von gottberg, A

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MONITORING SUSCEPT IB IL ITYApril 2004  Vol.22  No.4   CME 189Antimicrobials are frequently used for empirical therapy of suspected infections,before comfirming aetiology. The choice of empirical therapy should be guidedby current data on susceptibility patterns of bacteria that have been shown tocause defined clinical presentations, e.g. community-acquired pneumonia (CAP)or uncomplicated urinary tract infections. In South Africa it is essential that weconduct our own regular studies of defined clinical syndromes to identify theirinfectious causes and to evaluate their resistance profiles, as aetiology and sus-ceptibility patterns may vary from country to country. Within South Africa, thesedata may differ between regions.There are many public, private and academic centres which collect data. Forexample, different centres in the country collect a wide range of data about theagents causing sexually transmitted infections (STIs) and their susceptibility toantimicrobials. This guides clinicians in their choice of therapy, without the needto take specimens from each patient for diagnosis or susceptibility testing. Thewell-described syndromic approach followed in many STI clinics in South Africa,is used in an attenuated form for many other infectious presentations: cliniciansmake the diagnosis of CAP (the syndrome) and use published, anecdotal or own-experience data to assist them in the management of this infection. Althoughspecimens may be submitted for microbiological evaluation of respiratory tractinfections, the yield may be disappointing.1INTERPRETING SURVEILLANCE DATAThe purpose of surveillance is to monitor accurately the spread of resistance, andto limit this by appropriate antimicrobial usage and infection control strategies. Inorder for this to happen, surveillance data need to be returned timeously to clini-cians and the committees that formulate treatment guidelines.2In a study in the USA it was shown that data from a limited number of laborato-ries, rather than from all laboratories in a state, could reliably detect largechanges in penicillin susceptibility in pneumococci. However, this did not accu-rately reflect an area’s actual percentage of penicillin-resistant isolates.3We are clearly seeing a high degree of variability in resistance data from labora-tories and groups of laboratories in South Africa. This may be explained by anumber of factors that need to be kept in mind when interpreting surveillancedata (Table I).Disc diffusion testing is the most common form of routine susceptibility testing per-formed in diagnostic clinical laboratories. It may be adequate to guide the use ofantibiotics for some bacteria reliably (e.g. Gram-negative bacteria belonging tothe family Enterobacteriaceae, e.g. Escherichia coli). In other cases the identity ofANNE VON GOTTBERGMB BCh, DTM & H, FCPath (SA) MicroClinical MicrobiologistRespiratory and Meningeal PathogensResearch Unit (RMPRU)Medical Research Council/University of the Witwatersrand/National Institute for CommunicableDiseasesJohannesburgAnne von Gottberg completed her medicaltraining at the University of theWitwatersrand and then joined the Divisionof Clinical Microbiology and InfectiousDiseases at Wits to specialise in clinicalmicrobiology. At present she works withnational surveillance bacterial isolates thatcause pneumonia and meningitis, teachesat the University, and attends clinical wardrounds.PATTERNS OF ANTIMICROBIALSUSCEPTIBILITY AMONG BACTERIALPATHOGENS IN SOUTH AFRICAThe choice of empirical antimicrobial therapy should be guided by current data onsusceptibility patterns of bacteria obtained from surveillance data.190 CME April  2004  Vol.22  No.4MONITORING SUSCEPT IB IL ITYthe organism may be sufficient to pre-dict susceptibility to penicillin, e.g.Streptococcus pyogenes or Strepto-coccus agalactiae, where resistant iso-lates have not been described.With other organisms, such asStreptococcus pneumoniae, additionalfactors need to be kept in mind.Oxacillin discs are used to predictpenicillin susceptibility in the laborato-ry, as this has been found to be moreaccurate than using penicillin or ampi-cillin discs. Zone