Challenging infections in pregnancy: a multiparametric approach

REVIEW

Challenging infections in pregnancy: a multiparametric approach

Details of the mortality attributable to individual organisms were omitted from the most recent report, but presumably include the usual GAS and Gram negatives with less influenza. Morbidity rates are even more difficult to estimate, although the United Kingdom Obstetric Surveillance System UKOSS study 2014 suggested for each death there were some 50 patients with severe sepsis who survived. Viral infections in pregnancy rarely produce sepsis, and there are numerous publications and guidelines available to consult on viral hepatitides, HIV, parvovirus and Herpes viruses. Zika virus exposure in pregnancy is leading to a plethora of publications, but who to test, what methodology to use and optimal management are the subject of fierce debate, out with the scope of this review. The devastating effects of influenza pneumonia in pregnancy will, however, be considered. This review will concentrate on bacterial infections in pregnancies that are particularly problematic for clinicians, employing a clinical microbiologist’s multi-parametric approach to their diagnosis, aetiology, and management.

Marina Morgan

Abstract Despite advances in medical knowledge, infection still kills pregnant women. Early signs of sepsis may be missed or overlooked by busy healthcare workers, some with little experience of infections, and it can be difficult to recognise symptoms in a woman where infections present in subtle ways. The pregnant woman’s immune system is compromised and she may have other reasons for malaise, flushes, miscellaneous aches, nausea, vomiting and abdominal pain, all of which could herald sepsis. This review is intended to cover basic microbiology germane to the diagnosis and understanding of infection, and combine this with microbiologically orientated aspects of clinical skills and pertinent history taking. These parameters, together with appropriate laboratory tests, can help the clinician spot infection early, and point towards the identification of the underlying causative agent. A review of antimicrobials, the place of immunoglobulin and other adjunctive therapies completes the multiparametric and pragmatic approach to diagnosis and management of serious infection in pregnancy.

Keywords immunoglobulin; pregnancy; toxic shock

influenza;

necrotising

Causes of infection (Table 1) The major bacterial organisms causing fatal infection during pregnancy remain Streptococcus pyogenes (GAS) E. coli and coliforms e some multi-resistant Streptococcus pneumoniae Others, (mostly single case reports nowadays) include meticillin resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis (MTB) Clostridium septicum, and unusual Gram negatives e Serratia spp, Salmonella spp and Morganella morganii.

fasciitis;

Introduction

Influenza

Maternal mortality in the lying in hospitals fell initially after the introduction of hand washing and emphasis on hygiene by Semmelweis in Vienna and Oliver Wendell Holmes in the USA, with most sepsis then attributable to Group A beta-haemolytic streptococci (GAS) With the introduction of sulphonamides and penicillin in the mid-20th century, mortality fell further. A resurgence of invasive GAS in pregnancy in 2006e8 produced an infection related mortality of 1.13/100,000 pregnancies, (CMACE report) leading to new ‘Green top’ guidelines, and a drive to educate healthcare workers about sepsis. The subsequent MBRRACE report MBRRACE-UK: Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (2009e12 published 2014) found GASassociated mortality exceeded only by swine influenza, with an overall infection mortality rate of 0.63/100,000 live births. The subsequent dramatic decline to an overall figure of 0.08/100,000 (data from the 2009e14 MBRRACE report published 2016), probably reflects a combination of increasing influenza vaccine uptake, implementation of various sepsis-related guidelines and mandatory education of healthcare staff to recognise sepsis.

During 2009e12, a massive upsurge in influenza accounted for 43% of all infection-related deaths in pregnancy, thirty six women died, mainly because of H1N1, ‘swine flu’ (MBRRACE report), in stark contrast to only one death during the three years of the subsequent report (MBRRACE 16). As with the general population, morbidity and mortality was associated with a BMI of >30, and additionally, pregnant women are susceptible because of a low immunoglobulin, IgG4. Contributory factors to maternal mortality included diagnostic delay, and being unvaccinated. 75% died untreated whist awaiting confirmation of the diagnosis. Patients suspected of influenza should be tested immediately using viral Throat swab for Influenza PCR, barrier nursed and treated with antivirals before diagnosis confirmed, as per national PHE guidelines. H1N1 (‘swine flu’) has a predilection for young women, multiparous and in the first or second trimester of pregnancy. Early delivery may be indicated during the third trimester of pregnancy. Comparatively few pregnant patients have been treated with ECMO for influenza, with an overall survival of 66% was reported from a large Australian and New Zealand Intensive Care Society series. Pulmonary haemorrhage due to primary influenza or secondary necrotising pneumonia due to PVL-S aureus or GAS causes severe respiratory compromise with almost certain death.

Marina Morgan FRCPath is a Consultant in Medical Microbiology at Royal Devon & Exeter NHS Foundation Trust, Exeter, UK. Conflicts of interest: none declared.

