The 4th Bandolier Conference: Chlamydia


In this issue

The views expressed in Bandolier are those of the authors, and are not necessarily those of the NHSE, Anglia & Oxford.

Update on chlamydia screening

At time of going to press Tessa Jowell, Minister for Public Health, announced that action was necessary to assess whether a Chlamydia trachomatis screening programme would be an effective means of detecting this damaging disease in its early stages. As part of a general feasibility study into the effectiveness of professional and public information campaigns and the opportunistic screening of asymptomatic, sexually active young women, the Minister has ordered the setting up of two pilot projects in the Wirral and Portsmouth.

Bandolier conferences are always interesting and sometimes exciting, and this is due in no small part to the mix of people with different backgrounds bringing different perspectives and insights, both from the stage and from the floor. This Bandolier conference on chlamydia was no exception, and at times the atmosphere was electric with new information challenging accepted thinking.

Jenny Hopwood set the scene by filling in the background of what we are doing now about chlamydia infection, what the problems are with complications of untreated infection, and giving an insight into problems of screening and prevention.

Mike Catchpole gave us the epidemiology of chlamydia in the UK. It is much the same as other developed countries — with prevalence rates of 5% or more in women, with younger, unmarried women of low socioeconomic status with new sexual partners who do not use barrier contraceptive methods at greater risk of being infected.

Lucia Grun and Peter Greenhouse gave us perspectives from primary and hospital care. In both it is a serious issue, with clear needs for concerted action and considerable liaison, and with clear objectives.

One of the key talks came from Helen Lee, who gave a textbook introduction to new tests for chlamydia, and the new science of nucleic acid amplification. This represents a quantum leap in our ability to test for and detect chlamydia, and is likely to be important in changing attitudes to screening.

Geoff Ridgway then gave us good evidence that, if we can detect the organism, our chances of treating the infection effectively are excellent.

Finally, there are the issues of the economics of chlamydial infection. Mo Malek’s talk gave us a wide perspective on some of the issues.

A paper published by Howell and colleagues just after the conference [1] confirms many of the ideas discussed on the day. Using information from the literature, and from 7,700 asymptomatic women attending family planning clinics in Baltimore, researchers calculated the cost of the effects of several putative screening strategies and the cost of the effects of chlamydial infection. The effects of infection include pelvic inflammatory disease, ectopic pregnancy, pelvic pain and infertility for the women, conjunctivitis and pneumonia for any children they may bear and urethritis or epididymitis for their male partners.

Their conclusion was that screening women under 30 years at a family planning clinic saved $50 in healthcare costs for every woman screened with the new DNA-based systems.

RA Moore DSc
Editor, Bandolier

Reference

1. Howell MR, Quinn TC, Gaydos CA. Screening for Chlamydia trachomatis in asymptomatic women attending family planning clinics. Ann Intern Med 1998; 128:277—284.

Setting the scene: Chlamydia — what should we be doing?


Jenny Hopwood MB ChB D(Obst)RCOG MFFP DipVen, Liverpool

We have a duty to be as accurate as possible in the healthcare we provide. In the field of sexual health it is difficult for patients to question professionals when it is the most intimate part of their lives that is being examined and so they may accept suboptimal or frankly inaccurate management.
Prevention of pelvic inflammatory disease (PID) is an important part of reproductive healthcare (RHC) and chlamydia is the most common cause of PID. Common problems in RHC are:
There is no evidence to support the expense of well woman clinics. Urine tests for diabetes are only 22% sensitive in the asymptomatic, breast checks are of no value and the sensitivity and specificity of a bimanual examination is poor. At best, well woman clinics are p(m)aternalistic and at worst, they can do harm by giving attendees false reassurance about their pelvic health.
The results of cervical smears are often extrapolated as RHC by both health professionals and patients. If a woman presents with a minor symptom, then a smear may be taken. If this test is negative then she is falsely reassured. If there is a cytologically detected organism, such as candida or trichomona, treatment may be given that leaves the unrecognised coexistent chlamydia to destroy the fallopian tubes — is this iatrogenic infertility?
The use of a routine high vaginal swab to predict presence or absence of infection. Chlamydia detection requires an endocervical sample (unless a nucleic acid amplification test is used).
Women presenting with discharge, dysuria or bleeding are often told: ‘It is your age/your hormones/all women get that.’ These symptoms may be ignored or treated inappropriately. They could all be caused by chlamydia.
PID may be treated by GPs and in gynaecology departments without addressing the partners and the problem of reinfection.
Most women with chlamydia are asymptomatic, so they are not dealt with by the traditional diagnostic medical approach. Few doctors are involved in educational or preventive measures, that could be highly effective.
All of these serious errors are underpinned by inequitable and inaccurately focused funding. There has been money for sexual health programmes but this has been concentrated on HIV. Departments of genitourinary medicine (GUM) are able to carry out testing for all infections. However, it may be more cost-effective to focus on selective screening in GUM departments and to undertake universal screening in family planning clinics but this possibility has not been examined. A contributory factor may be the lack of accurate prevalence figures — the returns from GUM clinics and voluntary reporting from laboratories give only a partial picture.
The inequality in education and the varying degrees of enthusiasm of health professionals means that it is a lottery — based on where they attend and who they see — that determines how well a patient’s reproductive health is looked after. This situation cannot be ethical. There must be uniform access and expertise.