sizes read as resist-ant on oxacillin disc testing may occurwith penicillin-resistant, intermediate orcertain susceptible strains, and there-fore monitoring of resistance shouldnot be based on disc diffusion testingalone. Clinical reporting may be suffi-cient with this form of testing, becauseif the zone sizes are at least equal to20 mm, as determined in the laborato-ry, the isolate can reliably be reportedas being susceptible to penicillin.Minimum inhibitory concentration(MIC) testing is the gold standard forpredicting susceptibility, and can bedetermined by using E tests (used inclinical diagnostic laboratories) or thereference agar or broth dilution meth-ods (used in academic centres or larg-er laboratories in South Africa).Breakpoints define the concentrationof the antimicrobial, below which theisolate is called susceptible and abovewhich the isolate is determined asresistant.In addition to the in vitro testing of theorganism against the antimicrobial,the site of the infection and the pene-tration of the drug to the site must beconsidered when discussing optimaltherapy (pharmacokinetic and pharma-codynamic parameters). For example,the breakpoints for determination ofsusceptibility of pneumococci varydepending on the site of infection.Breakpoints for isolates from patientswith meningitis are higher than thosefor pneumonia, because achievablelevels of drugs in the cerebrospinalfluid (CSF) are less than thoseachieved in the alveolar space.RECENT DATA FOR SOUTHAFRICAN ISOLATESStreptococcus pneumoniaeResistant S. pneumoniae are more com-monly found in children, in HIV-seropositive individuals4 and from non-sterile isolates. Surveillance studiesshould ideally report according tospecimen source and patient age, anddiscuss details of the patient popula-tion and their clinical presentations.Cerebrospinal fluid isolatesOver a period of 12 months (August2001 - July 2002), 101 of 526viable isolates (19%) (including 9 fromthe private sector) from CSF wereintermediately resistant to penicillin,and 2 (0.4%) were high-level resistant.These were taken mainly from the pub-lic sector. None of these 526 isolateswas resistant to cephalosporins onMIC testing (Anne von Gottberg —unpublished data). Recent data fromprivate laboratories in Johannesburghave shown an increase in the numberof pneumococci isolated from CSF thatare resistant to third-generationcephalosporins: 25% of 14 isolatesduring a 6-month period from July2002 to December 2002 (AdrianBrink and the Antibiotic SurveillanceForum, ASF — personal communica-tion).Empirical therapy of meningitis withceftriaxone or cefotaxime covers peni-cillin-resistant isolates. However, theaddition of vancomycin is required foradequate therapy for 3rd generationcephalosporin-resistant isolates.Because of the frequency of theseresistant isolates in the USA theempirical therapy of meningitis in thatcountry includes vancomycin. This isnot currently recommended in SouthAfrica, although we are approachingthe time when such therapy may benecessary. Surveillance data areessential to guide such decisions.Blood culture isolatesPenicillin resistance increased from4.9% in 1979 to 14.1% in 1990 fornormally sterile site isolates frompatients presenting to the public sectorin South Africa.5 Currently 18% ofinvasive isolates submitted to theRespiratory and Meningeal PathogensResearch Unit (RMPRU) are resistant topenicillin (Table II). Small numbers ofisolates with high-level resistance topenicillin were documented (4 of2 127 tested (0.2%)). ApproximatelyTable I. Important components of surveillance systems to bekept in mind when interpreting dataAt laboratory levelMethod of susceptibility testing: disc diffusion testing v. MIC determina-tion with E tests or MIC determination with broth or agar dilutionsAntibiotics selected for testingQuality assurance programmes within the laboratory Information technology or method of data capture and analysis  Organism source Human or animalClinical or environmentalUnique v. repeat isolatesDefined specimens, or all specimens includedRestricted organisms, or all organisms included  Patient selection Community v. hospital populationAny clinical inclusion and exclusion criteria Adapted from Masterten RG. J