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Causes of infection Gram appearance

Morphology

Example

Site found

Presentation/associations

Gram positive (blue/purple stained) cocci

Chains of spheres

Streptococci e.g. GAS

Usually mucous membranes e throat, vagina

Gram positive cocci

Gram negative rods

Clusters (staphyle in Greek-roughly translates as bunch of grapes) Brick (rod) shaped

S. pneumoniae Staphylococci (aureus ¼ Latin, ‘golden’) Coliforms/ Enterobacteriaceae

Oropharynx Skin, mucous membranes, nose. Gut reservoir

Skin and soft tissue infections (SSTI) Puerperal sepsis (GAS) Neonatal and maternal sepsis (Group B Streptococci (GBS)) Respiratory infections SSTI, toxic shock

Gram negative rods

Slender rods

Gram positive rods (aerobic)

Slender rods

Intra-abdominal urinary tract infections (UTIs) Preterm Premature rupture of membranes Cerclage Rarely healthy patients, Catheter associated UTIs

Pseudomonas aeruginosa Listeria monocytogenes Gut, from unpasteurised Sepsis, meningitis in mother, animal products Listeriosis in fetus (microabscesses e “granulomatous infantiseptica”)

Anaerobes; 1] Gram negative rods Pink rods 2] Gram positive rods Blue/purple rods Spore producers, produce exotoxins

Bacteroides spp C. difficile C. perfringens

Gut, oral cavity

Abscesses

Gut Gut contaminated wounds, dead tissue

Antibiotic associated diarrhoea Gas gangrene

Table 1

Initiating Extra-Corporeal Membrane Oxygenation (ECMO) early can improve survival. It can be difficult to differentiate influenza from exotoxin syndromes, given they can all produce myalgia, high temperature, prostration, diarrhoea and vomiting and conjunctivitis, as illustrated in Table 2.

Infections by site Treatment of UTI in pregnancy Hormonal changes cause muscular relaxation and urinary stasis with decreased bladder emptying. Gram-negative rods, mainly coliforms and in particular Escherichia coli, are major

Comparison of influenza and TSS Influenza

Toxic shock syndrome (TSS) (S. aureus)

Streptococcal TSS (GAS)

Very acute onset of severe myalgia Cough High temp Severe prostration

Slower onset illness, myalgia Usu no cough High temp/low temp Confusion, prostration Exotoxins e nausea D V 100% rash if Staph (TSS) Multi-organ failure May be vaginal origin but uncommon. Small wounds most common source. High/rapidly climbing CRP Haemoptysis not associated with TSS, usually associated with PVL-S. aureus pneumonia

Usu no cough High temp/low temp Confusion, prostration Exotoxins e nausea D V 10% rash if GAS (STSS) Multi-organ failure May be vaginal origin Often soft tissue focus. High/rapidly climbing CRP Haemoptysis with severe pneumonia, but GAS pneumonia is rare

No rash

Low CRP (till bacterial superinfection) Haemoptysis (if severe pneumonia)

Table 2

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uropathogens. Asymptomatic bacteriuria (ASB) defined as >105 organisms per ml, is common in pregnancy (2.5e10%) and usually detected on the first antenatal visit. Progesterone’s relaxant effect on the vesico-urethral junction predisposes to urinary reflux and ascending infection. Pregnancy also provides favourable circumstances for stone development, namely increased urinary calcium oxalate and uric acids, stasis due to hydronephrosis and increased urinary pH, although stones may be passed a little easier via dilated ureters. Some 20e30% of those with ASB develop symptomatic infection and pyelonephritis, acute pyelonephritis being the most common cause of septic shock in pregnancy. Women with asymptomatic bacteriuria confirmed by a second urine culture should be treated. Seven days post antibiotic treatment a ‘test of cure’ should be performed and culture repeated at each antenatal visit until delivery. After urine and blood cultures, bearing in mind any previous sensitivities e pyelonephritis should be treated with intravenous empirical antimicrobials for at least 48 h. Hydronephrosis, renal stones and abscess should be excluded with an ultrasound scan. Acute pyelonephritis should be treated aggressively, and if septicaemia develops a stat dose of gentamicin may be lifesaving.

Extended spectrum beta-lactamase (ESBL) producing coliforms are increasingly causing problematic UTIs, consequent on resistance to cephalosporins, many penicillins and monobactams; empirical treatment may require intravenous carbapenems or rarer antimicrobials such as colistin. Inadequately treated ESBL-associated UTIs have been fatal. Patients from abroad have considerably higher rates of ESBL coliform gut carriage than those less travelled. An Irish study reported <2% prevalence of ESBL producing coliforms in a maternity unit. ESBL carriage obviates cephalosporins as caesarean prophylaxis, and therapy in penicillin-allergic women. Genuine urinary infection with pseudomonas is rare, mostly lower urethral colonisation. If treatment is necessary, the only oral antimicrobial ciprofloxacin is not an option because of side effects. Intravenous gentamicin, ceftazidime, piperacillin etazobactam, meropenem or aztreonam are alternatives. Whilst best avoided if possible, gentamicin is currently considered the safest of the aminoglycosides to use for severe infection. With a very wide spectrum of activity (except streptococci) and where side-effects may be outweighed by the benefits, a single dose may be justifiable. Hence a single dose would normally be used with another broad spectrum agent (such as piperacillin-tazobactam) to control bacteraemia, prior to completing therapy with an antimicrobial to which the organism is susceptible. Ertapenem has been used for continuation outpatient therapy since it given once daily intravenously, but unlike the other carbapenems has no activity against pseudomonas. For pyelonephritis, the treatment course may be followed by oral nitrofurantoin prophylaxis (upper tract infection is not responsive to nitrofurantoin). The true Gram negative ‘superbugs’ are those producing resistance to carbapenems, the metallo-betalactamases (Carbapenemase Producing Enterobacteriaceae or CPEs). Particularly associated with foreign travel, residence or inpatient stays in hospitals abroad, CPE producing organisms are easily spread, outbreaks causing closure of units to admissions. Most hospitals actively screen high risk patients for CPE using rectal swabs, barrier nursing patients till proven negative. CPE producers may be sensitive to aztreonam and colistin with mainly case reports of CPE in pregnancy reported to date (Table 3).