The current situation on chlamydia treatment, by facility

Some termination units test, some give blanket antibiotics, most do neither.
GUM clinics test, treat and contact trace. However, it is said that only 10% of chlamydia will be found there and 90% is in the community to be tackled — or not — in this haphazard way.
Family planning clinics (FPCs) traditionally do not treat, although they can find a high prevalence of the disease. In my local area the FPCs that screen referred more than one third of the women with chlamydia who attended the GUM clinic.
Gynaecology departments treat PID but may not test for chlamydia and usually do not address partners.
Some GPs test for chlamydia — but who do they test? They treat but they do not usually carry out partner notification. It takes organisation, equipment and maybe chaperons and, of course, time to offer testing and counselling. Added to which, in many practices, the reward for all this extra effort may be small if they detect only small numbers.
In addition, except for GUM clinics, addressing chlamydia may well be an unmandated use of the consultation in these settings.

Complications

For women a chlamydial infection can result in PID — leading to ectopic pregnancies, infertility and chronic pelvic pain. It is the most common cause of epididymitis in young men and can cause pneumonia and conjunctivitis in babies. The estimated health service cost is £100 million in England and Wales each year.
Of course most women do not get these complications, which means that many health professionals do not perceive the relation between the infection and its sequelae. The mean time-lag between a primary chlamydial infection and attending because of PID or ectopic pregnancy is approximately 7—8 years. It is easier to just give antibiotics for PID, without taking a sexual history or suggesting that partners are tested and treated. Ectopic pregnancies are surgical emergencies, which are not an ideal time to deal with the root cause. Infertility is years down the line and treatment advances are more exciting and attractive to the media than prevention.

Screening difficulties

It is difficult to establish the cost-balance of case finding or screening, be it universal or selective, to save the cost of complications. There has been one notable randomised, controlled study recently that confirms screening as an effective strategy4 and several computer models have been devised in the past, but even with the knowledge that testing and treating would save the health service a huge amount of money, the coordinated will is not present because the facilities that would spend money on testing would not be those that would benefit from the savings.
Who should fund screening? Locally a case was made for testing all women prior to termination of pregnancy. However, other hospital needs were deemed more important than funding this in the termination unit. Without a national policy there will always be dilemmas like this. Until everyone works together to establish guidelines, supported by funding, then matters will not improve. This issue does not seem to have been addressed by the Chief Medical Officer’s Expert Advisory Group. We feel that testing should be categorised into diagnostic, pre-instrumentation and screening. The first two are the responsibility of the service the woman attends, but any screening programme should be allocated extra money and resources if it is not to remain piecemeal.

Prevention of PID

Offering tests is easy but we should examine all the ways of improving the situation. PID prevention is all about education.

Primary prevention

— education about partners and barrier methods of birth control, so the infection is not spread.

Osler said: ‘The gonococcus is not a destroyer of life, but is the greatest preventer of it.’ Today the same could be said of chlamydia. Indeed there is a chlamydia campaign in Brisbane for young people, the poster says ‘Bye Bye Baby’, which is surely the up-to-date version of Osler’s statement.

Secondary prevention

— education to report symptoms and to have them addressed accurately.

Tertiary prevention

involves correct treatment so that tubal damage does not result.

Conclusion

A multidisciplinary approach is essential in improving this situation. The cervical screening programme was successful only when its initial piecemeal development became a unified entity. Microbiologists, GPs, family planning doctors, GUM specialists, gynaecologists, public health professionals and workers in health promotion all have different concerns and it is only by working together that RHC will improve n

References

  1. Simms I, Catchpole M, Brugha R et al. Epidemiology of genital C trachomatis in England and Wales. Genitourin Med 1997; 73: 122—126.
  2. Hopwood J, Mallinson H. Chlamydia testing in community clinics: a focus for accurate sexual health care. Br J Family Plan 1995; 21: 87—90.
  3. Ostergaard L, Moller JK, Anderson B, Olesen F. Diagnosis of urogenital Chlamydia trachomatis infection in women based on mailed samples obtained at home: multipractice comparative study. BMJ 1996; 313: 1186—1189.
  4. Scholes D, Stergaghis A, Heidrich F et al. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996; 334: 1362—1366.

Table 1. Prevalence of C trachomatis infection by facility attended: summary of prevalence study results

Survey population Median prevalence Range
General practice attendees 4.5 (1 - 12)
Women attending antenatal clinics or obstetric units 4.6 (2 - 7)
Gynaecology clinic attendees 4.8 (3 - 6)
Family planning clinic attendees 5.1 (3 - 7)
Termination of pregnancy clinic attendees 8.0 (7 - 12)
Genitourinary medicine clinic attendees 16.4 (7 - 29)

