Block DNA synthesis by bacteria (uniquely among antibiotics).
Good against gram negatives, including Salmonella, Shigella, Neisseria, Pseudomonas (one of the few oral antipseudomonals).
Good intracellular penetration so active against organisms such as Chlamydia, Mycoplasma, Legionella and some Mycobacteria.
Good tissue penetration including central nervous system. 80% of orally administered drug is bioavailable so the IV route is only used when absorption impaired.
But no anti-anaerobic activity, and not very good against common gram positives eg Pneumococcus, Enterococcus, Staphylococcus (in fact, use is associated with MRSA). The newer types (Gatifloxacin, Moxifloxacin, Levofloxacin) have better gram positive activity but would still not be your first line choice, and have less anti-pseudomonal activity.
Not licensed under 1yr.
Only contraindication is previous tendon problem caused by it!
Adverse Effects:
Disabling, long-lasting (even irreversible) musculoskeletal and neurological problems reported, v rarely. So only use for severe infections, unless no other antibiotic appropriate. And stop ASAP if symptoms (muscle pain, joint pain, weakness, neuropathy etc)
Seizures (+/- predisposing condition)
Tendonitis – rupture can occur within 48hrs of starting, but can also be months later! Steroids at same time may increase risk, as may renal impairment and solid organ transplants
Arthropathy in immature animals – so avoided in children (except Nalidixic acid) unless extenuating circumstances (only reversible musculoskeletal symptoms have been reported). Arthropathy occurs in CF anyway.
Can prolong QT
Photosensitivity
Valve regurgitation – so caution if preceding valve disease or other risk factor eg connective tissue disorder (Ehlers-Danlos, Marfans), hypertension (!), Turners (!)
sickle cell disease or other severe haemoglobinopathy
trisomy 21
complex or chromosomal genetic or metabolic conditions associated with significant comorbidity, multiple congenital anomalies associated with significant comorbidity
bronchopulmonary dysplasia – decisions should be made taking into account degree of prematurity at birth and chronological age
infants less than 1 year with cyanotic CHD, or haemodynamically significant acyanotic CHD with history of prematurity, or those due for corrective surgery (to avoid complications or delay)
Steroids
WHO recommends dexamethasone 150mcg/kg once daily for 10 days for severe/critical COVID19 disease, on basis of REACT metanalysis.
Severe defined as any of:
Sats <90%
Tachypnoea (>30 in over 5s, >40 over 2 etc)
Severe respiratory distress
Critical defined as ARDS, septic shock or anything else that would require critical care.
Remdesivir
For Patients at ‘high risk’ of complications (as above, in particular immunocompromise) plus:
>4 weeks of age and at least 3kg
Within 10 days of symptoms onset
NOT for patients requiring ventilatory support unless high risk, and not for ALT > 5x upper limit of normal .
5mg/kg loading dose on day 1, followed by 2.5mg/kg once a day for 4 days. May be extended to 10 days in immunocompromised.
Toculizimab is an option for pneumonitis.
Prophylaxis for high risk patients is available:
Remdesivir 3 days once daily infusions
Paxlovid (Nirmatrelvir +Ritonavir) 300/150mg BD for 5 days
Neutralising antibodies have also been tried but not in guidance.
Sotrovimab [NO LONGER AVAILABLE] – for 12-16yrs, pre-hospitalisation, PCR positive and onset of symptoms within previous 5 days. Not if new oxygen requirement or weight under 40kg. 1% vs 7% placebo hospitalisation or death (85% reduction).
Mostly against COVID spike (S) protein that facilitates host cell entry.
Pfizer vaccine is mRNA vaccine, completely in vitro derived, uses nanoparticles to aid absorption into host cells which then produce the S protein themselves from the mRNA.
AstraZeneca vaccine is chimp adenovirus vector for genetic sequence – mRNA produced once virus taken up by host cell.
From Autumn 2025, only children over 6/12 who are immunosuppressed are eligible for a COVID booster (given with flu in the autumn). The other clinical risk groups eg chronic heart/lung, DM no longer apply.
lung infections causing pneumatocoeles, which then invite aspergillomas
mucocutaneous candidiasis
eczema, eosinophilia and high IgE
PLUS bony abnormalities:
osteopenia and spontaneous bone fractures
dysmorphism: triangular jaw, wide nose, asymmetrical face
dental abnormalities eg retained primary
hyperflexibility and scoliosis
Also called Job’s (because of the Bible story, smitten by boils etc, but could equally have been CGD!) or Buckley syndrome.
