can be specifically-directed against pseudomonas based on microbiology, the authors recommend appropriate monotherapy.
Duration of Therapy
The current guidelines recommend 7 days of antimicrobial therapy for both HAP and VAP. The authors conducted their own meta-analysis and found no difference in mortality or recurrence between long and short-courses of therapy. This is incongruent with an often referenced trial in 2003 which noted a higher pneumonia recurrence rate if non-fermenting gram negative bacilli [e.g. pseudomonas] were isolated and patients were treated with 8 days versus 15 days of anti-microbials.
I return the reader to the quotation at the commencement of this post. The authors of the current IDSA/ATS guidelines note at the outset of their recommendations that one must respect the difference between a guideline and how one may proceed in any given clinical scenario. Consequently, the practitioner should guard him or herself against the tendency to blur recommendation with the absolute. This general message seems particularly poignant within the current political discourse in the United States. The strength of one’s conviction may have little semblance with objective evidence. Conversely, as the timeless Bertrand Russell reminds us:
“The degree of one’s emotions varies inversely with one’s knowledge of the facts.”
It is imperative to acknowledge, therefore, that of the 44 recommendations in the current guidelines, none [i.e. zero], are based on “strong-quality evidence,” and 7 of the 44 recommendations are based on “moderate-quality evidence.” Accordingly, the vast majority of the recommendations are based on “low quality” or “very-low quality” evidence. Consider the recommendation for dual anti-pseudomonal therapy for patients with underlying bronchiectasis. A thorough review by the British Thoracic Society does not recommend this practice unless a pseudomonas isolate is known to be resistant to at least one anti-pseudomonal antibiotic, and even that recommendation is based on the poorest-quality evidence. Contrast the use of two anti-pseudomonal antibiotics when treating bronchiectasis with the use of paralytics in ARDS; the latter is supported by at least one well-performed, randomized controlled trial yet pulmonologists invariably comply with the former – rarely, the latter.
I return to Bertrand Russell:
“If a man is offered a fact which goes against his instincts, he will scrutinize it closely, and unless the evidence is overwhelming, he will refuse to believe it. If, on the other hand, he is offered something which affords a reason for acting in accordance to his instincts, he will accept it even on the slightest evidence. The origin of myths is explained in this way.”