Discussion+

This( chapter( describes( serotyping( and( antimicrobial( susceptibility( data( for( all( S.# pneumoniae(isolated(from(children(admitted(to(QECH(between(April(2004(and(October( 2006.(

3.6.1 +Serotype+distribution+

An( appreciation( of( serotype( distribution( is( essential( when( designing( and( assessing( the( impact(of(intervention(strategies.(Only(two(studies(have(previously(reported(the(serotype( distribution( of( Malawian( pneumococci.( The( first( reported( the( serotypes( of( 906( pneumococcal(from(nasopharyngeal(carriage,(isolated(in(1997(and(the(second(reported( the( serotypes( of( 750( carriage( pneumococci,( isolated( in( 1998( (60,( 227).( The( data( presented( here( therefore( represents( an( important( contribution( to( our( current( knowledge,( as( it( is( the( only( study( to( report( the( serotype( distribution( amongst( invasive( pneumococcal(isolates(in(Malawi(to(date.(Furthermore,(the(distribution(of(pneumococcal( serotypes(is(known(to(fluctuate(naturally(over(time((228)(and(this(data(is(a(more(recent( representation(of(the(pneumococcal(population(in(Malawi(than(the(previous(studies.((A( limitation(is(that(the(data(derived(from(that(are(more(than(six(years(old((the(study(isolates( were( collected( 2004V2006)( and( may( thus( not( be( representative( of( the( current( pneumococcal( population.( It( is( therefore( essential( that( the( surveillance( of( circulating( serotypes(in(ongoing.((

(

The( serotyping( data( suggests( that( PCV7( would( provide( 40%( coverage( against( IPD( in( Malawi.(Serotype(1(was(the(most(common(serotype(identified,(responsible(for(23.7%(of( all(IPD(in(children(over(the(study(period.(Serotype(5(and(7F(accounted(for(1.4%(and(2.3%( of(IPD(respectively,(thus(the(addition(of(these(three(serotypes(to(the(vaccine(formulation( in(PCV10((PCV7(+(1(+(5(+(7F)(substantially(increased(the(predicted(coverage(to(67%.(The( multiplex(PCR(method(employed(to(establish(the(serotype(of(the(isolates(was(unable(to( differentiate(between(serotype(6A(and(6B.(PCV7(and(PCV10(include(serotype(6B(but(not( serotype( 6A,( when( calculating( serotype( coverage( for( PCV7( and( PCV10,( 6A/B( cross( protection( was( assumed.( Previous( studies( have( shown( that( immunization( with( the( CPS( from( serotype( 6B( is( capable( of( eliciting( cross( protection( to( serotype( 6A( pneumococci( (229).(Although(not(all(anti(6BVantibodies(are(functionally(crossVreactive((230)(and(so(the(

serotype(coverage(presented(here(for(PCV7(and(PCV10(may(be(a(slight(overestimation.( Serotype(3(and(19A(represented(only(a(small(proportion(of(the(study(isolates,(1.1%(and( 0.6%(respectively.(The(addition(of(these(serotypes(to(PCV13((PCV10(+(3,(6A(and(19A)(only( increased(the(predicted(coverage(of(PCV13(to(69%.(( ( The(incidence(of(serotype(1(reported(here((24%)(is(inconsistent(with(studies(from(other( African(countries,(which(report(serotype(14(as(the(most(common(serotype(in(South(Africa( and(Algeria,(responsible(for(13%(and(19.5%(of(IPD(in(these(countries(respectively((231,( 232).(The(global(serotype(project(recently(reported(that(serotype(14(is(the(most(common( cause(of(IPD(in(Africa((proportion(of(IPD:(13%).(Serotype(14(was(however(only(the(fifth( most(common(serotype(in(Malawian(children,(responsible(for(6.3%(of(IPD((233).(( (

Serotype( 1( is( an( important( cause( of( IPD( throughout( Africa,( the( global( serotype( project( reported( that( after( serotype( 14,( serotype( 1( is( the( second( most( common( cause( of( IPD,( responsible(for(11.7%(of(IPD(across(Africa((233).(The(distribution(of(serotype(1(fluctuates( throughout(the(continent.(In(Kenya(serotype(1(is(the(most(common(cause(of(IPD,(isolated( from(42%(of(children(with(IPD((234).(Serotype(1(in(responsible(for(11%(of(IPD(in(South( Africa((231),(while(in(Algeria(it(reported(to(contribute(to(only(5%(of(IPD(in(children((232).( The(data(presented(here(shows(that(serotype(1(is(an(important(cause(of(both(meningitis( and( pneumonia( in( Malawian( children,( it( is( therefore( essential( that( any( intervention( strategies,( target( this( serotype.( PCV13( is( currently( being( rolled( out( in( Malawi( with( the( support( of( the( GAVI( alliance( (section( 1.6.4).( The( protective( efficacy( of( PCV13( against( serotype( 1( pneumococci( is( however( yet( to( be( fully( established( (235).( The( serotype( distribution(data(presented(here(therefore(provides(an(important(platform(from(which(to( monitor(the(efficacy(PCV13(against(serotype(1(in(addition(to(the(other(vaccine(serotypes.((

