Antimicrobial use in Primary Care

From bench to bedside: Understanding translational research

27th June 2014

Robin A Howe

Penicillin• 1928: Fleming observed inhibition of bacteria on plates that were

contaminated with Penicillium.• 1931: Penicillin difficult to produce + highly unstable. (Fleming failed to

halt infections in animals with oral penicillin)• 1939: Howard Florey, Ernst Chain, and Norman Heatley re-examined

penicillin. They infected eight mice + co-injected half of the same mice with penicillin. Within a day, the four infected mice that had not been treated with penicillin were dead. By contrast, the four with penicillin remained alive.

• 1941: First treatment of patient, Albert Alexander, died when ran out of penicillin

• 1941: bulk production of penicillin at the US Department of Agriculture’s Peoria laboratory in Illinois (Mouldy Mary & Cantaloupe)

• 1942: 11 US patients had been treated using penicillin supplied by Merck. • 1943: Clinical trials of penicillin in North 1944: By June, penicillin was

used to treat allied troops injured during the D-Day landings.

Penicillin• 1928: Fleming observed inhibition of bacteria on plates that were

contaminated with Penicillium.• 1931: Penicillin difficult to produce + highly unstable. (Fleming failed to

halt infections in animals with oral penicillin)• 1939: Howard Florey, Ernst Chain, and Norman Heatley re-examined

penicillin. They infected eight mice + co-injected half of the same mice with penicillin. Within a day, the four infected mice that had not been treated with penicillin were dead. By contrast, the four with penicillin remained alive.

• 1941: First treatment of patient, Albert Alexander, died when ran out of penicillin

• 1941: bulk production of penicillin at the US Department of Agriculture’s Peoria laboratory in Illinois (Mouldy Mary & Cantaloupe)

• 1942: 11 US patients had been treated using penicillin supplied by Merck. • 1943: Clinical trials of penicillin in North 1944: By June, penicillin was

used to treat allied troops injured during the D-Day landings.

Penicillin• 1928: Fleming observed inhibition of bacteria on plates that were

contaminated with Penicillium.• 1931: Penicillin difficult to produce + highly unstable. (Fleming failed to

halt infections in animals with oral penicillin)• 1939: Howard Florey, Ernst Chain, and Norman Heatley re-examined

penicillin. They infected eight mice + co-injected half of the same mice with penicillin. Within a day, the four infected mice that had not been treated with penicillin were dead. By contrast, the four with penicillin remained alive.

• 1941: First treatment of patient, Albert Alexander, died when ran out of penicillin

• 1941: bulk production of penicillin at the US Department of Agriculture’s Peoria laboratory in Illinois (Mouldy Mary & Cantaloupe)

• 1942: 11 US patients had been treated using penicillin supplied by Merck. • 1943: Clinical trials of penicillin in North 1944: By June, penicillin was

used to treat allied troops injured during the D-Day landings.

Diagnosing Urinary Tract Infections

• V common (500-600 urines/day at UHW)• Gold-standard is culture (>10^5 cfu/mL

of uropathogen)– 24 hours

• Dipstick for nitrites/leucocyte esterase– Rapid– May not react for some organisms– No information about organism

• Soft rot a major cause of spoilage in potato storage• Signature of volatiles produced by E. carotovora

identified• Sensor arrays (“neural nose”, “artificial nose”)

developed to identify early soft rot with high sensitivity/specificity (differentiated Erwinia from Arthrobacter & B. polymyxa)

Erwinia carotovoraSoft Rot

• VOCs identifiable from urine infected with E. coli, Proteus, Klebsiella

• Sensitivity ~10^5 cfu/mL• ? Potential for near-patient test?

• VOCs NOT identifiable from urine infected with Pseudomonas, Staphylococcus

• Urine poor matrix/too variable (VOCs from infection not dominant)

• Cost of machine likely to be prohibitive• Patent issues

The liver breath! Breath volatile organic compounds for the diagnosis of liver disease.Khalid T, Richardson P, Probert CS.Clin Gastroenterol Hepatol. 2014 Mar;12(3):524-6. doi: 10.1016/j.cgh.2013.10.032. Epub 2013 Nov 7. No

abstract available.  The use of a gas chromatograph coupled to a metal oxide sensor for rapid assessment of stool samples from irritable bowel syndrome and inflammatory bowel disease patients.Shepherd SF, McGuire ND, de Lacy Costello BP, Ewen RJ, Jayasena DH, Vaughan K, Ahmed I, Probert CS,

Ratcliffe NM.J Breath Res. 2014 Jun;8(2):026001. doi: 10.1088/1752-7155/8/2/026001. A pilot study combining a GC-sensor device with a statistical model for the identification of bladder cancer from urine headspace.Khalid T, White P, De Lacy Costello B, Persad R, Ewen R, Johnson E, Probert CS, Ratcliffe N.PLoS One. 2013 Jul 8;8(7):e69602. doi: 10.1371/journal.pone.0069602. Print 2013 Analysis of faecal volatile organic compounds in preterm infants who develop necrotising enterocolitis

: a pilot study.Garner CE, Ewer AK, Elasouad K, Power F, Greenwood R, Ratcliffe NM, Costello Bde L, Probert CS.J Pediatr Gastroenterol Nutr. 2009 Nov;49(5):559-65. doi: 10.1097/MPG.0b013e3181a3bfbc. A pilot study of faecal volatile organic compounds in faeces from cholera patients in Bangladesh to determine their utility in disease diagnosis.Garner CE, Smith S, Bardhan PK, Ratcliffe NM, Probert CS.Trans R Soc Trop Med Hyg. 2009 Nov;103(11):1171-3. doi: 10.1016/j.trstmh.2009.02.004. Ep Identification of Campylobacter infection in chickens from volatile faecal emissions.Garner CE, Smith S, Elviss NC, Humphrey TJ, White P, Ratcliffe NM, Probert CS.Biomarkers. 2008 Jun;13(4):413-21. doi: 10.1080/13547500801966443 .  

Community-acquired Pneumonia (CAP)• Incidence 5-11/1000 adults/year• Mortality – 1% – 10% – 30%

Pneumococcal urinary antigen

• C polysaccharide cell wall antigen in urine• Test in 15 mins• 420 pts with CAP• 29% positive• 80% of pts with S. pneumoniae in BC• 52% of pts with S. pneumoniae in sputum

Murdoch DR (2001) JCM 39: 3495

• 100% of 68 pts with definitive pneumococcal pneumonia• 69% of 52 pts with probable pneumococcal pneumonia• 18% of 277 pts without pneumococcal pneumonia

• 69% remained +ve 1 month after discharge

• 8% of asymptomatic HIV pts had URT colonisation with pneumococci. 0% Ag positive

210 children aged 2-60 months

Now recommended for use across the world• BTS

• IDSA

WHY?

• All options aim to treat S. pneumoniae

What is needed for success

• Communication between clinicians, clinical academics, clinical scientists, basic scientists

• Clear description of clinical need

• Multi-disciplinary team