Caused by STAT3 defect, part of IL6 receptor. Not actually an immunoglobulin problem! Not to be confused with Hyper IgM syndrome. But if antibiotic prophylaxis is ineffective, IVIG is sometimes used.
An autosomal recessive form without the bone abnormalities but with vasculitis esp CNS involvement described.
The virus spread beyond its original outbreak in China when a businessman became unwell on his flight out of China and died in Vietnam in 2003. Further outbreaks appeared rapidly, as far afield as Toronto. Eventually led to 8000 cases globally, but rapid surveillance and isolation measured brought the epidemic to an abrupt end within 4 months.
Super shedders exist, who have much higher infectivity (1 case on a plane infected 120 others, whereas another plane had 4 cases on board, but no secondary cases occurred!). On the other hand, there is no documented transmission by asymptomatic cases, or between children.
Incubation period is 5-7 but up to 14 days. Spread is by respiratory, fomites, and faecal-oral routes. Peak shedding occurs at peak of clinical disease hence outbreaks were often among health care workers.
Symptoms are ‘flu-like, and non-specific. Fever is universal. Those who do badly have sudden deterioration on 10th day, with ARDS. Mortality is around 10%, but very age dependent, reaching over 50% in the over 65s. Children have lower viral loads, and generally have a benign course. Compared with adults, they perhaps get more gastrointestinal symptoms than respiratory.
Children under 5 yrs are hardly affected at all – perhaps because recent coronavirus infection protective, perhaps because of reduced immune reactivity.
No long term morbidity seen in children.
The diagnosis is suggested by the paucity of clinical signs (mild crepitations only, if anything) with an abnormal chest radiograph (non-specific), and laboratory evidence of leucopenia, lymphopenia, and thrombocytopenia. Raised AST/ALT also seen.
Definitive diagnosis is by ELISA or PCR, neither of which is very sensitive, or useful early on in disease.
Interferon alpha appears to be of benefit in vitro. Otherwise supportive.
Personal Protective Equipment effective if used properly – so buddy system.
Infection control – encourage self isolation, dedicated staff etc.
Middle East respiratory syndrome, caused by a coronavirus (MERS-CoV) . See also COVID19 and SARS.
Reported 2012. More than 2000 cases so far, mostly related to Arabian peninsula, but a single case of MERS-CoV in a returning traveller led to an outbreak involving 186 cases across 16 hospitals in the Republic of Korea.
36% mortality, mostly people with co-morbidities. More than 2000 cases so far.
One of WHO blueprint priority diseases – potential for serious outbreak, no treatment or vaccine (6-7 others: SARS, Crimean-Congo HF, Ebola, Lassa etc).
Incubation time 2-5 days but up to 14. Median onset to hospitalisation 4 days.
Risk factor appears to be camel contact – milk, meat, urine.
Management
Management based on experience of SARS etc.
Infection control – negative pressure, dedicated staff, cleaning, PPE for suspected cases, self isolation for close contacts.
Hogmanay 2019, WHO were informed of cluster of cases of pneumonia of unknown cause in Wuhan city, Hubei province, China.
Novel coronavirus identified, named SARS-CoV-2. “COVID19” is associated disease. 75% genetically identical to SARS (severe acute respiratory syndrome) and 50% to MERS (Middle East respiratory syndrome) but of course these are both similarly capable of causing severe disease, whereas many coronaviruses pretty benign.
Most likely origin is from live animal markets in Wuhan, although intermediate animal (SARS was found eventually to have crossed over via civet cars). Evidence suggests that there were 2 different llineages in Wuhan, so presumably 2 different Patient Zeroes (which goes against lab leak theory).
By end of February 2020, more than 70 000 cases reported across China, 2500 fatalities. Pandemic was declared by WHO on 11th March.
Cruise ships including the Diamond Princess in Japan (over 700 cases) and the Zaandaam were particularly hard hit.
Lockdown declared in UK on 23rd March 2020.
5 variants of concern, most recently Omicron.
Risk factors
Spike (s) protein binds to ACE2 receptors, primary role of which is to convert AntiThrombin-II into AT-1,7, controlling heart rate, hypertension, vasoconstriction, sodium retention, oxidative stress, inflammation, and fibrosis, as well as enhancing baroreceptor sensitivity. ACE2 variability across populations potentially explaining particular susceptibility among people with hypertension and Africans (nearly double rate of whites) and Asians (although Indian rates lower than Bangladeshi/Pakistani). Rates among Chinese females actually lower than among Whites! [UK data]
At least 3% of severely affected people have known or previously unrecognised genetic defects in type 1 interferon production (especially TLR3 and IRF7 which amplify production).