Epidemiology of genital Chlamydia trachomatis infection


Mike Catchpole MSC FRCP FFPHM Consultant Epidemiologist, PHLS Communicable Disease Surveillance Centre
Chlamydia trachomatis is the most prevalent bacterial pathogen causing sexually transmitted disease (STD) in the western world. Chlamydial infections often produce no symptoms or mild, non-specific signs and symptoms that, if left untreated, can persist for at least 15 months.[1] Infection can have potentially serious lifetime consequences and the main burden of morbidity falls upon women.[2]
Genital infection in women can result in cervicitis and urethritis — which may be complicated by salpingitis, ectopic pregnancy and infertility. In a 1989 joint report of two WHO working groups on genital C trachomatis infection it was estimated that, of the million cases of salpingitis that occur annually in Europe (120,000 of which result in infertility), 600,000 are caused by C trachomatis.[3]
C trachomatis prevalence surveys undertaken among young sexually active women attending family planning, termination of pregnancy, gynaecology and genitourinary medicine clinics in the UK have indicated a prevalence of between 2% and 29%.
Current knowledge suggests that C trachomatis does not conform to the familiar ‘core group’ model associated with other STDs (such as Neisseria gonorrhoeae), as infection is broadly distributed both geographically and by behaviour group.[4]

Qualitative aspects of surveillance and survey data

The data on diagnoses of genital C trachomatis infection in genitourinary medicine clinics represent only the `tip of the iceberg' in terms of all genital C trachomatis infections in England and Wales. It has been estimated, on the basis of the extrapolation of prevalence survey results of genital C trachomatis infection, that as few as 10% of all cases are seen in genitourinary medicine clinics. The genitourinary medicine clinic return data may, however, provide some insight into trends in the incidence of genital C trachomatis infection.
During the 1980s the overall upwards trend in laboratory reports of genital C trachomatis infection was largely determined by the increasing availability of chlamydial diagnostic services. In more recent years, trends are liable to be influenced by changes in diagnostic practice by genitourinary physicians and other clinicians that regularly investigate patients for possible infection. The current laboratory reporting system does not include information on the source of referral of a clinical specimen to the laboratory, and hence the data cannot be used to identify the proportion of diagnosed cases by clinical specialty that are confirmed by laboratory investigation.
A further deficiency is that not all laboratories take part in the national laboratory reporting scheme managed by the Communicable Diseases Surveillance Centre. Non-reporting is a particular problem in London where a small number of large laboratories, serving major GUM clinics, do not report.
Studies based on screening are the most reliable method of measuring the prevalence of infection within population groups because they are not affected by trends in case selection and laboratory testing. They are also the most reliable means of detecting asymptomatic cases. It is difficult, however, to extrapolate the findings of these studies to the general population since most have been of limited size and undertaken among health service attendees. Comparatively few studies have been undertaken in men.

Levels and trends in routine reports of genital chlamydial infection in England and Wales

There was a 15% rise in the incidence of NSGI in men seen at GUM clinics in England and Wales between 1981 and 1986, followed by a fall of 45% during the period 1986 to 1993, the majority of which occurred in the period 1986 to 1988. Among female attenders, cases of NSGI rose by 69% between 1981 and 1986, followed by a shallow decrease of 26% to 1993.
The rise in the number of reported cases of C trachomatis in the early 1980s probably reflects an increase in the availability of chlamydial diagnostic services, although rises in the sequelae of chlamydial infection suggest that this trend may also reflect a true increase in incidence.
New patterns of C trachomatis seen at GUM clinics between 1988 and 1993 show a consistent pattern in age specific rates. The highest rates of infection are among female attenders aged 16-24 years, with relatively high levels in those under 16 and much lower rates in those over 25 years of age. Over the past six years there has been a rising trend in the number of chlamydia cases in those under 16. This is of concern, particularly since younger women may be more susceptible to developing complications of chlamydial infection (such as PID) than older women.[5] In men the peak occurs in the 20-24 years age group.
The data are likely to underestimate the incidence because of the high prevalence of asymptomatic infection.

UK prevalence surveys

In prevalence surveys in the UK rates of C trachomatis infection ranged from 2-29%, the lowest rate was seen among GP and gynaecology clinic attendees whereas the highest rate was among women attending GUM clinics or requesting termination of pregnancy. (Table 1). The following factors were consistently associated with chlamydial infection in women, regardless of clinical settings or geographical location:
Women aged 16-20 were seen as being at highest risk of infection. However, none of the studies showed any of these factors to be significantly independent risk factors for infection.
A large reservoir of asymptomatic infection has been shown to exist in the female population, this amounted to 51% of detected cases in the Wirral study.[6] Studies among male clinic populations and among partners of infected women suggest that a substantial reservoir of asymptomatic infection also exists in the male population.[7]

Pelvic inflammatory disease and female infertility

A study of hospital discharges and deaths associated with PID using the HIPE dataset (England and Wales) showed a 28% rise in the discharge rate over the period 1975-85.[8] The rate in those aged between 20 and 24 rose by 50% during this period. Age-specific hospital discharge rates were highest in the 20-24 year age group.
In 1992-93 inflammatory diseases of the female pelvic organs accounted for 38,116 inpatient attendances. There were also 26,362 attendances for female infertility. The majority of attendances were for those aged 15 to 44 n

