Category Archives: PATHOGENS

Clostridium difficile (aka C. diff)

In light of the recently published IDSA guidelines on C. difficile, I thought I would write up a summary of the guidelines as well as provide some of the background microbiology of the organism for review.

Structure

  • obligate anaerobes
  • gram-positive bacilli
    – form spores (= dormant, non-reproductive structure that the bacteria can reduce itself to in order to survive for extended periods of time in extreme conditions)
  • produce toxins (toxin A and toxin B) that cause disease

 

clostridium-difficile gram stain

Environment

  • animal and human feces
  • soil
  • sewage

 

Mechanism of pathogenicity

*Not all strains of C. difficile are pathogenic – only the ones who produce toxins can cause C. difficile disease

Pathogenesis:

Transmission occurs with ingestion of spores via the fecal-oral route ⇒ spores activate in the colon to replicating bacteria ⇒ bacteria release toxins ⇒ toxins cause breakdown of the colon cells’ cytoskeleton framework ⇒ apoptosis ⇒ breakdown of the mucosal wall ⇒ DIARRHEA!

 

Risk factors for acquiring C. difficile:

  1. ANTIBIOTIC EXPOSURE
  2. Exposure to healthcare facilities
  3. Age and immunosuppression
  4. ?Gastric acid suppression (use of proton pump inhibitors or H2 receptor blockers)
    — the evidence-based-medicine jury is still out on this one

 

Clinical features

  • symptoms can develop during antibiotic treatment or up to 6 weeks after the course of antibiotics has been finished
  • patients can also become infected even without exposure to antibiotics (both in the healthcare setting but also in the community setting)
  • carrier state = a patient who is colonized with C. difficile but is currently asymptomatic

1.Symptoms and physical exam signs:

  • Non-bloody, WATERY DIARRHEA (≥ 3 loose stools in 24 hours)
    *occasionally patients can develop ileus with severe infection which will not result in diarrhea but rather lack of bowel movements
  • Abdominal pain/cramping
  • Fever and chills
  • Abdominal distention/tenderness
  • Nausea/anorexia

2.Laboratory findings:

  • High white blood count (occasionally precedes the diarrhea by 1-2 days)
  • Elevated creatinine
  • Elevated lactate and low albumin (in fulminant cases)

 

Pseudomembranous colitis = inflammation of the colon causing elevated white and yellow-colored plaques to form and coalesce together to create a pseudomembrane on the colon wall that can be seen by colonoscopy.

 

Diagnostics

  1. When to test: when patient has new onset, ≥ 3 unformed stools that cannot be explained by another cause (i.e. laxative use)
  2. Options for testing:

* C. difficile can be grown in culture, but anaerobes take a while to grow and it would not provide an answer as to whether the strain is toxigenic (i.e. produces toxin) or not, so it is not commonly used for clinical diagnostic purposes.

What it is Advantages Disadvantages
Toxin EIA assay Antibody assay that detect toxins High specificity (>84%) Low sensitivity (31-99%)
GDH assay Detects GDH (an enzyme produced by C. difficile) High NPV (>99%)

Quick turn-around

Cannot distinguish toxigenic vs. non-toxigenic C. difficile strains
NAAT/PCR PCR method that detects toxin production gene High NPV (>99%)

Quick turn-around

Poor specificity and PPV

*Changes depending on whom specimens are collected on (low suspicion vs. high suspicion)

EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NPV, negative predictive value; PPV, positive predictive value; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction.

Many healthcare facilities are currently doing only PCR testing. It’s highly sensitive and the results return quickly (usually within 24 hours).

The problem: this practice is yielding a lot of false positives (patients who are carriers but do not truly have an active infection) which ⇒ over-treatment ⇒ patient discomfort, potential side effects, infection control consequences for the hospital, and extra costs.

Why: This is thought to be due to the fact that a lot of tests are sent inappropriately (on patients that have diarrhea but no other evidence of infection such as leukocytosis, AKI, abdominal pain, fever, etc.)

