Aspiration pneumonia vs. Aspiration pneumonitis

Why this matters:

Let me briefly tell you a story that was published in JAMA:  A patient was admitted to the hospital for seizures and intubated for airway protection. CXR showed infiltrates so patient was started on antibiotics and despite rapid improvement in 24 hours, received a 7 day course of antibiotics ‘just in case’. He was re-admitted to the hospital a week later with severe C.diff infection that did not improve despite adequate treatment and died in the hospital.

 

Antibiotics can cause harm. Sometimes they can be life-saving but risks and benefits need to be weighed each time.

 

Did that patient have aspiration pneumonia or aspiration pneumonitis?

 

Aspiration pneumonia = clinical evidence of pneumonia due to a bacterial infection

Aspiration pneumonitis = chemical lung injury due to gastric acid in the lower airways

– 13-26% can progress to develop bacterial pulmonary superinfections

 

Aspiration pneumonitis Aspiration pneumonia
Fever Low grade only/- +/-
Cough/SOB ++ ++
Hypoxia ++ ++
CXR infiltrate Resolves w/in 48-72 hrs Takes weeks to resolve
Sputum culture negative Positive/negative; purulent
Time to sx resolution Quick (48-72 hrs) Slow (>72 hrs)
Bronchoscopy Bronchial erythema Bronchial purulence

 

Risk factors for aspiration pneumonia:

  1. Risk of aspiration
  • altered mental status
  • esophageal disorders (inc. GERD)
  • neurological disorders that promote dysphagia (i.e. ALS, stroke, etc.)
  • seizures
  • vomiting
  • heavy alcohol use
  • recent intubation, bronchoscopy, upper endoscopy, or NG tube (any mechanical disruption of the natural mechanisms that prevent aspiration)
  1. Risk of aspirating increased inoculum of bacteria
  • poor dental hygiene
  • acid-suppressive medications (H2-blockers, PPIs) – loss of gastric acidity allows more pathogens to survive in the stomach ⇒ higher inoculum is present when aspiration occurs

Prevention of aspiration:

  • aspiration is pretty common in small amounts
  • it becomes pathogenic when a patient has chronic, recurrent aspiration or when the inoculum of bacteria in the aspirate increases to reach the threshold for causing chemical lung injury +/- bacterial infection.
  • there are not enough data to suggest that any interventions help to prevent recurrent aspiration

 

Microbiology:

  1. Flora – oral cavity and stomach (strep spp., H.flu, anaerobes, aerobic GNR)
  2. Community: strep spp., haemophilus influenza > anaerobes
  3. Hospital/long term care facilities:
    staphylococcus aureus, aerobic gram-neg bacilli >> anaerobes
    – these pathogens colonize the oral cavity
    Staph and aerobic GNR are more likely to be the infectious cause in these patients due to their intrinsic higher pathogenicity
  4. Anaerobespeptostreptococcus, fusobacterium nucleatum, Prevotella, Bacteroides spp.
  5. Most of these infections are polymicrobial

 

Diagnosis:

– usually a clinical diagnosis

sputum culture may help to isolate aerobic gram-neg bacilli or staph aureus to alter antimicrobial therapy

– “anaerobic bacteria are virtually never detected in pulmonary infections due to lack of access to specimens that are uncontaminated with the normal flora of the upper airways” (UpToDate) and we also do not culture sputum anaerobically so obligate anaerobes would not be able to grow in a typical sputum culture.

CXR should be ordered to assess for evidence of an infiltrate

  • Imaging: does location of infiltrate matter? YES.
    • aspiration in sitting position: lower lobes
    • aspiration in lying position: lower lobes OR posterior segment of upper lobes

 

Workup:

  • consider repeat CXR to evaluate for resolution of pulmonary infiltrate if patient has clinically improved within 48 hours ⇒ if CXR infiltrate resolved and symptoms resolved, likely pneumonitis and can discontinue the antibiotics.

So far, no trials looking at the utility of pro-calcitonin in differentiating aspiration pneumonitis vs. pneumonia that I know of, although would be a great study to do!

 

When to suspect anaerobic involvement
in pneumonia:

  • indolent course
  • risk factors for aspiration
  • absence of rigors
  • no main isolated pathogen on sputum cultures
  • putrid odor sputum
  • evidence of periodontal disease
  • imaging shows cavitation/necrosis or empyema

 

Treatment:

1. To treat or not to treat

  • It seems difficult to imagine coming into a patient’s room who is in respiratory distress with a leukocytosis and possible fever, and deciding to withhold antibiotics. At that time, everyone will likely start antibiotics.
  • Consider clinically re-evaluation at 48 hours – if CXR infiltrates and symptoms have resolved, it’s likely aspiration pneumonitis and you can probably stop antibiotics