Risk of “critical illness “ from COVID-19 RR 1.44 if overweight, 1.97 if obese. UK OpenSAFELY analysis. Death 1.27 if BMI 30-39, 2.27 if BMI>40. ACE-2 higher in obese. Plus different immune responses and challenges to ventilate.
London has double the age standardised mortality of any other part of the UK (Birmingham next), as high as 144 per 100 000 in Newham. Glasgow’s rate is about 80 [UK data].
Diabetes, cancer and poorly controlled asthma associated with death in primary care records study. Residential care homes, health care workers, social deprivation, Black/Asian groups also seem to be particularly at risk of death.
Bronx worse hit than Manhattan, despite similar population density. Higher attack and death rates among Afro-Americans. Role for air pollution too?
Pregnancy increases risk slightly, not much risk to baby although elective preterm delivery may be part of management of sick mother.
Acute neurological presentations in adults, including stroke and Guillain Barre syndrome. Thrombosis risk.
Transmission from asymptomatic cases seems to be less important than symptomatic and pre-symptomatic (1-2 days).
In adults, low lymphocytes, high neutrophils and D-dimer predict mortality.
Probably more severe than SARS but still children tend to be less severely affected than adults. Cross protection from immunity from other coronaviruses? Differences in ACE2? Some asymptomatic.
16% of hospitalised children admitted to critical care. Age under 1 yr, or age 10-14 yrs, co-morbidities, black ethnicity are risk factors for critical care admission. Mortality rate less than 1% in hospitalised [Swann, ISARIC study]. 3 PIMS deaths in England, all 10-14yrs. 70% of all COVID related deaths in non-white groups. 24% of deaths had no co-morbidities, 60% had life limiting condition. No deaths in kids with asthma, diabetes, Trisomy 21.
Wheeze uncommon.
X-ray more often negative; CT more sensitive.
Can present with GI symptoms.
One baby born to an infected mother developed severe complications.
Neutrophil and LDH counts go up, lymphocytes go down.
A small series of children with COVID-19 has shown a greater prevalence of peripheral halo (halo-sign) lung consolidations on CT.
The criteria for the definition of Acute Respiratory Distress Syndrome (ARDS) and septic shock, the guidelines for the management of sepsis and septic shock and the use of non-invasive ventilation in children are different from those of adults.
Children desaturate more easily during intubation; therefore, it is important to pre-oxygenate with 100% O2 with a mask with a reservoir before intubating.
A rectal swab may be useful in children to determine the timing of the termination of quarantine.
[Chengdu and Italian experience, from PIPSQC]
WHO supports use of dexamethasone in patients with acute respiratory presentation and hypoxia (sats<90%), tachypnoea, or severe respiratory distress. RECOVERY trial continues to study dexamethasone in neonates, plus roles for azithromycin and toculizimab.
Sotrovimab is first line treatment, Remdesivir second line is licensed in hospitalised patients in oxygen, over 12 years and over 40kg and can be considered in this age group for patients with high-risk comorbidity for non-hospitalised patients also. Treatment should be commenced within 5 days of symptom onset (Sotrovimab), within 7 days of symptom onset (remdesivir). Paxlovid (Nirmatrelvir plus Ritonavir) is alternative first line option in adults.
Paediatric multi inflammatory syndrome associated with COVID19 (PIMS-TS)
Disseminated BCG reported, implies SCID or similar major immunodeficiency.
Severe BCG reaction can also indicate underlying TB infection!
More common issues are BCG abscess, and lymphadenitis.
Abscess at injection site appears after a few weeks, can persist for months. Treatment with isoniazid has been offered but no evidence of benefit. Incision probably makes things worse!
Non-suppurative lymphadenitis (not tender, no systemic symptoms) improves over a period of few weeks. Can progress to abscess however, with eventual spontaneous discharge and sinus formation. Healing then takes several months. Drug treatment does not appear to prevent abscess formation or speed up healing.
If an axillary abscess develops, needle aspiration can prevent perforation and sinus formation. Surgical excision might be needed if matted or multiloculated.
One of the major criteria for Rheumatic fever but can be seen in isolation. An acute (presumed autoimmune) neuropsychiatric condition, that often causes severe functional impairment, but that mostly resolves spontaneously. See Jelly Jumps page for videos and family support.
