Respiratory and Meningeal Pathogens Reference Unit (RMPRU)

Overview

The Respiratory and Meningeal Pathogens Research Unit (RMPRU) conducts national laboratory-based surveillance for invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. These organisms cause significant morbidity and mortality worldwide and are responsible for the majority of bacterial meningitis infections in the developing world. Meningitis is an infection of the membranes and cerebrospinal fluid surrounding the brain and spinal cord and has a high fatality rate. In addition, these organisms are a predominant cause of septicaemia, pneumonia, otitis media and sinusitis.

For more information on these organisms, as well as African and global efforts to combat the diseases caused by these organisms please visit the following websites:

PneumoADIP
The Network for Surveillance of Pneumococcal Disease in the East African Region
Hib Initiative
WHO | Haemophilus influenzae type B (HiB)
WHO | Bacterial Infections

Contact Us

Staff

Overview of 2006 and 2007

Research Activities

Publications

Postgraduate positions

History

The origins of the RMPRU are to be found in the creation of the MRC Pneumococcal Diseases Research Unit (PDRU) when the Medical Research Council (MRC) awarded this research unit to Professor Keith Klugman in 1995. The Unit was co-sponsored by the University of the Witwatersrand (WITS), and by the South African Institute for Medical Research (SAIMR), the forerunner of the National Health Laboratory Service (NHLS).

The PDRU developed the molecular studies on antibiotic resistance which continue to this day in the RMPRU, and continued the Pneumococcal National Surveillance originally started in 1980 by Professor Hendrik Koornhof.

A major expansion of the Unit’s activities occurred during the 1990s when the Unit opened a field site at Zola Clinic in Soweto to investigate the epidemiology of the pneumococcus in young children, and to study for the first time in Africa, the use of pneumococcal conjugate vaccine to prevent young children from getting pneumococcal diseases.

Further expansion then occurred at Chris Hani Baragwanath Hospital with the development of a clinical research unit there under the direction of Dr (now Professor) Shabir Madhi. The Unit conducted a very large clinical trial in nearly 40,000 children which proved the efficacy of the pneumococcal conjugate vaccine in preventing pneumonia and invasive disease in both HIV-infected and -uninfected children in Soweto.

Since 2000 the Baragwanath part of the Unit has developed laboratory capacity in the area of respiratory viral diagnostics and immunogenicity testing of respiratory vaccines.

In 1999 the surveillance functions of the Unit were expanded in collaboration with the EPI (Expanded Programme on Immunisation) program of the Department of Health to include surveillance of Haemophilus influenzae and Neisseria meningitidis throughout South Africa.

The Surveillance and Molecular division of the Unit became part of the National Institute for Communicable Diseases (NICD) in 2002 under the direction of Dr Anne von Gottberg.

In 2003 active surveillance was commenced for these pathogens at 10 sentinel sites in South Africa with support from the Centers for Disease Control and Prevention (CDC) and USAID. In 2005 the RMPRU was split into two distinct entities with Professor Madhi as Co-Director of the Unit with the MRC and WITS at Chris Hani Baragwanath Hospital, and the Surveillance and Molecular part of the Unit moving from the central laboratories in Braamfontein to the NICD in Sandringham, as a Unit of the MRC and the NHLS.

Professor Keith Klugman remains Co-Director of the Unit at Chris Hani Baragwanath Hospital and a Consultant to the Unit at the NICD.

RMPRU staff with colleagues:
Back row: Linda de Gouveia, Olga Hattingh, Pedwell Makutu (PRU), Muzi Hlanzi
Middle row: Portia Mogale (EDRU), Azola Fali, Kedibone Mothibeli, Lenny Lengwati, Thembi Mthembu (MRU), Ruth Mpembe, Happy Skosana, Ethel Maringa, Phyllis Hyde
Front row: Mignon du Plessis, Nicole Wolter

RMPRU staff at work.