2. Anaerobes: to treat or not to treat

  • community-acquired: always treat for anaerobes in addition to other common pathogens (see above)
  • hospital-acquired: consider treating if patient has poor dentition (that predisposes them to pathogenic anaerobic infections)

3. Antibiotic regimens (with anaerobic coverage)

  1. Community-acquired
    a) Amoxicillin-clavulanate or Ampicillin-sulbactam
    b) Ceftriaxone + metronidazole
    c) Clindamycin (if penicillin/cephalosporin allergic, not ideal regimen due to high resistance rates to certain pathogens)
    d) Moxifloxacin
  2. Hospital-acquired or recent history of antibiotics – cover for drug-resistant pathogens as well
    a) Vancomycin + Piperacillin-tazobactam
    b) Vancomycin + Carbapenem (if history of MDR pathogens)
  3. Duration – 7 days for uncomplicated pneumonia
    *For complicated pneumonia, duration of antibiotics will depend on the complication as well as patient’s clinical status and rate of recovery

 

Complications:

  1. ARDS (can happen both in pneumonitis and pneumonia)
  2. Lung abscess
  3. Empyema

 

Take-home points:

  • Aspiration pneumonitis ≠ Aspiration pneumonia
  • Re-evaluate patient in 48 hours and decide whether patient needs to continue antibiotics
  • Anaerobes are less likely to play a pathogenic role in hospital-acquired pneumonia (consider treatment for anaerobes if patient has poor dentition)

 

References:

1. Bartlett, J. G. 2017. Aspiration pneumonia in adults. Uptodate.
2. Finegold, S.M. 1991. Aspiration Pneumonia. CID. 13(9), S737-S742. DOI: 10.1093/clinids/13.Supplement_9.S737
3. Mandell, L. A. et al. 2007. IDSA guidelines for CAP. Section on aspiration pneumonia. 2007. CID. 44(S2): S27-72. DOI: 10.1086/511159
4. Dragan, V. et al. 2018. Prophylactic antimicrobial therapy for acute aspiration pneumonitis. CID. DOI: 10.1093/cid/ciy120
5. Loeb, M.B. et al. 2003. Interventions to prevent aspiration pneumonia in older adults: a systematic review. Journal of American Geriatric Society. 51(7):1018.
DOI: 10.1046/j.1365-2389.2003.51318.x
6.
Joundi, R.A. et al. 2015. Antibiotics “Just-In-Case” in a Patient with aspiration pneumonitis. JAMA Internal Medicine: Teachable moment – Less is more. 175(4); 489-490. DOI:10.1001/jamainternmed.2014.8030

Bactericidal vs. Bacteriostatic antibiotics

Does it matter whether we use a bactericidal antibiotic or a bacteriostatic one? Surely, the bactericidal one would be more effective, right? The answer is not that simple.

Bactericidal = antibiotics that kill bacteria

Bacteriostatic = antibiotics that inhibit the growth of bacteria (i.e. prevent the bacteria from continuing to grow/proliferate) without killing bacteria in vitro OR it is able to kill the bacteria in vitro but at a slower rate than bactericidal agent does.

– there is thought out there that bacteriostatic agents require more activity from the immune system to eradicate the bacteria (this has not been studied well in literature and there is no data to support or negate this hypothesis).

Bactericidal drugs:                                          Bacteriostatic drugs:
Aminoglycosides                                                Glycylcyclines (tigecycline)
Beta-lactams                                                        Lincosamides (clindamycin)
Fluoroquinolones                                               Macrolides (azithromycin, fidaxomicin)
Glycopeptides (vancomycin)                           Oxazolidinones (linezolid, tedizolid)
Lipopeptides (daptomycin)                             Streptogramins (quinipristin/dalfopristin)
Nitroimidazoles/nitrofurans                           Sulphonamides (sulfamethoxazole)
(metronidazole/nitrofurantoin)                     Tetracyclines
Rifampin

*Keep in mind – bactericidal and bacteriostatic effects depend on several factors, including the amount of:
1) bacterial inoculum: the burden of bacteria can change the antibiotic’s properties
2) the pathogen: certain antibiotics are “cidal” to certain pathogens, while “static” to others
–examples:
a)  vancomycin is “cidal” against staph and strep, but “static” against enterococci
b) azithromycin is “cidal” against strep, but “static” against staph
c) linezolid may be “cidal” against strep, but “static” against staph/enterococci
3) medium/location of infection: certain antibiotics are more effective in certain parts of the body (IV vancomycin doesn’t penetrate GI mucosa, tigecycline doesn’t achieve high concentrations in the bloodstream, etc.)

Why could this be potentially clinically irrelevant?

A systematic review published in CID in 2017 looked at all the 59 randomized-controlled trials on clinical outcomes when using bactericidal vs. bacteriostatic agents. They found that 49 (81%) of the trials showed no differences in clinical outcomes when using “cidal” vs. “static” agents.