Classically, involuntary, non-rhythmic movements, associated with emotional lability. Often misdiagnosed initially eg psychogenic [Mary King, ADC 2015]. Adults can get it rarely – tends to be relapse of childhood disease, female hormones seem to a trigger (eg pregnancy, oral or other contraceptives).
Chorea is a particular kind of movement – varies from smooth writhing (athetosis) to rapid, high amplitude jerks (ballism). Typical signs are repeated pouting of lips, milk maid sign (ask to squeeze fingers in hand), hyperextension of wrists, piano playing movements. Fine motor control usually lost, due to these extra movements. Gait disturbance common, can look like hip hop dancing! Ask to stick tongue out (unable to maintain – “motor impersistence”). Movements disappear in sleep. Can be hard to differentiate sometimes from stereotypies and tics, and of course these things are not uncommon so might co-exist.
Can be one side of the body predominantly in 20-30% of cases (hemichorea). Underlying the involuntary movements is often a loss of tone, which may not become obvious until treatment started to suppress the chorea.
In severe cases, the loss of tone and weakness predominate (chorea paralyticum).
Variable severity. May just be some instability on walking, some difficulty with hand writing. Or unable to walk, talk, feed yourself.
The “psychiatric” part of the neuropsychiatric condition is a mixture of different issues. Emotional lability common, mild anxiety and poor attention less so – although developing a new disability without any cognitive impairment may explain some of it. Tics (new) often seen.
Family history often seen, at least in historical reports, where it was part of the diagnosis! But perhaps cross infection rather than genetic predisposition.
Risk of cardiac involvement, as related to rheumatic fever – 20% of cases in BPSU study, but 71% of cases in Turkish study. Half if not more are subclinical (no findings on clinical examination). Significant risk of long term morbidity, probably more important than chorea itself, so always echo. Penicillin prophylaxis important for carditis (see below).
A new case every 2.5 weeks in the UK, according to BPSU study.
History
Previously called St Vitus’ dance by Thomas Sydenham, but confusing, because there were epidemics of uncontrollable dancing in the middle ages which probably weren’t all related to rheumatic fever – tarantism, for instance. St Vitus’s shrine was reputedly a source of healing.
In the late 1800s, Sydenham’s chorea was the fourth most common reason for children to be admitted to the Great Ormond Street hospital, London. Often there would have been a family history, probably due to cross infection.
Essentially clinical, with supportive evidence of recent streptococcal infection (history, ASO titre, throat swab). But recognised that infection can be up to 6 months before, or too mild to really notice, and ASO hardly reliable.
Look for key signs (chorea and hypotonia), but also important to screen for behavioral, mobility, swallowing, speech, and cognitive impairments, and acute rheumatic fever (ARF) features, particularly carditis.
Other tests depend on the risk of acute rheumatic fever in the local population and the likelihood of another diagnosis. Atypical features? No evidence of strep infection? Consider lumbar puncture, MRI brain (putaminal enlargement described in SC but not diagnostic) etc.
Although there is evidence of anti-neuronal antibodies directed against the basal ganglia (eg anti D2R, see Church 2003), these are not specific or sensitive (see Sugar 2003, same time as Church) so not used in clinical practice. Swedo and Cunningham (also 2003) found cross reactive antibodies that recognised N-acetyl Beta D glucosamine, the major strep surface epitope, and also lysoganglioside, activating CAMK II which may regulate neurotransmitters. “Cunningham panel” is private test, see PANDAS.
An echo can confirm presence of carditis (typically mitral/aortic valvulitis) if actually rheumatic fever, not just Sydenham’s. Mostly subclinical. Jones criteria suggest repeat echo in 2-4 weeks if initially normal.
Management
“At all times, patients, families, and educators should receive support, information, and guidance to minimize the impact of SC on academic and social functioning.”
A course of penicillin is usually given at diagnosis, to definitively clear any remaining/colonising strep but no evidence this really achieves anything and active infection probably long gone.
There is a UFMG rating scale for SC, from Brazilian Universidade Federal de Minas Gerais (UFMG), only looks at motor function, 27 items, so for research purposes only. Walker-Wilmshurst-Wendy scale just 16 yes/no, with 1 point for emotional lability, 1 for OCD and 1 for other behavioural disturbance.
Occupational and physiotherapy useful for maintaining function and muscle tone, especially for getting back to school.
Treatment with valproate is effective for controlling symptoms but doesn’t speed up recovery. May reveal hypotonia. Haloperidol used previously but prob more side effects. Case reports to support carbamazepine and levetiracetam.