(

In(this(study(Serotype(5(ranked(11th_{(in(the(list(of(most(commonly(isolated,(responsible(for(} only( 1.1%( of( IPD.( This( is( inconsistent( with( other( reports.( The( global( serotype( project( identified( serotype( 5( as( the( third( most( common( serotype( in( Africa( (proportion( of( IPD:( 10.7%)( (233).( Whilst( the( netSPEAR( surveillance( study( has( previously( reported( that( serotype(5(is(responsible(for(8%(of(IPD(in(children(in(Kenya,(Tanzania(and(Uganda((76).( Serotype(6A/B(was(the(second(most(frequently(isolated(serotype(in(Malawian(children,(

however(given(that(the(multiplex(PCR(was(unable(to(distinguish(between(serotype(6A(and( 6B(it(cannot(be(established(which(of(these(two(serotypes(was(more(dominant(within(the( study(population.(Data(from(the(global(serotype(project(suggests(that(serotype(6A(and(6B( are( responsible( for( a( similar( burden( of( disease( across( the( African( continent,( 9.4%( and( 8.5%(of(IPD(respectively((233).(

3.6.2 Antimicrobial+resistance+

At(QECH(and(all(other(governmentVfunded(hospitals(in(Malawi,(penicillin(is(the(proposed( first( line( treatment( for( the( management( of( pneumonia.( The( use( of( nonVmeningitis( breakpoints( in( this( study( demonstrated( that( none( of( the( pneumococcal( isolates( were( resistance( to( penicillin.( The( data( presented( here( therefore( confirms( the( suitability( of( penicillin(as(a(first(line(treatment(for(pneumonia.(Of(note,(resistance(to(erythromycin(an( alternative( drug( for( treating( pneumonia( was( present( in( 20%( of( isolates.( Ceftriaxone( is( used( as( a( second( line( treatment( for( the( management( of( pneumonia( and( as( a( first( line( treatment(for(the(management(of(meningitis.(None(of(the(pneumococcal(isolates(were( resistant( to( ceftriaxone( based( on( either( nonVmeningitis( and( meningitis( breakpoints,( confirming(the(suitability(of(ceftriaxone(for(both(of(these(applications.(It(should(however( be( noted( that( the( data( presented( here( is( based( on( pneumococcal( isolates( collected( between(2004(and(2006.(Ceftriaxone(was(introduced(into(use(in(Malawi(in(2003(and(its( initial(deployment(was(tightly(regulated.(Since(2007(ceftriaxone(has(however(been(freely( available(to(all(governmentVfunded(hospitals(in(Malawi(through(the(Global(Health(Fund( (Prof.( R.( Heyderman,( personal( communication,( June( 2011).( As( a( result( the( use( of( ceftriaxone(has(greatly(increased,(with(anecdotal(data(suggesting(that(upwards(of(70%(of( all( patients( admitted( to( QECH( will( be( given( ceftriaxone.( There( is( a( clear( association( in( previous(research(between(increase(in(antimicrobial(consumption(and(the(emergence(of( antimicrobial( resistance( (section( 1.6.1).( It( is( therefore( essential( that( the( surveillance( of( antimicrobial(resistance(amongst(the(Malawian(pneumococcal(population(is(ongoing.( ( The(study(isolates(were(susceptible(to(the(new(generation(antimicrobials(listed(in(Table( 3.4(by(antimicrobial(disc(susceptibility.(However,(as(stated(in(the(section(1.3,(there(is(a( wide(range(of(MICs(in(what(is(classed(a(‘susceptible’(by(antimicrobial(disc(susceptibility( testing.(It(is(feasible(that(although(Malawian(pneumococci(are(not(yet(exhibiting(clinically(

defined(resistance(to(these(antimicrobials(based(on(BSAC(criteria,(they(may(be(displaying( subtle(increases(in(MICs,(due(to(extensive(use(of(other(antimicrobials(that(may(be(serving( to(drive(crossVresistance.((

(

A(significant(association(was(observed(between(HIV(positive(children(and(MDR(IPD(in(this( study.( Increased( hospitalisation( and( exposure( to( antimicrobials( have( both( previously( been( identified( as( risk( factors( for( MDR( IPD( (236,( 237).( The( association( between( HIV( positivity( and( MDR( IPD( seen( here( may( be( due( to( increased( hospitalisation( leading( to( nosocomial( infection( of( HIV( infected( children.( It( may( also( be( due( to( the( increased( exposure( to( antimicrobials( experienced( by( this( cohort.( In( addition( to( antimicrobials( administered(for(the(treatment(of(bacterial(infections,(a(high(proportion(of(HIV(infected( children(are(given(antimicrobial(prophylaxis(against(severe(bacterial(infection(as(advised( by(the(WHO((169).(((

(

The(work(presented(here(is(not(a(formal(epidemiological(study,(as(it(does(not(comprise(a( true( random( selection( of( isolates.( Nevertheless,( QECH( is( the( only( governmentVfunded( hospital(in(Blantyre(and(so(the(majority(of(children(admitted(live(in(the(local(community( and(surrounding(townships.(Furthermore,(all(consecutive(cases(of(IPD,(both(severe(and( nonVsevere( were( studied( during( the( collection( period.( This( increases( confidence( in( the( idea( that( the( sample( of( pneumococcal( disease( in( the( children( studied( here( is( representative(of(the(incidence(of(disease(in(the(area(as(a(whole.((

(

Furthermore,( the( resistance( rates( reported( here( are( in( agreement( with( a( recent( study( reporting( the( resistance( rates( of( pneumococci( collected( from( all( patients( admitted( to( Kamuzu(Central(Hospital((KCH),(Lilongwe(over(a(twoVyear(period((2006V2007).(KCH(is(the( main(governmentVfunded(hospital(in(Northern(Malawi,(serving(a(population(of(nearly(two( million(and(subject(to(the(same(antimicrobial(treatment(guidelines(as(QECH.(Confidence( can( therefore( be( placed( that( the( burden( of( antimicrobial( resistance( reported( here( is( applicable(to(the(country(as(a(whole((238).(

( ( (

Chapter(4+

4

The+molecular+basis+of+antimicrobial+resistance+in+S.#

pneumoniae+from+Malawi+

(