Antimicrobials for UTI in pregnancy Prevailing sensitivity data should inform local guidelines and empirical therapy. Amoxicillin and cephalexin are considered safe in pregnancy but cephalexin will not cover ESBL producing bacteria. Trimethoprim is unlikely to cause problems in women with normal folate status. Hence oral options for ESBL coliforms in pregnancy are limited, necessitating consideration of nitrofurantoin, fosfomycin and pivmecillinam. Carriage/infection with ESBL bacteria needs flagging up for infection control precautions and to prevent any peri-partum infection being inappropriately treated. Nitrofurantoin should not be used in patients with G6PD deficiency or after 37 weeks in pregnancy because of the neonatal immature erythrocyte enzyme systems. Pivmecillinam cannot be used in penicillin-allergic patients.

Therapy of UTI in pregnancy Action

Possible oral options

Intravenous options

Asymptomatic bacteriuria

Confirmed at second culture treat empirically

N/A

Simple UTI (cystitis) with ESBLs

Flag notes as ESBL carrier to ensure correct empirical treatment if represents

Treat according to sensitivity and local guidelines Often 7 days Cephalexin if sensitive Nitrofurantoin Fosfomycin Pivmecillinam N/A

Piperacillinetazobactam or carbapenem Carbapenem (e.g. meropenem) then consider prophylaxis e e.g. nitrofurantoin

Complex UTI (pyelonephritis) Complex UTI (history of or suspected) ESBL producing organism

N/A

Ertapenem

Table 3

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Symptomatology and diagnostics Action in all cases: Blood cultures 2 Assess for signs sepsis (Sepsis 6)

Symptom

Enquire or examine for

Possible diagnosis

Fever Beware ‘normal’ temperature with antipyretics Diarrhoea or vomiting

Persistent spiking temperature Rigors e bacteraemia

Suggests abscess

Contacts/family similar? Any skin sepsis, rash, patient septic?

Viral or bacterial gastroenteritis may indicate exotoxin production (early toxic shock) ask if patient or contacts have tonsillitis/scarlet fever etc.

Vaginal discharge

Smelly Sero-sanguineous

Suggests anaerobes Suggests streptococcal infection (exotoxins lysing polymorphs)

Abdominal/pelvic pain and tenderness

Vaginal discharge Even watery can be infectious e.g. GAS

Rash

Generalised maculopapular rash (sunburn like)

Petechiae/purpura

Check vaccination (MMR) and exposure (VZV) history

Vesicular

?contacts with tonsillitis/scarlet fever etc. Suggests Streptococcal Recent surgery or wound Suggests staphylococcal early shock, meningococcal septicaemia some viruses (enteroviral, infectious mononucleosis, Zika) if not ‘cropping’ e different stages of evolution, suspect enterovirus

Send stool for virology bacteriology HVS throat swab culture Send stool for virology bacteriology Abdominal pain, fever (>38  C) and tachycardia (>90 bpm) necessitate immediate intravenous antibiotics, since once infection becomes systemic can deteriorate extremely rapidly Vaginal swab

Pain score Ensure no NSAIDS (renal impairment and prevent respiratory burst in polymorphs, so no intracellular killing of GAS) Swab throat and vagina Blood cultures

Swab fluid for virus PCR Beware respiratory compromise with VZV Inform infection control, isolate. D/W infection specialist re treatment

? varicella (‘cropping’ eevolving stages of development, itchy) usually history of contact Consult guidelines for rash in pregnancy

Lymphangitis and regional lymphadenopathy e e.g. groin e suggests streptococcal infection Signs sepsis Suggestive of toxic shock?

Cellulitis or skin discolouration

Pain score e needing increasing analgesia e consider Necrotising fasciitis (NF)

Cough Infectious causes

Productive e sputum thick yellowy/ green Dry cough, pleuritic pain Dry cough and severe myalgia

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Suggests ‘typical’ agents such as S. pneumoniae Sputum for Gram stain & culture ? Atypical agents (Mycoplasma)

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Mandatory pain score Note spread of any rash if evolving (Photographs better than marking skin) Overall 50% of GAS developed in to septic shock with rapid progression e 50% within 2 h. Acosta Agonising pain out of proportion to external signs of redness/bruising Suggest NF Hence scoring 7e8/10 or pain needing morphine e exclude NF Low threshold for ICU with respiratory compromise. Any severe pneumonia, consider whether referral for

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Table 4 (continued ) Symptom

Enquire or examine for

Haemoptysis e fresh- and low leucocyte count, high CRP

Possible diagnosis

Action in all cases: Blood cultures 2 Assess for signs sepsis (Sepsis 6)

Influenza e usually low CRP unless secondary infection Consider PVL-producing S aureus and GAS pneumonia (If CRP low ?influenza)