References

  1. McCormack WM, Alpert S, McComb DE, Nichols RI, Semine DZ, Zinner SH. Fifteen-month follow-up study of women infected with Chlamydia trachomatis. N Engl J Med 1979; 300: 123-125.
  2. Thompson SE, Washington AE. Epidemiology of sexually transmitted Chlamydia trachomatis infections. Epidemiol Rev 1983; 5: 96-123.
  3. Guidelines for the prevention of genital chlamydial infections. World Health Organisation Report 1989; 199: 1-38.
  4. Zimmerman HL, Potterat JJ, Dukes RL et al. Epidemiologic differences between chlamydia and gonorrhoea. Am J Public Health 1990; 80: 1338-1342.
  5. Westrom L, Mardh PA. Acute pelvic inflammatory disease (PID). In: Holmes KK (ed). Sexually Transmitted Diseases. New York: McGraw-Hill Information Services Company, 1990; 593-613.
  6. Hopwood J, Mallinson H, Agnew E. Chlamydia screening - should it be offered as a routine? Br J Family Plan 1990; 16: 59-67.
  7. Harry TC, Saravanamuttu KM, Rashid S, Shrestha TL. Audit evaluating the value of routine screening of Chlamydia trachomatis urethral infections in men. Int J STD AIDS 1994; 5: 374-375.
  8. Simms I, Catchpole M, Nicoll A. Pelvic inflammatory disease in England and Wales. In: Stary A (ed). Proceedings of the third meeting of the European Society for chlamydia research, September 11-14 1996, Vienna. Vienna: Study Group for STD and dermatological microbiology of the Austrian society for dermatology and venerology, 1996.

Perspectives from primary care

Lucia Grun MB BS DRCOG MRCGP GP Research Fellow, Department of Sexually Transmitted Diseases, UCLMS
STDs have traditionally been the preserve of specialised clinics, usually based in hospitals, that adhere to particularly stringent conditions of confidentiality. Those of us working in general practice have often felt that patients would rather attend STD clinics and, as a result, have become deskilled and have not necessarily developed testing facilities in our practices.
This has also been the case in family planning clinics, which are often run under circumstances that make the transport of samples a particular problem. In addition, the idea of discussing sexual histories and arranging appropriate contact tracing in primary care is daunting, posing challenges to our notion of the doctor-patient relationship and often involving people not registered with us.
This position makes the assumption that patients will appropriately self-refer to STD clinics or will be happy to attend them on our suggestion. However, in a situation where women have minimal symptoms, which they have not even thought to attribute to an STD, the suggestion that they attend a clinic may be met by confusion, distress or even anger. In the first instance, management in primary care would seem more appropriate.
Genital chlamydial infection is far more widely distributed in the population than other STDs and the notion of core groups of infected individuals, used for modelling GC and HIV infection, is less applicable. Furthermore, symptoms are often absent or minimal and may not lead patients to seek help in STD clinics. I believe that chlamydial infection is the STD that is likely to have most impact on primary care and that primary care could make a significant impact on chlamydial infection.
There are many ways in which primary care could contribute to the management and control of chlamydial infection. I have grouped them into three main categories:

Immediate clinical care

Because the symptoms of chlamydial infection are not always obvious or specific, we have to keep the diagnosis in our minds when seeing patients with a wide variety of symptoms and we need to have diagnostic facilities easily available if we want make a definitive diagnosis.
I would therefore argue that in primary care we should be in a position to take appropriate samples from any patient who presents with symptoms suggesting chlamydial infection. These would include women with pelvic pain, vaginal discharge, postcoital and intermenstrual bleeding and definitely those with suspected PID. Men with urethral discharge, urethritis and epididymitis should be offered testing or referral.
This policy would have significant financial, training and workload implications for those of us working in primary care. We need diagnostic facilities, which are costly and not always easily available. We need training in history taking, appropriate testing and treatment and we will have to accommodate the increased workload generated by follow-up and contact tracing. These things will not happen spontaneously and will require a clear and concerted strategy on the part of healthcare planners.

Selective screening

Some asymptomatic patients are at particular risk of infection. Top of this list are women requesting termination of pregnancy as they have definitely had unprotected intercourse. All the available studies show a high prevalence of infection in this group. Following the same argument, women having an IUCD fitted should be screened; however, this may pose logistic problems if an IUCD is being offered on the spot.
Young sexually active women, especially teenagers, have also been shown to have high rates of infection. In our study, in a small group of teenagers, the prevalence was 11%.[1] Other groups have had similar findings.[2] These young women are at increased risk of PID and its sequelae, are possibly less likely to access treatment services and are unlikely to have started their families, let alone completed them. Thus I would suggest that women under 25 who are sexually active should be considered for screening.

Widespread register-based community screening

Widespread screening is the most controversial topic of all. To provide a framework I am going to work through the criteria for a screening test proposed by Wilson and Junger.[3]

What would this mean for primary care?

First, it is clear that any policy would need to involve family planning clinics as well as GPs. I would suggest it should also encompass non-Government provision such as Brook advisory clinics. A discussion would need to be made about whether screening was only on an opportunistic basis or whether any register should be compiled and call and recall be instituted.
At present I think it is unlikely that the majority of practices would be in a position to fill this screening role. A great deal of training and preparation would be required to introduce a programme that can make a significant impact on prevalence and sequelae of infection. Not least is the need to raise the profile of infection in the general population.

