Category Archives: Microbiology

Antibiotic resistance

General paediatrics, Infectious disease, Microbiology

Penicillin resistance

Resistance to penicillin is usually due to Beta lactamase enzymes.  Therefore adding a  beta-lactamase inhibitor eg clavulanate (as found in co-amoxiclav) overcomes the resistance and extends the spectrum.

An alternative resistance mechanism however is production of defective Penicillin Binding Proteins – this is the mechanism of resistance in Pneumococci.  Beta lactamase inhibitors therefore do not help.

Macrolide resistance

Variable resistance seen; sometimes effective against penicillin resistant staphylococci including some MRSA, but poor activity against Haemophilus. Variable resistance seen in streptococcus, pneumococcus. Resistant mycoplasma are rare but do exist – try cipro, else tetracycline.

Using Azithromycin probably improves efficacy in Haemophilus (more active) but pneumococci that are resistant to erythromycin (approximately 5 to 20% of strains currently) will also be resistant to azithro, and no difference in in vitro activity between the newer and old macolides against other common respiratory pathogens.

Multiresistant organisms

In theory, you should use a combination of antibiotics (if possible) to treat a multiresistant organism, to prevent resistance developing (as in TB).  However there is no good clinical data to support this, beyond TB treatment (which is slow growing, so probably different).  On the contrary, meta-analyses demonstrate no difference in clinical outcomes between the two treatment strategies (for infections with Gram-negative bacteria), but there are well-documented increased toxicities with combination therapy.

Having said that, given the greater mortality associated with delays in appropriate and effective antimicrobial treatment, starting with combination therapy in critically ill patients seems sensible.

If there is poor response to treatment, rather than simply adding a second agent, consider:

  • dose, frequency – are you achieving adequate time above MIC?  Consider prolonged antibiotic infusion strategy
  • route – give IV if not already
  • duration – extended treatment course?

[doi: 10.1128/CMR.05041-11 Clin. Microbiol. Rev. July 2012 vol. 25 no. 3 450-470]

 

 

ESBL – extended spectrum beta lactamase

Scenario 1: lower renal tract infection with ESBL producing Gram negative

Bacteriuria with urinary symptoms but minimal systemic symptoms and no fever

  • Treatment duration 3 days
  • First line – trimethoprim / nitrofurantoin  (not used in under 3 months)
  • Depending on sensitivities and age alternative options include ciprofloxacin, single dose aminoglycoside, pivmecillinam or fosfomycin

Scenario 2: upper renal tract infection with ESBL producing Gram negative

Bacteriuria with urinary symptoms and associated systems symptoms including fever

  • Treatment duration 7-10 days (as per NICE)
  • Always consult with infection management specialist
  • First line – if seriously unwell or under 3 months carbapenem  + consider one dose of aminoglycoside
  • Alternative: tazocin and consider one dose of aminoglycoside (if sensitive and not seriously unwell and after discussion with local microbiologist)
  • OPAT : Ertapenem
  • Daily IVOST review required
  • Potential IVOST options when afebrile, clinically improving, falling CRP and able to take and absorb oral medicines: ciprofloxacin, trimethoprim
  • There was less consensus on the role of pivmecillinam and its ability to penetrate renal tissue. It should be considered only to offer an oral option to finish a course of antibiotics in a clinically improving child

Scenario 3 – infection with ESBL producing Gram negative outside the renal tract (except for meningitis)

  • As per IDSA – carbapenem, meropenem (especially if child unwell)
  • Stepdown co-trimoxazole or ciprofloxacin (would consider fosfomycin on rare occasion)
  • Temocillin not empirical therapy until we understand PK/PD profile better plus expensive and difficult to obtain – consider not including
  • Recommendation would need caveat, how unwell, age of child.  Not experienced discuss with infection specialist. BNFC reference
  • Ertapenem OPAT

Scenario 4 – meningitis complicating ESBL producing Gram negative

  • Carbapenem, limited ability to step down
  • Treatment duration – 3 weeks
  • Lumbar puncture to ensure infection cleared.