Extra Corporeal Membrane Oxygenation (ECMO) warranted

Table 4

Respiratory tract infection Since pregnant women have less respiratory reserve, severe pneumonia in pregnancy should be managed in consultation with a respiratory physician, intensivists and an infection specialist, with a low threshold for intensive care admission. A beta-lactam antibiotic, e.g. amoxicillin or cephalosporin for the ‘typical’ pneumonia agent (S. pneumoniae) together with a macrolide antibiotic (for ‘atypical agents’ such as Mycoplasma spp) are the usual empirical combination; tetracyclines and quinolones are contraindicated in pregnancy. Some features in the history or presentation may suggest more unusual pathogens. Haemoptysis with brown sputum suggests pneumococcal pneumonia, whereas severe haemoptysis and a relatively low (or ‘normal’) peripheral white cell count suggests Panton-Valentine Leucocidin (PVL)-producing S. aureus necrotising pneumonia. PVL-producing S. aureus kills leucocytes, and can act with another toxin to cause devastating necrosis and haemorrhage in the lung. Hence PVL-Staph pneumonia typically presents with a low peripheral white cell count, fresh haemoptysis and a very high C reactive protein. Rapid development of cavitating pneumonia and fulminant sepsis follows with >70% mortality in young, fit people if not rapidly recognised and appropriately treated. Generally, S. aureus pneumonia typically follows a viral infection, or can be haematogenously spread e from infected boils or abscesses, e.g. as in a case reported from a Bartholin’s abscess. Usually the patient or close contacts will have a history or recurrent boils or abscesses. During one hospital UK outbreak of PVL S. aureus, a healthcare worker died from pneumonia post caesarean section. Antimicrobials such as clindamycin that switch off production of exotoxins at the ribosomal level are the mainstay of therapy for necrotising infections. National guidelines should be consulted regarding infection control and public health issues. Vancomycin is inadequate therapy for staphylococcal pneumonia. With very low epithelial lining fluid levels, bacteraemia continues for days. Hence for serious MRSA or PVL staphylococcal pneumonia, clindamycin and rifampicin are used; the only other anti-exotoxin agent linezolid can produce thrombocytopenia and peripheral neuropathy, and interacts with some selective serotonin re-uptake inhibitors. However, one case of clindamycin resistant MSRA necrotising pneumonia in a 14 week pregnant woman was successfully treated with linezolid and rifampicin for a month, with no toxicity or teratogenesis reported. Severe respiratory failure in pregnant and postpartum women should trigger early referral to a centre for extra corporeal membrane oxygenation (ECMO) 2016 MBRRACE.

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Mycobacterium tuberculosis With a six-fold increased rate of perinatal death, a twofold increased rate of premature birth and low birth weight, M. tuberculosis (MTB) in pregnancy must be managed by a respiratory physician, in strict isolation whilst an inpatient, and in accord with infection control advice. Guidelines also recommend treatment of latent MTB in pregnancy, especially if associated with high risk of reactivation such as concurrent HIV infection. Rashes in pregnancy The excellent PHE guidelines on the investigation and management of rash in pregnancy, especially those due to viral infection, obviate an in-depth review here. Briefly, a history of appropriate immunisation usually rules out rubella and measles, and a history of chickenpox usually infers protective immunity for the pregnant mother. If immunity is in doubt, as with parvovirus, booking bloods may be tested for evidence of immunity or recent seroconversion, then national guidelines followed. Skin and soft tissue infection; necrotising fasciitis and toxic shock Skin should be carefully examined for inflamed or purulent injection sites and intravenous cannulae. Pus should be aspirated from any abscesses and cultured. Discharges should be swabbed and swabs pre-moistened with sterile water when sampling dry or scabby skin. Skin and soft tissue infections are particularly associated with toxic shock syndromes. Worrying features suggestive of Gram positive sepsis are fever, diarrhoea, and vomiting, abdominal pain, generalised maculopapular rash (staphylococcal or streptococcal sepsis) offensive vaginal discharge and wound infection. The majority of serious skin and soft tissue infections are due to GAS and S. aureus. GAS was responsible for one third of the infections causing maternal deaths in the UK during 2006e2008. S. aureus traditionally causes yellow pus, and some wound strains produce an exotoxin (TSST-1) resulting in toxic shock syndrome (TSS). Tampon-associated TSS is very rare nowadays. Some 10e17% of women carry S. aureus asymptomatically in the lower vagina, with vaginal MRSA carriage rates of 2.1% reported in the USA. Management of skin infection can be difficult. Blisters suggest streptococcal whereas reddened ‘peau d’orange’ skin suggests staphylococcal infection. Mild cellulitis usually responds to flucloxacillin alone orally in high dosage, and local treatment guidelines should be consulted. However, for pregnant patients unwell enough to be hospitalised, a beta-lactamase stable

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penicillin such as flucloxacillin in high dosage (e.g. 2 g six hourly) plus clindamycin to prevent exotoxin production (900 mg qds) is usually successful, stepping down to oral clindamycin or flucloxacillin when the CRP has fallen to about 50 and the woman is clinically well. For MRSA skin and soft tissue infections vancomycin may be used, although clindamycin covers many MRSA, and for severe infections where clindamycin resistance is present, daptomycin has been occasionally used in pregnancy with no ill effect. Generalised erythema, blanching on pressure reminiscent of sunburn rash, conjunctival suffusion, diarrhoea and vomiting all suggest TSS, exotoxins produced by the Gram positives S. aureus TSS or GAS (Streptococcal TSS or STSS). Although all TSS patients by definition have a rash, only 10% of Streptococcal TSS patients present with a rash, and the morbidity and mortality is far higher than Staphylococcal TSS. Evidence of old surgical drainage or healed scars suggests chronic staphylococcal colonisation. For superficial infections, decolonisation with topical antisepsis or is more helpful than oral antibiotics in eradicating carriage. Recurrent boils and SSTIs in the patient or family contacts suggests colonisation with PVLproducing S. aureus, with numerous case reports of abscesses e including a case of labial abscess e acting as a focus for haematogenous spread to the lungs.