“Immunotherapy (corticosteroids) is recommended in moderate to severe SC (ie Motor +/- behavioral/psychiatric symptoms with impact on activities of daily living, school and family life).
“In those with inadequate recovery, intravenous immunoglobulin or plasma exchange should be given.”
One RCT supporting steroids from Paz, Brazil 2006, 22 cases of SC, remission reduced to 54 days from 119 days. Various other reports of use of oral or IV steroids from Israel, Italy [Fusco 2012, 2017], Brazil [Cardoso 2005], immunoglobulin [Holland, 2016, South Africa 2016]. Some of these studies report response with days, and remission within 7 to 54 days, even where cases are severe and have already been treated with anticonvulsants. South African group found less neuropsychiatric complications at 6 months with IVIG treatment (IVIG preferred due to fear of TB reactivation). [Review by Deans and Singer, 2017]
Prophylaxis
Penicillin prophylaxis essential if you have other features of rheumatic fever – regimens vary globally.
If Sydenham’s chorea is not part of broader rheumatic fever diagnosis, then practice varies regarding offering prophylaxis. Evidence is that recurrence is less where penicillin prophylaxis is used, and used reliably, but that it doesn’t always prevent it. Given the high rate of recurrence, the level of disability and potential for long term complications, the benefits seem to outweigh the costs (review in 2017 favours it but does not seem to strictly distinguish non-RF Sydenham’s) and American Heart Association 2009 guidelines recommend it wholeheartedly, but not straightforward. Australian 2020 guidance states “Even in the absence of echocardiographic evidence of carditis, patients with chorea should be considered at risk of subsequent cardiac damage. Therefore, they should all receive secondary prophylaxis, and be carefully followed up with echocardiography for the subsequent development of RHD” but this seems to be based on high rates of rheumatic heart disease found later in patients with chorea who probably never had echo done at presentation in the 1980s.
Patients find injections of benzathine penicillin painful; measures to reduce pain and distress associated with intramuscular antibiotics eg combination with local anaesthetic will aid in adherence. Downside of oral twice daily penicillin is the restrictions around meal times (absorption affected by food, so advised best given at least 1 hour before or 2 hours after), which can be challenging. But remembering to take it probably more important!
Recurrence
Recurrence seen in 16-40%. More likely if poor compliance with penicillin prophylaxis, of course. Sometimes associated with rise in ASO or other evidence of new streptococcal infection but certainly not always the case. No obvious clinical parameter that might predict those at risk of recurrence. More likely if failure to remit in initial 6 months. Can recur with pregnancy and possibly with other female hormone treatments eg oral contraceptives or HRT.
Higher recurrence rates seen in longest follow up – can recur up to 10 years after the initial episode, so might be underestimated by series with shorter follow up.
Usually recurrence is just chorea, even if you had other features of rheumatic fever to begin with. Just two reports of heart disease worsening after recurrence of chorea [Israel and Thailand]. The Thailand study also had 2 cases where carditis, which had improved after initial diagnosis, came back again. Some suggest that perhaps recurrent chorea is a different disease altogether. [Israel, Arch Neurol. 2004; Turkey, PMID 27209549]
“In SC relapse, repeat clinical assessments, etiological investigation, and antibiotics plus corticosteroid therapy should be considered.”
Prognosis
Most resolve within 2-4 months. Improvement tends to be rapid once it begins.
10% reported long term tremor in one study (10 years follow up). Long term neuropsychiatric difficulties increasingly recognised (49 studies so far, {Michael Morton and Nadine Mushet 2016 PMID 25926089] esp Obsessive-compulsive disorder but also Attention-deficit-hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, psychotic features, language impairment.
Heart involvement improves in about a third of cases (whether silent or not).[PMID 22734303]
Benign hereditary chorea (BHC) – rare. In infants low muscle tone, chorea, lung infections, and respiratory distress. In older children, delayed motor and walking milestones, myoclonus, dystonia (esp upper limb), motor tics, and vocal tics. The chorea often improves with time, in some cases myoclonus persists or worsens. Some have learning and behaviour problems, thyroid problems and recurring chest infections. Caused by mutations in the NKX2-1 gene (autosomal dominant)
Bilateral striatal necrosis is a rare condition where similar symptoms but chronic and permanent. Various causes, has been seen in association with streptococcus. Has been described in a case of Sydenham’s where symptoms recurred and then persisted, so not clear whether coincidence or it wasn’t really Sydenham’s in the first place.
