De-Escalation in the Setting of Culture-Negative Pneumonia

This In the Literature piece features a case vignette on the de-escalation of antibiotics for culture-negative pneumonia.

Highlighted Study:

Bultas AC, Bery AI, Deal EN, Hartmann AP, Richter SK, Call, WB. Predictors of treatment failure following de-escalation to a fluoroquinolone in culture-negative nosocomial pneumonia. Ann Pharmacother. 2019;53(12):1207-19. doi: 10.1177/1060028019867114.


RS is a 65-year-old male who was admitted to your medical floor with a diagnosis of nosocomial pneumonia. Empiric antibiotics were initiated with vancomycin and cefepime, dosed appropriately. Quality sputum samples were obtained. On the morning of day 3, the patient has clinically improved and the sputum culture has resulted in no significant growth. As the antimicrobial steward, you are asked if there are any interventions or de-escalation that could be made at this time.

Depending on the type and presentation of pneumonia, cultures are recommended as a tool to help guide therapy. However, even when obtained, sometimes these cultures do not yield an organism. Culture-negative pneumonia is a clinical situation that is very difficult for antimicrobial stewardship efforts. Concern for treatment failures, increased mortality, and increased health care costs are all considerations when de-escalating from appropriate empiric antimicrobials in culture-negative pneumonia. An early study by Labelle and colleagues found that culture-negative pneumonia differed significantly from culture-positive pneumonia, particularly in severity of illness, hospital mortality and length of stay. This suggests that an opportunity for stewardship may exist.1 While national guidelines support de-escalation to pathogen directed therapy, no guideline currently provides recommendations for de-escalation in patients lacking pathogen growth.

One of the major issues in de-escalation of culture-negative pneumonia is choosing the appropriate antibiotic to utilize. Musgrove and colleagues used a microbiologic nudge to decrease anti-methicillin resistant Staphylococcus aureus (MRSA) and antipseudomonal antibiotics when sputum cultures did not grow either pathogent.2 The authors did not find any differences in mortality, either in-hospital or all-cause when de-escalation occurred. A limitation was that the chosen antibiotic was only referred to as narrower spectrum, and a breakdown of individual antibiotics utilized was not provided.

Most studies evaluating de-escalation in different types of pneumonia have excluded patients with negative cultures. However, a small number of studies looking at outcomes of de-escalation that included patients with culture-negative pneumonia found similar results. Joung et al looked at de-escalation in intensive care unit-acquired pneumonia.3 This study found that de-escalation did not increase mortality, and concluded that de-escalation could be utilized even in patients with culture-negative pneumonia. As with the previous study, de-escalation antibiotics were not discussed. Schlueter and colleagues evaluated de-escalation activity in culture-negative health care-associated pneumonia and found that patients with culture-negative pneumonia were de-escalated 1 day earlier than culture-positive patients, had shorter lengths of hospitalization and lower mortality rates.4 A majority of patients (70%) were de-escalated to a respiratory fluoroquinolone, with moxifloxacin, used most frequently.

Previous studies were small in number and lacked clarity in choice of medication. Bultas and colleagues tackled this clinical conundrum by performing a retrospective evaluation of possible risk factors for treatment failure when empiric antimicrobial therapy was de-escalated to monotherapy with a fluoroquinolone.5 Patients were included if they were older than 18 years of age, had a confirmed pneumonia (verified by a second physician), had negative cultures, cultures with normal flora or if cultures were not collected, had at least 24 hours of a respiratory fluoroquinolone monotherapy (levofloxacin or moxifloxacin) following receipt of at least 24 hours of appropriate empiric antibiotics (defined as 1 agent with activity against MRSA and 1 agent with activity against Pseudomonas aeruginosa). Exclusion criteria was quite extensive (see original paper for complete list).

A total of 164 patients were included in the total population, and 23 met criteria for failure (14%). Treatment failure was defined using a composite of all-cause death within 30 days of discharge (4.9%), treatment re-escalation (1.8%) or readmission for pneumonia within 30 days of discharge (7.3%). Both a univariable analysis (Table 1) and multivariable analysis (Table 2) were used in analyzing predictors of treatment failure. In both analyses the authors found that duration of empiric antibiotics did not increase risk of failure. Limitations include that the retrospective nature of the analysis may have led to missing data, selection bias, and a limitation regarding the ability to draw robust conclusions. Another possible limitation was that patients who were discharged on oral medications were unable to be followed for adherence, which could possibly affect the treatment failure arm.

Although there are no guideline recommendations for de-escalation in this patient population, there are a few studies that did show de-escalation in culture-negative pneumonia is a reasonable option. Based on the study by Bultas and colleagues, a de-escalation to either moxifloxacin or levofloxacin would be a safe option to limit broad antipseudomonal and anti-MRSA exposure, with the caveat that the patient is responding favorably to therapy. In addition to narrowing therapy, this strategy presents an option for intravenous to oral substitution as well. However, all these benefits must be weighed against the small risk of serious adverse reactions of the fluoroquinolones, as recently highlighted by the US Food and Drug Administration. More studies are needed to evaluate non-fluoroquinolone based de-escalation before non-fluoroquinolone antibiotics can be recommended.

Zimmer is an ID/Antimicrobial Stewardship pharmacist at CoxHealth in Springfield, MO. Drew enjoys fly-fishing, hunting, the St. Louis Cardinals and all things ID. You can find him on Twitter @zimrx17.

*He is an active member of the Society of Infectious Disease Pharmacists.


  1. Labell AJ, Arnold H, Reichley RM, Micek ST, Kollef MH. A comparison of culture-positive and culture-negative health care associated pneumonia. Chest. 2010;137(5):1130-7 doi: 10.1378/chest.09-1652
  2. Musgrove, MA, Kenney RM, Kendall RE, et al. Microbiology comment nudge improves pneumonia prescribing. OFID. 2018;5(7):ofy162 doi: 10.1093/ofid/ofy162
  3. Joung MK, Lee JA, Moon SY, et al. Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia. Crit Care. 2011;15(2):R79 doi:10.1186/cc10072
  4. Schlueter M, James C, Dominguez A, et al. Practice patterns for antibiotic de-escalation in culture negative healthcare associated pneumonia. Infection. 2010 Oct;38(5):357-62 doi:10.1007/s15010-010-0042-z
  5. Bultas AC, Bery AI, Deal EN, Hartmann AP, Richter SK, Call, WB. Predictors of treatment failure following de-escalation to a fluoroquinolone in culture-negative nosocomial pneumonia. Ann Pharmacother. 2019;53(12):1207-19. doi: 10.1177/1060028019867114.