The cardinal feature of necrotising fasciitis of agonising pain, out of proportion to what can be seen, necessitates increasingly stronger analgesia culminating in opiates. Patients need emergency referral to a plastic surgeon and an intensivist. Although usually due to GAS in young fit people, when penicillin and clindamycin may suffice, since NF can be mixed Gram negative and positive organisms, initial therapy should be

Staphylococcal and Streptococcal toxic shock syndrome clinical disease definitions

Necrotising fasciitis Usually arriving in the area from bacteraemia, or implanted after an operation such as caesarean section, any organism can cause necrosis of the fascial layers. In young women, the cause is less likely to be synergistic (type 1, mixed organisms) which are more associated with elderly patients with co-morbidities and cancer, and easier to diagnose and manage, Young women have more exposure to GAS from small children who carry GAS asymptomatically. Hence type 2 (GAS) necrotising fasciitis is relatively far more common, but more difficult to diagnose early because exotoxins may produce misleading vomiting and diarrhoea. Easily overlooked as the focus of GAS sepsis is the vagina. Vaginal discharge is characteristically unimpressive, thin and watery because leucocytes are destroyed by GAS leucocidins. The M28 strain of GAS, with newly acquired pathogenic and adherence mechanisms is specially adapted for vaginal colonisation. Hence rates of infection have increased dramatically, almost approaching the incidence of prevalent M1 strains. Vaginal GAS colonisation in pregnancy is rare, only 0.03% e0.06% of pregnant women, but often associated with itching and perianal dermatitis. Ascending vaginally, GAS causes endometritis, peritonitis, septicaemia and Streptococcal toxic shock syndrome (STSS), or simulates venous thrombosis in a limb when actually the cause is underlying necrotizing fasciitis. A deep tissue focus, usually from a bacteraemia, results in infection spreading along the fascia, causing increasing pain due to swelling and thrombosis. Regular pain scores must be collated, in order to detect worsening of infection, and an ominous sign is when the skin becomes numb after the necrotising process ascends to the surface in late infection when bruising, blisters, obvious redness and discolouration appear. . Non steroidals should be avoided because they depress the respiratory burst, preventing intrapolymorph GAS destruction.

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Staphylococcal toxic shock syndrome (TSS)

Streptococcal toxic shock syndrome (STSS) (Modified CDC definition 2010)

1. Fever  39.9  C 2. Rash e diffuse blanching erythema (‘sunburn’ like) 3. Desquamation e 10e14 days after onset of illness e palms and soles 4. Hypotension e systolic BP <90 mmHg adults Multisystem involvement Three or more of the following systems affected: Gastrointestinal e vomiting or diarrhoea at onset illness Muscular e severe myalgia or elevated Creatinine phosphokinase Mucous membranes e vaginal, oro-pharyngeal or conjunctival hyperaemia Renal e blood urea nitrogen or creatinine twice upper limit of normal Hepatic e total bilirubin twice upper limit normal Haematological e platelets <100  109/L Central nervous system e disorientation or alterations conscious level with no focal neurological signs Case classification: Probable e four of the five clinical findings positive Confirmed e case with all five clinical findings

A. Isolation of GAS from: 1. Normally sterile site e blood, CSF, peritoneal fluid, tissue biopsy. 2. non-sterile site e throat, vagina, sputum

Overall better prognosis e mortality 2%

B. Clinical case definition Multi-organ involvement characterised by two or more of the following: 1. Hypotension 2. Two or more of the following: Renal impairment e creatinine> 2 mg/dl Coagulopathy e platelets <100  109/L or disseminated intravascular coagulation. Liver involvement e ALT, AST or bilirubin levels twice normal upper limit for age Acute respiratory distress syndrome. Generalised erythematous macular rash e (10% patients) may desquamate Soft tissue necrosis- necrotising fasciitis, myositis or gangrene Case classification: Probable e meets clinical case definition (above) plus isolation from non-sterile site Definite e meets clinical case definition (above) plus isolation of Group A streptococcus from a normally sterile site Poor prognosis especially if associated with necrotising fasciitis: mortality >40%

Table 5

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very broad. A combination of intravenous piperacillintazobactam plus clindamycin (1.2 g qds) covers most organisms. If ESBLs are likely (previous history recent foreign travel) meropenem may substitute for tazocin. If MRSA is likely,

vancomycin may be added until tissues have been Gram stained and/or culture results are available. Intravenous immunoglobulins are the last therapeutic approach, but note, are only effective in Gram positive infections (see below).