Antimicrob Chemother 2000; 46: 53-58.2MONITORING SUSCEPT IB IL ITYApril 2004  Vol.22  No.4  CME 19199 of 2 245 (4.4%) were casesreported from the private sector.Penicillin resistance has remained sta-ble over the past 5 years.6 Of theseisolates, 9% were erythromycin resist-ant.Data from the private sector for bloodculture isolates in patients with proba-ble lower respiratory tract infectionsshow intermediate resistance to 3rdgeneration cephalosporins, rangingfrom 0% to 25% between centres, withno high-level resistance being docu-mented in isolates (Adrian Brink andthe ASF — personal communication).Erythromycin resistance of these iso-lates ranges from 22% to 30%.Sputum isolatesThe role of sputum isolates in diagnos-ing the aetiology of lower respiratorytract infections is controversial.1Pneumococcal isolation may notalways represent the true bacterialcausation of pneumonia, and unlesssome effort is made to exclude coloni-sation, these data may represent onlyinformation about colonising pneumo-cocci in a certain population.Data from a recent study identifiedhigh levels of resistance in pneumo-cocci isolated from non-sterile sitespecimens: 30% intermediate and46% high-level resistance topenicillin.7 However, 82% of these iso-lates were submitted from one labora-tory in Pretoria. Additional informationabout patient characteristics and typeof specimen collected would makethese very important figures more help-ful to clinicians, not only in Pretoriabut also in South Africa as a whole.The Alexander Project received 83pneumococcal isolates from SouthAfrica in 1996 and 66 in 1997.Intermediate resistance to penicillinwas quoted as 31% and 26% respec-tively, and high-level resistance as 4%and 4.5%.8 These isolates were from areferral laboratory, which may haveled to the biased results.There is wide variation in susceptibilitydata for pneumococcal isolates fromnon-sterile sites. This may be due to anumber of factors and additional stud-ies are needed to determine rates ofresistance accurately.Haemophilus influenzaeThe proportion of sterile site isolates ofHaemophilus influenzae producingbeta-lactamase and submitted to thesurveillance laboratory since 1999remains constant (Table III).Beta-lactamase production from H.influenzae sputum isolates is document-ed at 7% in some South African studies.7, 8Although not clearly stated, most ofthese isolates would be non-typeableH. influenzae, as non-typeable strainsare more commonly described inlower respiratory tract infections with-out bacteraemia.Neisseria meningitidisIncreasing MICs of Neisseria meningi-tidis have been documented in SouthAfrica and elsewhere in the world,although the clinical significance ofdisease caused by these isolates isunknown. Currently penicillin remainsthe drug of choice for treatment ofinvasive disease. Ongoing surveil-lance remains important.Salmonella spp.The Enteric Diseases Reference Unit(EDRU) has received a number of mul-tidrug-resistant Salmonella isolatesfrom hospitals in South Africa duringthe past 2 years. These isolates arepredominantly S. enterica serovarTyphimurium and S. enterica serovarIsangi. Many of the S. typhimuriumand all the S. serovar Isangi strainsexpress an extended spectrum beta-lactamase (ESBL). These isolates com-prise approximately 50% and 20%respectively of all isolates received atEDRU (approximately 500 isolateseach year). Nalidixic acid resistancein S. serovar Isangi has increased from25% to 70% in isolates received in thepast 6 months (K H Keddy — personalcommunication).ESBL-producing organisms were classi-cally Klebsiella sp., and are oftenassociated with nosocomial infection.The above-mentioned Salmonella sp.Table II. Antimicrobial resistance in invasive pneumococcal isolates sent to RMPRU, NICD(August 2001 - July 2002)No. and % of resistant isolates   < 5 yrs ≥ 5 yrs Age unknown Total  (N = 746) (N =1 095) (N = 286, 2 not tested)(N = 2 127, 2 not tested)Antibiotic No. % No. % No. % No. %  Penicillin         Intermediately resistant* 212 28 131 12 48 17 391 18  Fully resistant† 2 0.3 2 0.2 0 0 4 0.2  Trimethoprim/sulphamethoxazole 433 58 320 29 89 31 842 40  Cefotaxime 0 0 0 0 0 0 0 0*0.12 mg/l -1 mg/l.