Contact us

Please direct any queries via one of the following:

Anne von Gottberg
Tel: 011 555 0316
e-mail:

Linda de Gouveia
Tel: 011 555 0327
e-mail:

Mignon du Plessis
Tel: 011 555 0387
e-mail:

Postal address:
Private Bag X4
Sandringham
2131
Gauteng
South Africa

Physical address:
SAVP Building - North Block - Lower Level
1 Modderfontein Rd.
Sandringham
Johannesburg

Staff

NAME	QUALIFICATIONS	DESIGNATION
Anne von Gottberg	MBBCh, DTM&H, FCPath (SA) MICRO	Pathologist, Head of Unit
Linda de Gouveia	National Diploma in Medical Technology (Microbiology)	Laboratory Manager
Ruth Mpembe	National Diploma in Medical Technology (Microbiology)	Medical Technologist
Olga Hattingh	National Diploma in Biomedical Technology (Microbiology & Clinical Pathology)	Medical Technologist
Happy Skosana	National Diploma in Biomedical Technology (Microbiology)	Medical Technologist
Lenny Lengwati	National Diploma in Biomedical Technology (Microbiology)	Medical Technologist
Mignon du Plessis	PhD	Senior Medical Scientist
Azola Fali	MSc (Biotechnology)	Medical Scientist
Kedibone Mothibeli	BSc (Hons)	Medical Scientist
Nicole Wolter	MSc (Biochemistry)	Medical Scientist
Chivonne Moodley	B.Sc (Hons)	Intern Medical Scientist
Thembi Mthembu	Matric, N5 Management Assistant	Data Clerk
Keith Klugman	MBBCh, PhD, DTM&H, MMEd, FCPath (SA), FRCPath (Lond), FRSSAfr	Professor & Director of Research Unit (RMPRU Bara and NICD)
Phyllis Hyde	B.A.	Personal Assistant to Research Director

Overview of 2006 and 2007

During 2006, the administration and coordination of the rapidly expanding Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) was successfully handed over to a newly formed unit within the Microbiology Division at the NICD, the National Microbiology Surveillance Unit (NMSU). This unit coordinates bacterial and fungal surveillance involving four units within the NICD (EDRU, MRU, PRU and RMPRU) and Dr Nelesh Govender was hired in March 2006 to run this unit. All medical officer and surveillance officer staff transferred to NMSU. Surveillance database management for all these units was still coordinated, in part, by Linda de Gouveia, RMPRU. Penny Crowther was hired in 2007 as a database manager to assist and ultimately take over this function as surveillance activities for all Microbiology Units continue to expand.

RMPRU continues to perform active laboratory-based surveillance for invasive disease throughout the country due to Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. The unit reports weekly data on these diseases to the Epidemiology Unit, NICD; provides data for presentation at the monthly National Outbreak Response Team (NORT) meeting, National Department of Health, Pretoria and for publication in the quarterly NICD Communicable Diseases Surveillance Bulletin. All of these infections are vaccine-preventable, and our ongoing surveillance data informs pharmaceutical companies, vaccine manufacturers, public health specialists and clinicians working nationally and internationally. In addition, we offer reference diagnostics related to these diseases, as well as outbreak response assistance, in particular for meningococcal cases.

In 2007, pneumococcal serotyping data from our surveillance programme were shared with the Pneumococcal Vaccines Accelerated Development and Introduction Plan (PneumoADIP) at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States, for the Global Serotype Project. This project requested data from partners worldwide, and will help to inform the decision-making process about pneumococcal vaccine development in the future, and to ensure that these vaccines are relevant throughout the world.

We continue to participate in two external quality assessment programmes relevant to our surveillance and reference functions: SIREVA (Sistema regional de Vacinas) Vigia - Surveillance of S. pneumoniae, H. influenzae and N. meningitidis, Instituto Adolfo Lutz, Sao Paulo, Brazil; CAP (College of American Pathologists), Bacteriology Survey, Northfield, Illinois, USA.

Selected Surveillance And Research Activities In 2006

Molecular basis and clonal nature of increasing pneumococcal macrolide resistance in South Africa, 2000-2005
The prevalence and molecular epidemiology of pneumococcal macrolide resistance in South Africa was investigated. Minimum inhibitory concentrations and serotypes of pneumococcal isolates causing invasive disease from 2000 through 2005 (n=15 982), were determined. Randomly selected isolates from 2005 (51%, 260/508) had resistance mechanisms determined, and clonality was investigated by pulsed-field gel electrophoresis (PFGE) (n=64) and multilocus sequence typing (n=7). Macrolide resistance increased from 9% (160/1828) in 2000 to 14% (508/3656) in 2005 (P<0.001). Serotype 14 was the most common macrolide-resistant serotype (40%, 760/1921). The majority of macrolide-resistant isolates (75%, 1437/1921) displayed the macrolide lincosamide streptogramin B (MLSB) phenotype. Of the strains screened genotypically, 57% (147/260) contained erm(B), 27% (71/260) contained mef(A) and 15% (40/260) contained erm(B) and mef(A). One percent (2/260) contained ribosomal mutations. Macrolide-resistant isolates were predominantly penicillin-nonsusceptible and multidrug-resistant. Isolates clustered according to serotype by PFGE, and 22% (14/64), 11% (7/64) and 5% (3/64) of isolates were related to the Taiwan19F-14, England14-9 and Spain9V-3 global clones respectively.