Similarly, studies demonstrated that using linezolid (a bacteriostatic agent) against MRSA was non-inferior to vancomycin (a bactericidal agent) against MRSA.
Because clinical outcomes depend on 3 factors:

  1. The host
  2. The pathogen
  3. The drug (with many internal factors coming into play as listed below
    -Tissue penetration
    -Pharmacokinetics
    -Drug interactions
    -Optimal dosing

TAKE-HOME POINTS:

  1. Antibiotics can be bacteriostatic for some pathogens and bactericidal for others
  2. Clinical outcomes depend on a variety of factors and the bactericidal property of an antibiotic ultimately appears to have little clinical relevance.

References:

  • Nemeth, J., Oesch, G., and Kuster, S.P. 2015. Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis. Journal of antimicrobial chemotherapy. 70:382-395.
  • French, G.L. 2006. Bactericidal agents in the treatment of MRSA infections – the potential role of daptomycin. Journal of Antimicrobial Chemotherapy. 58 (6): 1107-1117.
  • Wald-Dicker, N, Holtom, P, and Spellberg, B. 2017. Busting the myth of “static vs. cidal”: A systemic literature review. CID
  • Panckey, G.A. and Sabath, L.D. 2004. Clinical relevance og bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. CID, 38(6): 864-870.

 

SPICE organisms

First topic at hand is SPICE organisms. These are the organisms that appear to be sensitive to many antibiotics, but once they are exposed to certain antibiotics (ex. 3rd generation cephalosporins), they quickly develop resistance to them.

SPICE stands for:

S: Serratia spp.

P: Providencia

I: “indole-positive” Proteus spp. (this includes: P. vulgaris) *NOT P.mirabilis

C: Citrobacter spp.

E: Enterobacter spp.

*There are other, less known bacteria included in this group (Cronobacter, Edwardsiella, Hafnia, Morganella, Aeromonas)

 

*[Organisms like Pseudomonas and Acinetobacter produce AmpC gene normally – which is why they have intrinsic resistance to 3rd generation cephalosporins and do not technically fall into the AmpC inducer SPICE group.]

 

The SPICE pathogens can be induced to produce an AmpC beta-lactamase gene that encodes an enzyme that cleaves the beta-lactam group in the antibiotic and renders it inactive.

 

This gene may not be detected initially (low level of expression of the gene) but may appear (induced to express higher levels of gene) after a period of exposure to beta-lactam antibiotics.

(Clinical translation: Initially they will appear susceptible to beta-lactams, but eventually will develop resistance to them. *tricky little bastards, aren’t they?)

 

Once beta-lactam is removed, the AmpC gene production is reduced once more and the pathogens will appear sensitive to 3rd generation cephalosporins and penicillins again. .

 

Resistance develops anywhere from 24h to 2-3 weeks.

 

Clinical relevance:

  • If the course of antibiotics is short or if the antibiotic can easily overcome the MIC concentration needed for bacterial killing, then the risk of inducing AmpC gene production is low
    • Clinical examples (~<1 week duration of antibiotics):
      • UTI
      • Pneumonia
  • Short course for intra-abdominal infectionHowever, this becomes an issue in areas where antibiotics have difficulty penetrating (because it is less likely to overcome the MIC concentration needed) or when antibiotics are needed to be given over a longer period of time.
    • Clinical examples:
      • Endocarditis
      • Bacteremia
      • Osteomyelitis
      • Septic arthritis
      • Abscesses

 

Antibiotics to avoid:

  • Penicillin class (including piperacillin-tazobactam)
  • Most cephalosporins (1st, 2nd, and 3rd generation)

 

Antibiotics to use:

  • 4th generation cephalosporins (i.e. cefepime at higher doses, q8h)
  • Carbapenems
  • Aminoglycosides
  • Fluoroquinolones

TAKE-HOME POINTS:

  1. Remember the members of the SPICE group
  2. You may be successful in treating an infection in short courses of therapy or in infections where antibiotic penetration is high. But in patients with bacteremia, bone, joint, or valve infections – strongly consider 4th generation cephalosporin or a carbapenem.

 

 

Have a question, comment, or a suggestion for a future blog post? Post your comment below!

 

 

References:

  • http://m.antimicrobialstewardship.com/clinical_summaries/index.php?page=esbl_and_spice
  • Jacoby, G.A. AmpC beta-lactamases. Clinical Microbiology Review. 2009. 22(1):161-182. doi: 10.1128/CMR.00036-08
  • Harris, P.N.A, and Ferguson, J.K. Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the lternatives to carbapenems, quinolones, and aminoglycosides? 2012. International Journal of Antimicrobial Agents, 40: 297-305.