Points to note in history re infection Recent febrile illnesses

Chills, rigors Chills, rigors, myalgia

Exposure history

Impetigo, tonsillitis cellulitis Recurrent boils or abscesses

Prior UTI? Intravenous drug misuse

Diarrhoea and vomiting

Zoonotic exposure

Unpasteurised milk products Animals with diarrhoea Birthing animals, washing clothes of partners exposed to such, feeding pet lambs

History of carriage/infection with multiresistant organisms

Foreign travel/hospitalisation abroad

Recent antimicrobials

Allergies

Exactly what happens? Nausea/vomiting ¼ intolerance Rash with penicillins Anaphylaxis with penicillins

Suggests bacteraemia (or influenza) Influenza (in flu season) (beware dual infection with both if pneumonia) Enteroviral infection Staphylococcal/streptococcal bacteraemia Likely GAS PVL producing S aureus Check sensitivities in case ESBL Check recent treatment Endocarditis (may present as pneumonia if tricuspid valve involved) S aureus and GAS infections, immunosuppression of chronic disease Blood borne viruses Gastroenteritis e food-borne pathogens, Salmonella spp. Campylobacter spp Early toxic shock (exotoxins acting as enterotoxins) C difficile Norovirus Salmonella, Campylobacter or Listeria Campylobacter, C. difficile, salmonella, Cryptosporidium As above plus Q fever Chlamydophila (Can be rapidly fatal in pregnancy) ESBL producing Gram negatives MRSA, Carbapenemase Producing Enterobacteriaceae (CPE) Vancomycin Resistant Enterococci (VRE) Need infection control precautions (e.g. side room) Limits empirical antimicrobial choice Discuss with infection specialist re isolation procedures and diagnostic tests Knowing spectrum of any recent failed treatment may suggest the infecting organism.(e.g. if failed on amoxicillin then beta-lactamase producing Staph or coliform may be responsible) see chart Ensure not unnecessarily precluding beta lactams with a weak history of possible allergy (vomiting with co-amoxiclav e an intolerance) 3%e10% chance of cross reaction with cephalosporins Avoid cephalosporins and carbapenems altogether d/w infection specialist but erythromycin, clindamycin or vancomycin may be appropriate alternatives

Table 6

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cabbage e.g. coleslaw) unpasteurised cheeses and milk, and cured meats. With no serological diagnostic test available, diagnosis relies on culture from sterile sites such as blood and cerebro-spinal fluid (CSF). Rarely, a genetic test (16S PCR) to detect traces of bacteria may be performed by reference laboratories.

Meningitis and Listeria Viral meningitis is far commoner than bacterial meningitis, and in pregnancy enteroviral infection is of most concern, with implications for any baby born around the time of infection. Enteroviral infections may produce little or no gut symptoms, and instead often produce rashes. A CSF, throat swab and/or stool should be tested for enterovirus PCR. Although usually self-limiting for the mother, perinatal enterovirus infection can produce a sepsis syndrome often reminiscent of meningococcal sepsis which if unrecognised is commonly fatal in the neonate. With little in the way of inflammatory markers (low CRP) a high creatinine kinase (myocarditis and muscle inflammation) may provide the clue to underlying enteroviral infection. Early intravenous immunoglobulin therapy has been used with success. Pneumococcal meningitis deaths in pregnancy continue to be reported, meningococcal infections less common with vaccination. Bacterial meningitis should be managed as in non-pregnant women with an empirical cephalosporin, usually ceftriaxone; empirical amoxicillin must be added since Listeria monocytogenes is inherently resistant to cephalosporins. During 1990e2010, in England and Wales, 15% of reported cases (462 cases) were in pregnant women, with 315 cases (68%) resulting in a live birth. Risk foods for Listeriosis remain raw, faecally contaminated foodstuffs (organically manured

Gastroenteritis Campylobacter spp and salmonella spp are the commonest bacterial causes of gastroenteritis. Uncomplicated gastroenteritis should be managed symptomatically unless features of bacteraemia are present, in which case advice from an infection specialist should be sought. Severe systemic infection is rare but is associated with abortion. Diarrhoea and vomiting are also features of viral gastroenteritis such as norovirus, typically occurring in family and hospital outbreaks. Beware assuming that diarrhoea and vomiting in septic patients is due to primary gut infection as exotoxins produced by GAS or S. aureus acting as enterotoxins may be responsible. C. sordellii happily, is a very rarely seen, fatal pregnancyassociated infection, producing a toxic shock syndrome and usually occurring after abortion. Superinfection with C. difficile follows disruption of the normal balance of the gut flora (microbiome) by antimicrobials with anaerobic activity. The more resistant organisms (Candida

Microbiological investigations Investigation

Points

Blood cultures (two sets) Midstream urine High vaginal swab Sputum Cerebrospinal fluid Throat swab Throat swab Nasal swab

Culture Culture Gram stain and culture Gram stain and culture Gram stain and culture Bacterial culture Viral PCR MRSA screening (if local guidelines)

Prior to antibiotic administration Prior to antibiotic administration

Stool

Routine gastroenteritis pathogens

Recent foreign travel

Tissues/pus

Post antibiotics, or offensive diarrhoea with no history of antibiotics If meningitis Outbreak, profuse vomiting and diarrhoea Few leucocytes and Gram positive cocci in chains Gram positive cocci in clusters massively outnumbering leucocytes Mixed Gram negative and positive organisms Gram positive rods Gram positive rods