Detection of Serotype 6C among South African Serotype 6A Pneumococci causing Invasive Disease, 2005-2006
A new serotype (6C), indistinguishable from serotype 6A using the conventional Quellung reaction, was recently identified. Serotype 6B in the 7-valent pneumococcal conjugate vaccine cross-protects against 6A. Serotyping was performed on submitted isolates causing invasive pneumococcal disease (IPD) from January 2005 through December 2006 using the Quellung reaction. All serotype 6A isolates (n=606) were screened by PCR for the presence of a 1029-bp sequence that replaces the 1222-bp sequence in the wciN region of the capsular locus, differentiating serotype 6C from 6A. Five percent (30/600) were identified as serotype 6C, 13 strains from 2005 and 17 from 2006. The fraction of IPD due to 6C in children in South Africa is small. All 6C isolates identified were susceptible to penicillin.

Risk factors for trimethoprim-sulfamethoxazole resistance in Streptococcus pneumoniae causing invasive disease in South Africa, 2003-2006.
The study design included a descriptive component to investigate the trends in resistance and a cross-sectional study for the risk factor analysis. The study population included laboratory-confirmed cases of invasive pneumococcal disease reported to the national surveillance system. Data were available for approximately 15000 cases for the descriptive component and approximately 7000 cases for the analytic component. The main outcome variable was infection with an isolate which is non-susceptible to cotrimoxazole while the main exposure variables will include age, gender, race, province, specimen type, prior antibiotic usage, severity of illness, HIV serological status, current antiretroviral therapy, tuberculosis treatment and cotrimoxazole prophylaxis. An initial univariate logistic regression analysis followed by a multivariate logistic regression analysis were performed to assess the possible association between the exposures and outcome. This work will be submitted as part of an MSc (Med) in Epidemiology & Biostatistics thesis.

High levels of HIV-coinfection in adults with invasive pneumococcal disease, South Africa, 2003 to 2006
Cases with pneumococci isolated from normally sterile sites from January 2003 through December 2006 were reviewed. Enhanced surveillance included clinical data collection and HIV ELISA testing at sentinel sites. Adults were defined as =15 years. Of 15,179 cases of IPD reported, 94% (14,309) had available age of which 57% (8085) were adults. Median age in adults was 35 years (range 15-105); and enhanced surveillance identified 3787 (47%) of these cases. HIV was known in 61% (2316/3787) of these; 91% (2119/2316) were HIV-seropositive. HIV-seroprevalence was higher in females [1216/1288 (94%) vs. 901/1026 (88%), p<0.001]. HIV-coinfection differed by age group: 192/233 (82%) in 15-24 years; 1570/1659 (95%) in 25-44 years; 333/386 (86%) in 45-64 years; 24/38 (63%) in >64 years (p<0.001). The majority of IPD in adults was associated with HIV-coinfection with seroprevalence highest in 25-44 years. CFR increased with age, but did not differ by HIV serostatus. Serotype prevalence fluctuated over the 4 years, in a time of minimal vaccine use.

Differences in blood culturing practices in rural and urban areas of South Africa
We aimed to gather detailed data about the number of blood cultures performed at each centre, quality of specimen submission and processing, and to explore clinicians’ perceptions of blood culture utility and burden of pneumococcal disease. Our goal was to characterize regional differences in blood culturing practices to assist in the interpretation of existing laboratory-based surveillance for invasive pneumococcal disease on a national level in South Africa. Doctor questionnaires were returned from 20 of 22 hospitals, 341 questionnaires in total. Responses from academic and non-academic hospitals were compared. Preliminary review of responses to questions in the questionnaire for doctors indicated that non-academic hospitals' doctors are less likely to take blood, urine and cerebrospinal fluid (CSF) specimens; while pus, pleural and sputum specimens were reported to be taken equally frequently by both groups of doctors. Approximately 40% of doctors responded that the microbiology laboratory is not useful in the diagnosis of respiratory tract infections, but this did not differ by type of hospital. Blood cultures are taken less frequently at non-academic hospitals for all syndromes cited. Also to be noted was that only half of the doctors at the academic centers “always or almost always” take blood cultures for respiratory tract infections.