Solution (as proposed by IDSA guidelines):

  1. A multiple step algorithm:
  • GDH assay + EIA assay
  • GDH assay + EIA assay with NAAT as a tiebreaker
  • NAAT + EIA assay

                  OR

  1. We can agree to be more mindful of when we send the test (when the pre-test probability is high) and continue to use the NAAT/PCR method alone.

Bottom line: Many hospitals are switching over to the two-step testing method for multiple reasons:

  • behavior change is difficult to implement and sustain
  • provides more accurate incidence of nosocomial-acquired infections in the hospital

WHEN YOU THINK OF SENDING A C. DIFFICILE TEST, ask yourself:

  1. Does this patient have an unexplained fever, leukocytosis, or new abdominal pain/distention, in addition to the diarrhea (or in presence of ileus)?
    if yes ⇒ send the test
  1. If not, is there another explanation for the diarrhea?
    (i.e. laxatives, new medications (especially antibiotics), part of already known illness, etc.)
    if yes ⇒ consider removing the potential cause (if possible) and re-evaluate or monitor for worsening symptoms
    if not ⇒ send the test

 

Treatment

The IDSA has a really great table to reference when choosing treatment options for your C. difficile infected patient.

***PO Metronidazole is no longer the 1st-line agent for C. diff infection treatment***

C.diff treatment chart

                                                                                                            McDonald et al. CID 2018

 

Recurrence

Recurrence of C. difficile infection = reappearance of symptoms within 2-8 weeks after completion of therapy

  • up to 25% of patients will experience a recurrence
  • once patient had one recurrence, they are at higher risk for future recurrences

 

TAKE-HOME POINTS:

  • The MAJOR risk factor for C. difficile infection is ANTIBIOTIC EXPOSURE
    ⇒ DO NOT give antibiotics to those who do not truly need them
  • Symptoms/signs include watery diarrhea, abdominal cramping/pain, and elevated WBC and creatinine
  • C. difficile infection CAN cause ileus (i.e. no diarrhea)
  • Only send test when you have a high pre-test probability to avoid false positives
  • Metronidazole is NO LONGER recommended for treatment of C. difficile

 

Got questions? Disagree? Leave your comments below!

 

References

  1. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018. 66(7):1-48. [PMID: 29562266]
  2. Jorgensen JH, Pfaller MA, Carroll KC, et al. Manual of Clinical Microbiology, Eleventh Edition.
  3. Lamont JT. (2018). Clostridium difficile infection in adults: Epidemiology, microbiology, and pathophysiology. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-epidemiology-microbiology-and-pathophysiology]. Accessed May 25, 2018.
  4. Lamont JT, Kelly CP, and Bakken JS. Clostridium difficile infection in adults: Clinical manifestations and diagnosis. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-clinical-manifestations-and-diagnosis]. Accessed May 25, 2018.
  5. Kelly CP, Lamont JT, and Bakken JS. Clostridium difficile infection in adults: Treatment and prevention. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-treatment-and-prevention]. Accessed May 25, 2018.

Blood culture contaminants

There are some bacteria out there that usually don’t cause disease. They tend to just hang out and not cause any harm. When we see them in the bloodstream, they often are contaminants, meaning they were introduced during collection of the sample, and are not truly in the bloodstream. Figuring out which ones are contaminants and which ones are not can be tricky. Some are almost always (see * below) contaminants while others are NEVER contaminants. Some can be a contaminant or an infection, like streptococcus viridans group.

*Important to note: any organism can cause an infection in the right context, even those who are usually deemed as contaminants. If you are unsure whether a true infection is present, it’s always best to call an infectious disease specialist to assist with management.

Contaminant =  growth of bacteria in the blood culture bottle that were not present in the patient’s bloodstream and thus introduced during the collection of the sample (Dawson et al.)