[Conor Docherty]

E. coli O157

Gastro, General paediatrics, Infectious disease, Microbiology, Renal

Notorious STEC/VTEC producing strain of E coli. STEC is shigella toxigenic E coli, VTEC is verocytotoxin toxigenic E coli (same thing).

Cause of potentially fatal Haemolytic uraemic syndrome. But other strains also recognised.

1996 Lanarkshire outbreak, traced back to meat pies from John Barr’s butcher’s in Wishaw.  21 deaths, 512 cases of HUS, esp Wishaw Parish Church Hall luncheon and a local pub birthday party. At the time it was the most deadly food related disease outbreak in world history.  As of 2023 it is still the 6th most deadly food related outbreak in history, and still the worst death toll from O157.

A sad claim to fame for the town.  John Barr was eventually fined £2500.

Emerged in late 80s, rates in Scotland have always been highest in UK until Northern Ireland outbreak with 140 cases in 2012. Odd because England has a lot more cows…

Scotland is said to have 2nd highest incidence globally, although not great data from many places, high regional variability, under-reporting…  Canada and Iran worse?

At the same time as the Lanarkshire outbreak, there was an outbreak in Sakai city, Japan – 12 000 cases of infection, mostly primary school kids.  121 developed HUS, 3 died.  Traced to white radish sprouts.

Since then, another major outbreak in 2011, Northern Germany. O104 strain however, enteroaggregative plus toxin. 800 cases HUS (90% adults), 53 deaths.  Traced to organic fenugreek sprouts, although Spanish cucumbers blamed initially, exports dropped £120 million per week until consumer confidence returned.

Ratio of unreported human VTEC O157 infection to reports to national surveillance is estimated at 7.4 to 1.

Cows

E coli O157 is now commonly found in cattle, but causes no clinical effect, therefore no incentive for farmers to control. Supershedders are recognized, with one such cow able to contaminate a huge proportion of other animals’ hides.   Current FSA research project underway.  A vaccine has been developed.

Sheep have also been found to carry it…  Likely cause of outbreaks related to “Tough Mudder” events.

Pathology

Lots of acronyms!

  • EHEC = Enterohaemorrhagic E coli
  • O157:H7 = serotype
  • STEC = Shiga toxin producing E coli, same as VTEC (verocytotoxin)
  • STX1/2 genes (same as VTX) code for this toxin.
  • D+/- = Diarrhoeal illness associated (or not)
  • HUS – Haemolytic uraemic syndrome

More than 400 O:H serotypes – 6 account for most HUS.

Other genes are also relevant for virulence eg Intimin (an adherence factor, coded for by eae gene).

Diagnosis

  • Stool culture – should be collected and processed urgently.  State if bloody diarrhoea present and/or suspicion of STEC infection. Routinely tested for the presence of E. coli O157 at local laboratory, which takes 24-48 hours from sample receipt, but will miss non-O157 types. If positive, isolates are referred to SERL for confirmation of identity and typing.
  • PCR stool testing – if stool culture negative, and clearly bloody (or clinical info suggests likely STEC), then Scottish (SNERL) guidance is to send stool for PCR at the Scottish E. coli O157/ STEC Reference Laboratory (SERL), which detects both E. coli O157 and non-O157 STEC.
  • Serum serology – is used for suspected cases where culture/PCR negative.
  • Rectal swabs – may be submitted directly to SERL from cases of HUS who are unable to produce a stool sample.

Do not delay appropriate clinical and public health management while awaiting reference laboratory results.

Regarding laboratory processes:

  • Rapid referral of samples from diagnostic laboratories to SERL is important to improve the probability of culture confirmation.
  • Positive PCR results will be telephoned immediately to the referring diagnostic laboratory and culture results will follow.
  • The local diagnostic laboratory will inform the clinical team and the local public health team of positive PCR and culture results.
  • PCR (stool) may become available to local diagnostic laboratory, removing need for samples to be referred to SERL . However, if a patient presenting with HUS or acute bloody diarrhoea tests negative by local PCR and is causing clinical concern, please discuss referral of stools for further testing with SERL.