Conclusions

At present there are still important questions to answer about a call and recall type of screening programme. However, I do not think that is an excuse for not initiating training, awareness raising and the introduction of some of the simpler and less costly measures I outlined earlier.
There are a number of primary care perspectives on the treatment and management of chlamydia. The key themes are:

References

  1. Grun L, Tassano-Smith J, Carder C et al. Comparison of two methods of screening for genital chlamydial infection in women attending general practice. BMJ 1997; 315: 226-230.
  2. Oakeschott P. Secual health in teenagers. Lancet 1995; 346: 648-649.
  3. Wilson JMG, Jungner G. Principles and practice of screening for disease. Public Health Papers 1968; 34.

Perspectives from the hospital

Peter Greenhouse MA MB BChir MRCOG MFFP Consultant in Sexual Health Medicine, Ipswich Hospital
The principal challenge for prevention and management of chlamydial infection in women in the hospital setting is its biologically covert nature and protean presentation across separated clinical specialties. There are considerable gaps and inconsistencies in our current state of knowledge, prompting the questions: `What more do we need to know?' and `What extra resources do we need?' As the hospital population is either referred or self-selecting, recognition of subclinical chlamydial infection is the first priority, given the current limitations of insensitive diagnostic tests.

Subclinical infection

The spectrum of ascending chlamydial infections in women is a continuum from the asymptomatic millions to the moribund few. Minor signs are disputed, ignored or confused with other conditions, for example:

Inaccurate diagnosis and ubiquity

The poor sensitivity and specificity of clinical signs in symptomatic pelvic infection have long been demonstrated by laparoscopy, which is frequently normal despite pain and proven infection.[4] Laparasocopy has been shown to be inaccurate when audited by fimbrial histology,[5] casting doubt on the findings of some classic epidemiological studies.
Chlamydia has been demonstrated in the fallopian tubes of half of a small group of entirely asymptomatic women: the cumulative lifetime risk of acquisition is unknown, but might be as high as 50% for women now aged 35-45 years.[P] If one-quarter of women may have had a tubal infection, why is tubal factor infertility and ectopic pregnancy relatively rare?

Variable sequelae

The relative importance of the factors that determine the development of adverse sequelae in women is unknown - many have a strong evidence base and/or biological plausibility:

Partner notification

Given that male partners of women with chlamydia or PID are almost all infected asymptomatically when seen in research studies and yet are rarely tested in routine practice,[9] reinfection is probably the norm. Although there are substantial inaccuracies in diagnosis of chlamydia and non-specific urethritis in the male, there is also an unquantified risk of male infertility. Thus doctors have a duty of care to advise women to abstain from intercourse until their partner is treated. The problems of broaching the subject, the need for - and the methodology of - destigmatising public health education have been reviewed elsewhere.[9] If reinfection is the principal determinant of long-term sequelae, then the male-targeted education campaign in Lund was probably more important than population screening in causing a six-fold drop in recurrent salpingitis cases between 1978 and 1983.[9]

Recommendations for practice

The Royal College of Obstetricians & Gynaecologists' study group published a detailed review and clinical practice recommendations, graded by weight of evidence.[10] The strongest, by pooled randomised control trial results, relates to reducing short-term morbidity from iatrogenic salpingitis at termination of pregnancy, as teenage women seeking abortion have a higher incidence of chlamydial infection than any other
easily identifiable group.
However, the RCOG's preferred option - of universal antibiotic prophylaxis without chlamydia screening - will not prevent subsequent reinfection. There is a clear requirement for enhanced epidemiological surveillance of ectopic pregnancy, and routine sentinel reporting of chlamydia diagnostic testing at termination of pregnancy, in addition to targeted primary health screening.[11]

Conclusion

Despite the gaps in our knowledge and the need for future evidence-based research, the Scandinavian experience shows that commonsense principles of STI management[12] are more important than high-technology diagnostics in reducing both the incidence and sequelae of chlamydial infection.
We need a greater appreciation of the features of subclinical pelvic infection, closer integration within hospital specialties and better communication with community practitioners. Traditional low-technology solutions such as widespread medical and public education, a high index of clinical suspicion, appropriate antibiotic therapy, and meticulous partner notification and treatment must be universally applied before we can maximise the benefits of recent advances in screening technique
Footnote
[P] Postulated or provisional research findings.

