Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

Conventional wisdom has been that in active tuberculosis (TB) patients harbor large numbers of replicating Mycobacterium tuberculosis (Mtb), requiring multiple antibiotics to prevent the emergence of resistant mutants. In contrast, Mtb under latent or “inactive” conditions is presumed to have little capacity for mutation due to reduced bacterial replication, thus generally requiring only one antibiotic for preventive therapy.1

However, the assumption that Mtb has a low capacity for mutation in latent TB due to slow bacterial replication has been challenged in recent years. An experimental study in macaque monkeys with latent Mtb infection using whole genome sequencing demonstrated that despite reduced replication, Mtb acquires a similar number of chromosomal mutations during latency as it does during active infection.1

This finding supports the more current and evolving concept of latent TB which assumes diverse mycobacterial growth states, ranging from complete absence of organisms to actively replicating bacterial populations.2 It also explains why, although effective, isoniazid monotherapy may be a risk factor for the emergence of INH resistance in latent TB. 1,3

 Bonus Pearl: Did you know that INH treatment of latent TB in adults is 60-80% protective when given for 6 months, and 90% protective when given for 9 months? 4

References

  1. Ford CB, Lin PL, Chase M, et al . Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011;43:482-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101871/
  2. Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res 2011;50:202-12. https://www.ncbi.nlm.nih.gov/pubmed/21717066
  3. Balcells ME, Thomas SL, Faussett PG, et al. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51. https://www.ncbi.nlm.nih.gov/pubmed/16704830
  4. Piccini P, Chiappini E, Tortoli E, et al. Clinical peculiarities of tuberculosis. BMC Infect Dis 2014; 14 (Suppl 1):S4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015485/

 

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Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

What could be causing low serum haptoglobin in my patient with no evidence of hemolysis?

 

There are many causes of low serum haptoglobin besides hemolysis, including1-4:

  • Cirrhosis of the liver
  • Disseminated ovarian carcinomatosis
  • Pulmonary sarcoidosis
  • Elevated estrogen states
  • Repetitive physical exercise
  • Hemodilution
  • Blood transfusions
  • Drugs (eg, oral contraceptives, chlorpromazine, indomethacin, isoniazid, nitrofurantoin, quinidine, and streptomycin)
  • Iron deficiency anemia
  • Megaloblastic anemia (by destruction of megaloblastic RBC precursors in the bone marrow)
  • Congenital causes

Less well-known is that congenital haptoglobin deficiency (“anhaptoglobinemia”) may not be so rare in the general population at a prevalence of 1% among whites and 4% among African-Americans (>30% in blacks of West African origin)3. Measurement of serum hemopexin, another plasma protein that binds heme, may help distinguish between this condition and acquired hypohaptoglobinemia— in the absence of hemolysis, hemopexin levels should remain unchanged3,5.

Final Fun Fact: Did you know that serum haptoglobin is often low during the first 6 months of life?

References

  1. Shih AWY, McFarane A, Verhovsek M. Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol 2014;89: 443-47. https://www.ncbi.nlm.nih.gov/pubmed/24809098
  2. Sritharan V, Bharadwaj VP, Venkatesan K, et al. Dapsone induced hypohaptoglobinemia in lepromatous leprosy patients. Internat J Leprosy 1981;307-310. https://www.ncbi.nlm.nih.gov/pubmed/7198620
  3. Delanghe J, Langlois M, De Buyzere M, et al. Congenital anhaptoglobinemia versus acquired hypohaptoglobinemia. Blood 1998;9: 3524. http://www.bloodjournal.org/content/bloodjournal/91/9/3524.full.pdf
  4. Haptoglobin blood test. https://medlineplus.gov/ency/article/003634.htm. Accessed August 6, 2017.
  5. Smith A, McCulloh RJ. Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders. Front. Physiol 2015;6:187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485156/pdf/fphys-06-00187.pdf

 

In collaboration with Kris Olson, MD, MPH, Mass General Hospital, Boston, MA

What could be causing low serum haptoglobin in my patient with no evidence of hemolysis?