Antibiotic classes

Microbiology

Protein synthesis inhibitors

Act on ribosome.  In theory, reduce toxin production as well as growth.

  • Macrolides
  • Aminoglycosides
  • Clindamycin
  • Chloramphenicol
  • Tetracyclines
  • Linezolid

Aminoglycosides

Eg Gentamicin.  Broad spectrum but poor CSF penetration (but still used for Listeria meningitis!).

Some important bacteria are usually resistant to the aminoglycosides, including gentamicin:

  • most streptococcal species (including Streptococcus pneumoniae and the Group D streptococci),
  • most enterococcal species (including Enterococcus faecalis, E. faecium,  and E. durans),
  • anaerobic organisms, such as Bacteroides species and Clostridium species.
  • Salmonella and Shigella
  • Pseudomonas unless you use ones with antipseudomonal activity eg tobramicin

Hearing damage is an important side effect, known genetic marker for this but usually not done ahead of treatment.

Renal excretion.

Quinolones

Block DNA synthesis.  Broad spectrum but not great gram positive, excellent absorption, penetration and intracellular too.  See quinolones.

Lyme Disease

Cardiology, General paediatrics, Infectious disease, Microbiology, Neurology, Rheumatology

Borrelia (spirochaete) infection, spread by ticks (Ixodes), common in localized areas of Europe and North America (forest environments).

Differential includes possible co-infection from other tick born organisms viz anaplasmosis, or babesiosis.

Vaccine available if likely to be at risk.

Clinical

Infection occurs a minimum of 48 hours after bite!

Skin – Erythema migrans is the classic skin lesion, a spreading ring usually at the site of the bite but can be multiple and at different sites.  Typically not hot, itchy or painful. Takes a while for central clearing to develop. Develops over 1-4 weeks (from 3 days to 3 months!), can last months.  Looks like erythema multiforme, but time scale different.  Insect bite hypersensitivity/superinfection looks similar but usually hot, itchy and/or painful, and develops/recedes within 48 hours!

Lyme lymphocytoma is a painless bluish red nodule or plaque, especially on the ear but also reported on the nipple and scrotum.  More common in children.  May persist for months, can precede other features.  Acrodermatitis chronica atrophicans (ACA) is almost exclusively seen in adults, predominantly women, and is an eruption with chronic, progressive red or bluish-red lesions, usually on the extensor surfaces, with later atrophic, fibroid or sclerodermic changes.

Consider Lyme as possible (but unlikely) cause for:

  • fever and sweats
  • swollen glands
  • malaise
  • fatigue
  • neck pain or stiffness
  • migratory joint or muscle aches and pain
  • cognitive impairment, such as memory problems and difficulty concentrating (sometimes described as ‘brain fog’)
  • headache
  • paraesthesia

Arthritis – uncommon, presents as recurrent inflammation of 1 or more large joints, usually the knee. Swelling can be disproportionate to pain.  Can become more persistent – in a minority, despite treatment, inflammation becomes chronic (presumably immune-mediated).

Carditis occurs rarely, and almost always with other clinical features.  Usually partial heart block, but can be complete, usually resolves within a week.

Neurological – isolated facial palsy, meningitis, other cranial nerve palsies, meningoencophalitis, polyradiculopathy.  There is a small proportion of children who can present with non-specific headache, fatigue, neck pain without clear neurological signs (and also the rare case of raised intracranial pressure).

Other rare disease manifestations include uveitis, iridocyclitis and keratitis.

Diagnosis

For erythema migrans, clinical diagnosis is adequate, and antibodies only positive in 30-70% anyway!

Use a combination of clinical presentation and laboratory testing to guide diagnosis and treatment in people without erythema migrans. Do not rule out diagnosis if tests are negative but there is high clinical suspicion of Lyme disease.