References

1. Krettek JE, Arkin S, Chaisilwattana P, Monif G. Chlamydia trachomatis in patients who used oral contraceptives and had intermenstrual spotting. Obstet Gynecol 1993; 81: 728-731.
2. Korn AP, Hessel N. Commonly used diagnostic criteria for pelvic inflammatory disease have poor sensitivity for plasma cell endometritis. Sex Transm Dis 1995; 22: 335-341.
3. Greenhouse P. Chlamydial Salpingo-Appendicitis: an explanation for the excess rate of appendiciectomy in young women. In: Stary A (ed). Proceedings of the Third Meeting of the European Society for Chlamydia Research. Vienna: ESCR, 1996: 148.
4. Eschenbach D, Wolner-Hanssen P, Hawes S et al. Acute Pelvic Inflammatory Disease: associations of clinical and laboratory findings with laproscopic findings. Obstet Gynecol 1997; 89: 184-192
5. Sellors J, Mahony J, Goldsmith C et al. The accuracy of clinical findings and laparoscopy in pelvic inflammatory disease. Am J Obstet Gynecol 1991; 164: 13-20.
6. Money D, Hawes S, Eschenbach D et al. Antibodies to the chlamydia 60 kd heat-shock protein are associated with laparoscopically confirmed perihepatitis. Am J Obstet Gynecol 1997; 176: 870-877
7. Hillis S, Owens L, Marchbanks P-A, Amsterdam L, MacKenzie W. Recurrent chlamydial infections increase the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease. Am J Obstet Gynecol 1997; 176: 103-107
8. Egger M, Low N, Davey Smith G et al. Ectopic pregnancy and the control of chlamydial infections: Ecological study. BMJ (in press).
9. Robinson AJ, Greenhouse P. Prevention of recurrent pelvic infection by contact tracing: a commonsense approach. Br J Obstet Gynaecol 1996 103: 859-861.
10. Templeton A (ed). The prevention of pelvic infection. London: RCOG Press, 1996.
11. Scholes D, Stergachis A, Heidrich FE et al. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. New Engl J Med 1996; 334: 1362-1366.
12. FitzGerald M (ed). Central Audit Group in Genito-Urinary Medicine: Clinical guidelines and standards for the management of uncomplicated chlamydial infection. London: RCP, 1997.

Testing: the challenge of chlamydia control

Helen H Lee PhD Reader of Medical Biotechnology, Department of Haematology, University of Cambridge
Sexually transmitted diseases (STDs) have been ranked as the second most prevalent treatable disease type among women aged 15-44 worldwide.[1] In 1990, the World Health Organisation (WHO) estimated that there were more than 250 million new STD cases worldwide every year. Gonorrhoea and chlamydial infections are common causes of pelvic inflammatory disease (PID), ectopic pregnancy, and infertility in women.
The treatment costs for chlamydial and gonococcal infection and the adverse post-disease complications in patients and their affected children run into billions of pounds and far outweigh the costs of an effective diagnostic and early intervention programme. For example, the treatment costs of the 1 million cases of PID that occur annually in the USA exceed $2 billion.
However, attempts to identify infected individuals and early treatment efforts have been hindered by the lack of simple and inexpensive diagnostic tests that could be used at first-level health facilities in developing countries or in the inner cities of developed countries, where the STD problem is the greatest.

Test methods

Early detection of Chlamydia trachomatis infections relies predominantly on specific laboratory testing. Culture analysis of endocervical or endourethral swab specimens has generally been considered the diagnostic gold standard. In addition, infection with C trachomatis has been detected by analysing male urethral or female endocervical swab samples by direct fluorescent antibody (DFA) assay, enzyme immunoassay (EIA), or non-amplified nucleic acid hybridisation.

Problems

The detection of chlamydial infection in women is particularly difficult because between 5-30% of infected women are infected only in the urethra, which is not detected by endocervical swab culture.[2] An additional problem has been inadequate specimen collection,[3] a common mistake being the collection of discharges from affected sites rather than a genuine sample of epithelial cells. Indeed, one study estimated that 10-35% of endocervical specimens were inadequate.[4] Furthermore, some commercially available swabs are toxic for C trachomatis, resulting in false negative culture results.[5] The taking of endocervical or urethral swabs is an uncomfortable, time-consuming, and relatively expensive procedure that requires a pelvic examination.
The development of a sensitive and specific test capable of detecting infections in urine samples would overcome the above problems and be an alternative to the collection of endocervical or urethral swabs, particularly in resource-poor settings.
Early attempts to isolate C trachomatis from urine by cell culture were unsuccessful.[6] Although urine appears to be inhibitory to culture, EIA or DFA assay of first void urine (FVU) was shown to identify as many symptomatic positive men as did urethral swab cultures, with few, if any, false positive results.[7] However, similar studies with female FVU tested by EIA failed to identify 40% of the women with positive endocervical swabs.[2]

Nucleic acid amplification

More recently, diagnosis of C trachomatis infection in males has been achieved by testing FVU with nucleic acid amplification assays based on the polymerase chain reaction (PCR)[8] or the ligase chain reaction (LCR).[9] LCR testing of FVU specimens is also highly successful for diagnosis of C trachomatis infections in women.[10]
Because DNA amplification techniques are capable of higher sensitivity than culture, EIA, or non-amplified nucleic acid-based methods, investigators working with a variety of assay approaches have advocated the use of an `expanded gold standard' for the calculation of assay sensitivities and specificities. This gold standard includes culture-positive samples as well as culture-negative/LCR- or PCR-positive samples that are confirmed positive in one of two ways: a DFA assay, or a PCR or LCR assay based on a DNA sequence different from that used in the initial screening assay.