†≥ 2 mg/l.RMPRU = Respiratory and Meningeal Pathogens Research Unit; NICD = National Institute for Communicable Diseases.192 CME April  2004  Vol.22  No.4MONITORING SUSCEPT IB IL ITYisolates (isolated from blood culturesand stool) may also have been noso-comial infections originally, especiallyin paediatric wards. Recently patientsfrom the community, without any histo-ry of previous hospital admissions,have been presenting to both paedi-atric and adult wards with these resist-ant organisms.Fluoroquinolone-susceptible strains ofSalmonella that test resistant to nalidix-ic acid may be associated with clini-cal failure or a delay in response totherapy in fluoroquinolone-treatedpatients with extra-intestinal salmonel-losis. This may need to be consideredwhen treating patients with bacter-aemia due to the Salmonellae men-tioned above. Vibrio choleraeThe current cholera epidemic is associ-ated with a multidrug-resistant strain ofVibrio cholerae El Tor Ogawa and V.cholerae El Tor Inaba. The currentstrains are resistant to ampicillin,trimethoprim-sulphamethoxazole, tetra-cycline (doxycycline) and erythromy-cin. MICs for nalidixic acid areincreasing and recent isolates receivedat the EDRU show intermediate resist-ance to nalidixic acid (K H Keddy —personal communication). Rehydrationof the patient remains the mainstay oftherapy.CONCLUSIONSAccurate surveillance of antimicrobialsusceptibility, taking into account localneeds, is important for the develop-ment of rational empirical therapyguidelines.Some of the data detailed abovebegin to answer these needs.However, surveillance programmeslocally and nationally need to continueto improve their efforts to assist thefight against resistance. Increasing thenumber of laboratories participating insurveillance systems may improve theaccuracy of information.In order for South Africa to answerthis need, both private and publicmicrobiology laboratories have cometogether to form a surveillance group(National Antimicrobial SurveillanceForum (NASF) — funded by supportfrom pharmaceutical companies*) thatwill collect data from as many labora-tories as possible, and then presentthese data regularly, with breakdownrelevant to clinicians in the private andpublic sector.Hopefully this initiative will lead toimproved patterns of antimicrobialusage within South Africa.* Pharmaceutical companies supporting NASF:Abbott, Aspen, AstraZeneca, Aventis, Bayer, Bristol-Myers Squibb, Sandoz (Novartis), GlaxoSmithKline,Lilly, Merck, Sharpe & Dohme, Pfizer, Roche, andWyeth.References available on request.Antimicrobial susceptibility surveil-lance plays an important role inguiding empirical antimicrobialtherapy.Interpreting such data needs to takeinto consideration the method oftesting in the laboratory, the type ofspecimen from which the organismwas isolated, and the type ofpatient who was selected.Between 15% and 20% of Strepto-coccus pneumoniae causing menin-gitis and bacteraemia in SouthAfrica are intermediately resistantto penicillin (levels are higher in theprivate sector).High-level resistance to penicillin orresistance to 3rd generationcephalosporins is still uncommon,especially in the public sector.Multidrug-resistant Salmonellaspecies are being isolated through-out the country.Accurate antimicrobial susceptibilitydata for all health care sectorsneed to be a goal for laboratoriesthroughout the country.IN A NUTSHELLTable III. Beta-lactamase production of submitted Haemophilus spp. isolatesYear 1* Year 2* Year 3*  Age N B/L + % N B/L + % N B/L + %  Haemophilusinfluenzae type b< 5 yrs 109   14 of 108 tested 13 49 10 20 39 8 of 36 22   ≥ 5 yrs 15 1 7 28 6 21 14 1 of 13 8Unknown 9 2 22 12 3 25 6 0 of 4 0133 17 of 132 13 89 19 21 59 9 of 53 17Haemophilus spp.not type b< 5 yrs 23 6 26 18 3 17 32 4 of 30 13≥ 5 yrs 12 0 0 21 0 0 9 1 of 8 13Unknown 6 1 17 5 1 20 4 0 of 3 041 7 17 44 4 9 45 5 of 41 12B/L = Beta-lactamase-producing isolate.*Year 1: July 1999 - July 2000; year 2: August 2000 - July 2001; year 3: July 2001 - August 2002.

Patterns of antimicrobial susceptibility among bacterial pathogens in South Africa

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Patterns of antimicrobial susceptibility among bacterial pathogens in South Africa

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