  • Offer an enzyme-linked immunosorbent assay (ELISA) test for Lyme disease – consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion. (Test for both IgM and IgG antibodies)
  • If the ELISA is positive or equivocal, perform an immunoblot test for Lyme disease (again, consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion). [Western blot increases specificity, but cut offs (for both serology and Western blot) can be an issue, with potential false positives for other acute infections and autoimmune conditions.  Definitely needs to be an approved lab…]
  • If ELISA negative and the person still has symptoms, review their history and symptoms, and think about the possibility of an alternative diagnosis.  If tested within 4 weeks from symptom onset, repeat the ELISA 4 to 6 weeks after the first test.
  • If Lyme disease is still suspected in people with a negative ELISA who have had symptoms for 12 weeks or more, perform an immunoblot test.  If negative, consider synovial fluid aspirate/biopsy, or lumbar puncture [PCR – culture is difficult – or CSF antibodies for neuroborreliosis; consider for isolated facial palsy]
  • If immunoblot negative and symptoms resolved, no treatment is required.

For early neuroborreliosis, antibodies 80% sensitive, rises to virtually 100% for late or ACA.

Early antibiotic treatment is also believed to potentially block antibody production.

Antibodies can then persist for months or even years after successful treatment of the infection, so repeat testing is not useful for monitoring treatment success.

First line ELISA test can have false positives for other spirochaetes, glandular fever and autoimmune conditions.

The idea that there are seronegative “chronic Lyme” cases has little evidence to support it, with only 2 possible cases reported (ACA and arthritis, not neuro).

NICE says “Discuss the diagnosis and management of Lyme disease in children and young people under 18 years with a specialist, unless they have a single erythema migrans lesion and no other symptoms. Choose a specialist appropriate for the child or young person’s symptoms dependent on availability, for example, a paediatrician, paediatric infectious disease specialist or a paediatric neurologist.”

Treatment [check NICE]

The most commonly recommended first-line treatments for different stages of Lyme borreliosis in Europe are:

  • Erythema migrans/borrelial lymphocytoma:  10-14 days Doxycycline if 9yr+ (initially 5 mg/kg in 2 divided doses on day 1, then 2.5 mg/kg daily in 1–2 divided doses, max dose 200mg, for a total of 21 days, option for higher dosing) – 10 days courses of doxy effective in US trials.  Else Amoxicillin 50mg/kg/d, max 500mg TDS (10-14 days)[BNFc says 30mg/kg/d, max 1g, TDS for 21 days].  Don’t delay treatment pending test results.  Scandinavia use 10 days Pen V (100mg/kg/d, max 1000mg TDS). BNFc says Azithromycin as alternative.
  • Isolated facial palsy: 14 days Oral doxycycline  – else as above.  Doesn’t probably help resolution but may prevent later complications.
  • Meningitis/radiculopathy: PO Doxycycline or IV Ceftriaxone  50-100mg/kg/d, max 2g daily (14-21 days). [BNFc talks about CNS disease separate from cranial/peripheral nerves]
  • Encephalitis, myelitis: Ceftriaxone (14 days)
  • Lyme arthritis: Doxycycline (28 days) else Amoxicllin (21-28 days)
  • Carditis: Ceftriaxone during pacing, else PO doxycycline (14 days)

Ceftriaxone is the most commonly preferred parenteral agent, with once-daily dosing facilitating outpatient treatment. Recent prospective studies have shown that oral doxycycline is noninferior to ceftriaxone in neuroborreliosis, and it is now recommended in Europe for the treatment of acute facial palsy (FP), meningitis and radiculoneuritis. Ceftriaxone currently remains the preferred choice for children with other presentations of neuroborreliosis and for those with contraindications to doxycycline.

Several recent EM treatment studies have incorporated noninfected control groups. Excellent responses were seen, with resolution of rash within 7–14 days. Nonspecific symptoms including headache, myalgia, arthralgia, fatigue and parasthesias were no more common in cases than controls at 6-month follow up.

[position statement by the British Infection Association, J Inf 2011;62:329]

[Pediatric Infectious Disease Journal Volume 33(4), April 2014, p 407–409]