Efficacy

When the performance of the various current methods was assessed according to this expanded gold standard, the overall sensitivities of amplified DNA tests were in the range of 90-95%, compared to a sensitivity of only 60-65% for culture, 50-60% for non-amplified nucleic acid methods, and only 30-40% for EIA.
The specificities of PCR or LCR assays are similar to culture, whereas EIA and non-amplified nucleic acid tests can generate 2-5% false positive results. LCR was equally effective in the detection of C trachomatis in urine from asymptomatic individuals as it was for patients with symptoms of genitourinary tract infection.
Recent advances in nucleic acid technologies have revealed the potential of molecular approaches for detecting infectious agents. Most assays based on nucleic acid hybridisation and amplification techniques are characterised by excellent sensitivities and specificities.
Nucleic acid hybridisation techniques rely on the ability of complementary nucleic acid strands to align specifically and associate to form a stable double-stranded complex. The key reagents, the nucleic acid probes, are specific to the organism to be detected and are thermostable.
Nucleic acid-based tests are less susceptible to sample degradation, and viability of the organism is not required as in the case of culture. However, currently available DNA amplification assays are technically complex, require expensive instrumentation and take two to six hours to complete.

Conclusion

Due to the lack of simple, rapid and inexpensive diagnostic tests for STDs and the importance of treating these diseases at the point of first encounter within the healthcare system, WHO recommends syndromic management for symptomatic STD infections in resource-poor settings in both developing and industrialised countries.
Syndromic management, which requires treatment for all infections associated with the same clinical syndrome, leads to over-treatment with relatively expensive drugs and unnecessary antibiotic use that could increase the rate of selection for antibiotic-resistant strains. Symptomatic men and women are likely to receive appropriate treatment because therapy is relatively simple and straightforward; however, up to 25% of infected men and 50-70% of infected women are asymptomatic.
Consequently, the challenge of chlamydia control remains the identification of asymptomatic individuals. In order to achieve this goal, simple, inexpensive and rapid diagnostic tests capable of detecting C trachomatis infections using non-invasive samples (such as urine) with appropriate sensitivity and specificity are urgently needed.

References

1. World Bank. World Development Report. Washington DC: World Bank, 1993.
2. Morris R, Legault J, Baker C. Prevalence of isolated urethral asymptomatic Chlamydia trachomatis infection in the absence of cervical infection in incarcerated adolescent girls. Sex Transm Dis 1993; 20: 198-200.
3. Schachter J. Chlamydial infections. West J Med 1990; 153: 523-534.
4. Larson J, Wulf H, Friis-Moller A. Comparison of a fluorescent monoclonal antibody assay and a tissue culture assay for routine detection of infections caused by Chlamydia trachomatis. Eur J Clin Microbiol 1986; 5: 554-558.
5. Mahony J, Chernesky M. Effect of swab type and storage temperature on the isolation of Chlamydia trachomatis from clinical specimens. J Clin Microbiol 1985; 22: 865-867.
6. Smith TF, Weed LA. Comparison of urethral swabs, urine, and urinary sediment for isolation of Chlamydia trachomatis. J Clin Microbiol 1975; 2: 134-135.
7. Chernesky M, Castriciano S, Sellors J et al. Detection of Chlamydia trachomatis antigens in urine as an alternative to swabs and cultures. J Infect Dis 1990; 161: 124-126.
8. Bauwens JE, Clark AM, Loeffelholz MJ et al. Diagnosis of Chlamydia trachomatis urethritis in men by polymerase chain reaction assay of first-catch urine. J Clin Microbiol 1993; 31: 3013-3016.
9. Chernesky M, Jang D, Lee H et al. Diagnosis of Chlamydia trachomatis infections in men and women by testing first-void urine by ligase chain reaction. J Clin Microbiol 1994; 32: 2682-2685.
10. Lee H, Chermesky M, Schachter J et al. Diagnosis of Chlamydia trachomatis genitourinary infection in women by ligase chain reaction assay of urine specimens. Lancet 1995; 345: 213-216.

Treatment of chlamydial genital infection

Geoffrey L Ridgway MD MRCP FRCPath Consultant, Department of Microbiology, University College London Hospitals
Effective treatment is available for most sexually transmitted bacterial diseases, although in many cases it still falls short of being ideal. A major problem is that the symptoms of genital infection are non-specific, being variations on the themes of genital ulcer or genital discharge, and it is difficult to make a precise aetiological diagnosis.
Furthermore, the underlying cause is frequently polymicrobial. The specific treatment of chlamydial genital infection is therefore inextricably entwined with the syndromic management of genital disease.
Lower genital tract infection usually precedes infection of the upper genital tract, and it is the latter which is responsible for the more serious consequences of chlamydial genital infection - for example infertility, increased risk of ectopic pregnancys and persistent pelvic pain following pelvic inflammatory disease (PID) in women. Reactive arthritis may also be a debilitating consequence of sexually acquired chlamydial infection in either sex.
Because of the likelihood of further sexual transmission and the possibility of upper genital infection and its sequelae developing in patients with only minimal symptoms or signs, it is important to treat Chlamydia trachomatis infection whenever it is detected, and to ensure that treatment schedules for the management of all genital infections includes adequate cover for possible C trachomatis infection.