NEVER assumed to be contaminants:

Staphylococcus aureus
Streptococcus pneumoniae
Group A/B streptococcus
Listeria monocytogenes
Neisseria meningitidis
Gram negative bacilli
Fungus (yeast or mold)
…Amongst many other numerous organisms that will take too long to mention in a list

Common blood contaminants:

Coagulase-negative staphylococci
Propionibacterium acnes
Micrococcus spp.
Corynebacterium spp.
Bacillus spp. (*except Bacillus anthracis which causes anthrax!!)

What if multiple bacteria are growing?!

  • multiple growth of bacteria can suggest contamination.
  • however, it again depends on the pathogens involved. If all are skin flora, then probably contaminant. If any of the aforementioned ‘USUALLY NOT CONTAMINANTS’ are present, then it is not a contaminant!

 

Where do contaminants come from:

  1. Patient’s skin
  2. Equipment used to obtain sample and transfer it to culture bottle
  3. Provider’s skin
  4. General environment

 

Factors to consider when deciding whether culture
is contaminant or not:

  1. Patient’s clinical status
    • are there any signs or symptoms to suggest infection with this microbe?
    • Example:
      • You would not expect a patient with pneumonia to grow CoNS in their blood.
      • However, you would take CoNS seriously in a patient with recent valve replacement and fevers.
  1. Microbiology of the species – see above
  2. Time to positivity of blood culture – studies have shown that the average time of positivity of true infections is ~12 hours vs. ~24 hours for contaminants
  3. Inoculum of the isolate – how much growth is there?
    • If only 1 out of 4 blood culture bottles are positive –> MORE LIKELY contaminant
    • If >1 out of 4 blood culture bottles are positive –> true pathogen
  1. Any foreign material? – Contaminants become pathogens when they infect hardware and prosthetic valves/grafts. If those are present and there is a possibility they are infected, would not disregard any pathogen as a contaminant.
  2. Patient’s response to antibiotics and isolate’s susceptibility pattern – clues to whether an isolate is a contaminant or a true infection
    • Contaminant: patient does not respond to antibiotics that treat the blood culture isolate
    • True pathogen: patient DOES respond to antibiotics that treat the blood culture isolate
    • Contaminant: patient responds to antibiotics despite blood culture isolate resistant
    • True pathogen: patient does not respond to antibiotics and isolate is resistant

 

FUN FACT: A retrospective review looked at 626 blood cultures and discovered that by 48 hours, 98% of aerobic gram-positive and gram-negative bloodstream infections were identified.

*This shows that unless there is a high suspicion for anaerobe growth, antibiotics can be de-escalated at 48 hours if there is no growth. (Pardo, J., Klinker, K.P, et al. 2014. Time to positivity of blood cultures supports antibiotic de-escalation at 48 hours. Annals of Pharmacology. 48 (1): 33-40).)

TAKE HOME POINTS:

  • Microbes known to be common contaminants CAN cause disease in certain circumstances
  • Always repeat blood culture when first one is positive for microbes
  • If you’re not sure if it’s a contaminant or not ⇒ call ID
    (it’s always better to double check rather than to miss a true infection)

 

References:

1. Dawson, S. 2014. Blood culture contaminants. Journal of Hospital Infection; 87, 1-10. DOI: 10.1016/j.jhin.2014.02.009
2. Pardo, J., Klinker, K.P, et al. 2014. Time to positivity of blood cultures supports antibiotic de-escalation at 48 hours. Annals of Pharmacology. 48 (1): 33-40).
DOI: 10.1177/1060028013511229
3. Hossain, B., Islam, M.S., et al. 2016. Understanding bacterial isolates in blood culture and approaches used to define bacteria as contaminants: a literature review. Pediatric Infectious Disease Journal. 35(5): S45-51.
DOI: 10.1097/INF.0000000000001106
4. Pien, B.C., Sundaram, P., and et al. 2010. The clinical and prognostic importance of positive blood cultures in adults. American Journal of Medicine. 123 (819-828).
DOI: 10.1016/j.amjmed.2010.03.021

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.