Culture in case asymptomatic carriage Influenza, enterovirus Pre-moistened anterior nares swab for maximal yield Salmonella spp. Campylobacter spp culture e 24e48 h Listeria spp e only if high risk (consumption of soft cheese, cured meats) Ova cysts parasites S. typhi, V. cholerae culture C. difficile toxin testing Enterovirus PCR Norovirus PCR Streptococcal infection PVL S. aureus likely Suggests presence of anaerobes may indicate synergistic infection Listeria or Clostridium spp

Table 7

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REVIEW

spp and C. difficile) multiply to fill the niches, and then exotoxin production by C. difficile kills enterocytes, producing typical offensive diarrhoea. Diagnosis is by toxin-testing stool (not culture); Polymerase chain reaction (PCR) merely demonstrates the presence of C. difficile capable of producing toxin. Mortality up to 30% has been reported, but early treatment is effective. Oral metronidazole or vancomycin for 10 days is advised. In practice vancomycin is more effective, much more palatable, causes less disruption to the residual bowel anaerobes and leads to a quicker recovery. Mostly occurring peripartum, especially after caesarean prophylaxis, C. difficile infection can present at any time, and has a high complication rate, including toxic megacolon that necessitates colectomy in up to 5% (Tables 4 and 5). Given good local obstetric guidelines for management of sepsis, microbiologists usually have little to add except in the detail of the history taken. Below are some particular points of note that may be elicited during a good history, which may point to the organisms (Table 6).

ribosomal level, switching off exotoxin and super antigen production). For known or suspected MRSA a glycopeptide such as vancomycin or teicoplanin infusions may be added until sensitivities known. If allergic to penicillins or for convenient outpatient therapy, (e.g. cellulitis) intravenous daptomycin once daily is quickly bactericidal and reportedly successful in pregnancy (Table 10). Intravenous immunoglobulin (IVIG) IVIG is available from the blood transfusion department. Commercial IVIG is imported from the USA, and contains exotoxinneutralising antibodies from pooled donors. IVIG is mostly used in Gram positive sepsis to neutralise super-antigens and exotoxins such as TSST-1 (from S. aureus), haemolysins and DNASes (from GAS) and leucocidins (from S. aureus and GAS) in toxic shock, necrotising pneumonia and necrotising fasciitis.

Laboratory results suggestive of bacterial sepsis

Management of infection Severe sepsis with acute organ dysfunction has a mortality rate of 20e40% rising to >50% if septicaemia occurs, hence early referral for intensivist opinion is warranted. The Modified Early Obstetric Warning Scoring (MEOWS) system helps identify seriously ill pregnant women, and shock or other organ dysfunction mandates intensivist involvement. Optimal infection management relies on early recognition, appropriate antimicrobial therapy and source control (drainage of abscesses, debridement of infected tissue). The UK Sepsis Trust Inpatient Maternal Sepsis Tool is a helpful guide to the ‘red flag’ symptoms. These include any one of the following: response only to voice or pain/unresponsive, systolic BP 90 mmHg (or drop >40 from normal), tachycardia (130 per minute), tachypnoea (respiratory rate 25 per min), oxygen need to keep SpO2 92%, a non-blanching rash, mottled/ ashen/cyanotic, anuria or output less than 0.5 ml/kg/h and a lactate 2 mmol

Neutrophil polymorphs Elevated or very low neutrophil counts can both indicate sepsis Lymphocytes

Suggests

>35 ‘Normal range’ but with high CRP Very low

C. difficile colitis Early evolving/PVL staph sepsis Overwhelming sepsis, PVL staph

Absolute lymphopaenia (<1  109/L)

Often suggests overwhelming Gram positive infection (exotoxins) less frequently Gram negatives Sepsis/viral suppression Collection-pus or fluid Severe bacterial infection (unless complicated with pancreatitis/thrombosis) Intravascular haemolysis-GAS

Platelets

Thrombocytopenia Thrombocytosis C reactive protein Rapidly rising (or e.g. >200 mg/L)

Microbiological investigations (Table 7) The list is not exhaustive, but intended as a general guide. When following the guidelines for sepsis, clues that can be gleaned from ‘routine bloods’, especially if repeated after 4 h, include a high or rapidly rising CRP (suggests bacterial sepsis). Falling haemoglobin out of proportion to the fall in haematocrit during fluid resuscitation suggests intravascular haemolysis typical of GAS. C-reactive protein (CRP) is unaffected by viral infections. When managing exotoxin (S aureus or GAS) disease, sequentially falling CRP with rising lymphocyte and platelet counts are reassuring (Tables 8 and 9). Hospital guidelines should reflect the incidence of resistant organisms locally, but the following principles are useful. Prescribers of antimicrobials are responsible for administering the first dose. The least toxic, broadest spectrum cover for severe sepsis in pregnancy, is a combination of a cell-wall active agent (piperacillin/tazobactam or carbapenems) covering most Gram positive and negative organisms, plus clindamycin (acting on the

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-

Parameter

Haemoglobin

Creatinine kinase

Falling with little relative decrease in haematocrit High/rapidly rising

Myositis or (deep fascia) NF

Raised blood glucose Metabolic acidosis Raised serum lactate Abnormal coagulation Rising creatinine Raised bilirubin Falling albumin Table 8