Molecular characterization of serogroup B meningococcal isolates causing invasive disease in South Africa
Currently there is no licensed vaccine for prevention of bacterial meningitis caused by serogroup B N. meningitidis. Outer membrane protein LP2086 has been shown to elicit a good antibody response in animal models and is therefore a promising vaccine candidate. The aim of this study is to investigate the prevalence, distribution and sequence diversity of LP2086 in both serogroup B and other serogroups of meningococci circulating in South Africa. The study is ongoing and is a collaborative study funded by Wyeth Pharmaceuticals.

Publications

Publications (2006 - July 2008):

von Gottberg A, de Gouveia L, Madhi SA, du Plessis M, Quan V, Soma K, Huebner R, Flannery B, Schuchat A, Klugman KP. Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa. Bull World Health Organ. 2006 Oct; 84(10):811-8.

Anderson R, Steel HC, Cockeran R, Smith AM, von Gottberg A., de Gouveia L., et al. Clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae. J Antimicrob Chemother 2007 Feb;59(2):224-9.

Anderson R, Steel HC, Cockeran R, von Gottberg A, de Gouveia L, Klugman KP, Mitchell TJ, Feldman C. Comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones, on the production of pneumolysin by Streptococcus pneumoniae in vitro. J Antimicrob Chemother. 2007 Nov;60(5):1155-8.

Coulson GB, von Gottberg A, du Plessis M, Smith AM, de Gouveia L, Klugman KP, et al. Meningococcal disease in South Africa, 1999–2002. Emerg Infect Dis. 2007; 13(2): 273 - 281.

Dini L, du Plessis M., Wong M, Karstaedt A, Fernandez V, Frean J. Prevalence of DHPS polymorphisms associated with sulfa resistance in South African Pneumocystis jirovecii strains. J Eukaryot Microbiol 2006 Nov;53 Suppl 1:S110-1.

von Gottberg A, de Gouveia L, Madhi SA, du Plessis M, Quan V, Soma K, Huebner R, Flannery B, Schuchat A, Klugman KP for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa. Bull WHO. 2006; 84: 811 - 818.

Wadula J, von Gottberg A, Kilner D, de Jong G, Cohen C, Khoosal M, et al. Nosocomial outbreak of extended-spectrum beta-lactamase-producing Salmonella Isangi in pediatric wards. Pediatr Infect Dis J 2006 Sep;25(9):843-4.

Wolter N, Smith AM, Farrell DJ, Klugman KP Heterogeneous macrolide resistance and gene conversion in the pneumococcus. Antimicrob Agents Chemother 2006 50(1): 359 - 361.

Wolter N, Smith AM, Low DE, Klugman KP. High-level telithromycin resistance in a clinical isolate of Streptococcus pneumoniae. Antimicrob Agents Chemother 2007 Mar;51(3):1092-5.

Wolter N, Smith AM, Farrell DJ, Northwood JB, Douthwaite S, Klugman KP. Telithromycin resistance in Streptococcus pneumoniae is conferred by a deletion in the leader sequence of erm(B) that increases rRNA methylation. Antimicrob Agents Chemother 2008 Feb;52(2):435-40.

von Gottberg A, du Plessis M, Cohen C, Prentice E, Schrag S, de Gouveia L, Coulson G, de Jong G, Klugman K; Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa. Emergence of endemic serogroup W135 meningococcal disease associated with a high mortality rate in South Africa. Clin Infect Dis. 2008 Feb 1;46(3):377-86.

von Gottberg A, Klugman KP, Cohen C, Wolter N, de Gouveia L, du Plessis M, Mpembe R, Quan V, Whitelaw A, Hoffmann R, Govender N, Meiring S, Smith AM, Schrag S; Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Emergence of levofloxacin-non-susceptible Streptococcus pneumoniae and treatment for multidrug-resistant tuberculosis in children in South Africa: a cohort observational surveillance study. Lancet 2008 Mar 29;371(9618):1108-13.

Wolter N, von Gottberg A, du Plessis M, de Gouveia L, Klugman KP; for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Molecular basis and clonal nature of increasing pneumococcal macrolide resistance in South Africa, 2000-2005. Int J Antimicrob Agents 2008 Jul;32(1):62-67.

Annual Reports
Click here to view NICD Annual Report (2007)

Click here to view GERMS-SA Annual Report (2007)

Click here to view Medical Research Council (MRC) 5-year report

Postgraduate opportunities

MSc/PhD opportunities.
We have positions available for students who wish to complete an MSc or a PhD degree. Please contact Dr. Mignon du Plessis () or Dr. Anne von Gottberg () for more information.