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REVIEW

Antimicrobial choices and limitations of antimicrobials

Co-amoxiclav

Clindamycin

Cefuroxime and cefotaxime Metronidazole Carbapenems

Nitrofurantoin

Effective against

Ineffective against

Most coliforms, streptococci MSSA Most MSSA >90% GAS Many anaerobes MSSA Many coliforms

MRSA Pseudomonas Amp C producing Gram negatives Coliforms, pseudomonas

Almost all anaerobes, some parasites Almost all Gram negatives and anaerobes, MSSA Many urinary pathogens

Pseudomonas ESBL-producing coliforms Enterococcus faecalis Aerobes MRSA CPE (carbapenemase) producing Gram negatives Proteus

Notes

Stops exotoxin production not renally excreted or nephrotoxic association with C. difficile Association with C. difficile superinfection Poor anaerobic activity Not known to be harmful Renal sparing (in contrast to aminoglycosides)

Haemolytic anaemia if G6PD deficiency

Table 9

Antibiotic spectra

Table 10

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REVIEW

The main contraindication to IVIG use is congenital immunoglobulin A deficiency. Since IVIG administration produces immunodulatory effects, neutralises super-antigens (exotoxins) inhibits tumour necrosis factor (TNF) and interleukin production, a flurry of case reports and some small series have reported dramatic improvement with IVIG. In the author’s experience, administration of IVIG to patients with recalcitrant Gram positive (exotoxic) shock is lifesaving, but there is little value in using IVIG in Gram negative (endotoxin related) sepsis. A plateauing or falling CRP and rising lymphocyte count, together with decreased need for vasopressors, are heartening signs of an ultimately successful outcome. Clinicians noting the decreasing need for vasopressors and visible improvement in the patient are convinced by its efficacy, but for the detractors, randomised double blind controlled trial data is sparse and it is expensive. Furthermore, IVIG dosages and timing of administration into the septic event differ widely between centres, hence meaningful interpretation of the published data is difficult. Patients not sick enough to be in the intensive care unit are not sick enough to warrant IVIG. Administration of IVIG should be through a blood warming device and local hospital guidelines/protocols for replacement therapy in haematology patients may be used. The Mount Sinai hospital protocol may also be helpful [http://microbiology.mtsinai.on.ca/protocols/pdf/k5a. pdf]. High dose IVIG (2 g/kg) has been used successfully with no ill effects in pregnant and postpartum women.

Prevention of infection/indications for prophylaxis to family and staff Public Health England has produced detailed guidelines for investigation, control and prevention of spread of GAS in healthcare settings. Antimicrobial prophylaxis should be considered for healthcare workers with exposure to GAS or meningococcal infected respiratory secretions (eg suctioning). Healthcare workers should have been vaccinated against influenza. Although very rare, suspected Q-fever pneumonia may infect those present at delivery, hence infection control precautions and FFP3 masks are recommended. A FURTHER READING Acosta CD, Kurinczuk JJ, Lucas DN, Tuffnell DJ, Sellers S, Knight M. Severe maternal sepsis in the UK, 2011e2012: a national casecontrol study. PLoS Med 2014; 11: e1001672. http://dx.doi.org/10. 1371/journal.pmed.1001672. Centre for Maternal and Child Enquiries (CMACE). Saving mothers’ lives:reviewing maternal deaths to make motherhood safer: 2006 e08. The eighth report on confidential Enquiries into maternal deaths in the United Kingdom. BJOG 2011; 118(suppl 1): 1e203. Guidance on the diagnosis and management of PVL-associated Staphylococcus aureus infections (PVL-SA) in England. PHE 2008, https:// www.gov.uk/government/uploads/system/uploads/attachment_ data/file/322857/Guidance_on_the_diagnosis_and_management_ of_PVL_associated_SA_infections_in_England_2_Ed.pdf. Management of sepsis in pregnancy, (Green-top Guideline No. 64a), Royal College Obstetricians & Gynaecologists, https://www.rcog. org.uk/globalassets/documents/guidelines/gtg_64b.pdf. ska J, Ma1yszko J, Wieliczko M. Urinary tract Matuszkiewicz-Rowin infections in pregnancy: old and new; unresolved diagnostic and therapeutic problems. Arch Med Sci 2015; 11: 67e77. McCracken D. Mount Sinai hospital guidelines for the treatment of necrotising fasciitis and toxic shock syndrome, http://microbiology. mtsinai.on.ca/protocols/pdf/k5a.pdf. Morgan MS. Diagnosis and management of necrotising fasciitis: a multi-parametric approach. J Infect 2010; 75: 249e57. UK Sepsis Trust. Inpatient maternal sepsis tool. 2016, http:// sepsistrust.org/wp-content/uploads/2016/07/Inpatient-maternalNICE-Final-1107-2.pdf.

Infection control issues and sepsis GAS spreads easily among healthcare workers and patients, still causing devastating outbreaks on maternity units, hence isolation in a single room with en suite facilities is recommended. With the general rise in resistant organisms, local guidelines should be followed for all patients with sepsis; staff should wear personal protective equipment including disposable gloves and aprons when in contact with GAS carriers, and cover breaks in the skin with a waterproof dressing to lessen possible transmission of staphylococci or streptococci. Fluid repellent surgical masks with visors must be used at operative debridement/ change of dressings of GAS, nursing patients with influenza or necrotising fasciitis when droplet spread is possible.

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