Tetracyclines

Tetracyclines have been the mainstay of antichlamydial therapy, and of non-specific genital infection, for over 20 years. The current Centers for Disease Control and Prevention (CDC) recommendation is oral doxycycline 100 mg bd for seven days.[1] There is no advantage in prolonging the course. For acute upper genital tract infection, such as PID, intravenous therapy may be necessary. Intravenous preparations of doxycycline are not available in the UK, necessitating the use of parenteral tetracycline hydrochloride.
The current widely used alternative to oral doxycycline is erythromycin, usually recommended as erythromycin base 500 mg six-hourly for seven days. However, a large number of patients will experience gastrointestinal side-effects on this regimen. Another option is to give erythromycin as the stearate 500 mg bd for ten days. The incidence of gastrointestinal side-effects with either the tetracyclines or erythromycin is a cause for concern, resulting in unreliable compliance. Furthermore, although the eradication of C trachomatis approaches 100%, the clinical cure rate is approximately 80%.

Penicillins

The use of penicillins for chlamydial infections continues to be controversial. Amoxycillin has the CDC seal of approval in a dose of 500 mg orally tds for seven to ten days but only for pregnant women with chlamydial infection who are unable to tolerate erythromycin.[1]
Other penicillins, and all cephalosporins, have no role in the management of chlamydial infections.

Quinolone antibiotics

The clinical efficacy of older quinolone antibiotics (such as ciprofloxacin, norfloxacin, fleroxacin, lomefloxacin and pefloxacin) has been somewhat disappointing.
Ofloxacin, which is only twice as active as ciprofloxacin in vitro, is highly effective in eradicating C trachomatis.[2,3]
While authorities appear to accept the use of a 400 mg single oral dose of ofloxacin for treating gonorrhoea, the CDC recommends 300 mg bd for seven days for chlamydial infection.[1] Not only is a 300 mg regimen incompatible with the 400 mg single dose for gonorrhoea, but ofloxacin is not marketed in the UK in a 300 mg formulation.
Further studies are required to confirm the ideal regimen, particularly with regard to the efficacy of single daily dosage, the length of course, and prolonged follow-up with particular emphasis on clinical cure in contrast to organism eradication.
Reports on the in vitro activity of newer quinolones (such as sparfloxacin and clinafloxacin) continue to appear, but reports of good clinical studies are few.[4]
Trovafloxacin, a fluoronaphthyridone antibiotic, shows excellent activity against C trachomatis.[5]
The in vitro activity of quinolones against M hominis and U urealyticum is variable, with generally greater activity against M hominis. This may explain the disappointing lack of clinical cure in non-gonococcal infections (NGI) achieved with quinolones effective against C trachomatis.
The spectrum of activity of quinolones suggests that they may have a role in the treatment of PID. PID is a poly-microbial condition and, although C trachomatis is the major pathogen, therapy should also be active against Neisseria gonorrhoeae, M hominis, coliforms and the non-sporing anaerobes. Therefore, only the more recently developed quinolones are likely to be effective.
Although ofloxacin is now an acceptable single-agent outpatient therapy for PID,[1] the anaerobe controversy will continue. Whether compounds with greater in vitro activity against anaerobic organisms, such as clinafloxacin or trovafloxacin, will demonstrate superior clinical results remains to be seen.
Nielson et al failed to demonstrate any advantage of giving women undergoing first trimester abortion a single oral dose of 400 mg ofloaxcin 1.5-2 hours beforehand, compared with a placebo.[6] Quinolones with similar antimicrobial activity and longer half-life may prove more effective.

Macrolides

The macrolides roxithromycin, josamycin and clarithromycin are all effective in chlamydial and non-chlamydial, non-gonococcal, lower genital tract infection when given in standard doses twice daily for 7-10 days.
A single 1 g oral dose of azithromycin is of equivalent efficacy to oral doxycycline 100 mg bd for seven days, and is recommended as a first-line treatment for uncomplicated urethral, cervical and rectal chlamydial infection.[1]
The approximate cost of 1 g azithromycin is £7-£9, compared with £3-£5 for a week's course of doxycycline (100 mg bd). However, Carlin and Barton[7] looked not only at drug costs, but also the cost of follow-up clinic visits. They found that for every 100 patients there was an overall saving of £360 in the azithromycin-treated group compared with the doxycycline-treated group.
The syndromic approach to treating non-gonococcal urethritis with azithromycin was addressed by Stamm and colleagues.[8 ]As expected, eradication of C trachomatis was similar in the azithromycin-treated and doxycycline-treated groups, although it is noteworthy that three patients in the former group, apparently clear of the organism at two weeks' follow-up, were infected at week five, raising the possibility of suppression rather than eradication of the organism.
Despite good in vitro activity of both azithromycin and doxycycline against U urealyticum, overall microbiological cure rates were only 45% and 47% respectively.[9]
The role of azithromycin in PID is less clear, although preliminary studies suggest that it may be at least equivalent to conventional therapy.

Conclusion

We clearly still have much to learn about both the pathogenesis and the therapy of genital infection associated with C trachomatis. New therapies have advantages with regard to compliance and side-effects profile, but still do not offer optimal clinical cure. To the patient, eradication of a known pathogen is cold comfort if symptoms persist and the clinician cannot explain why, or guarantee cure.

References

1. Centers for Disease Control and Prevention. Recommendations for the prevention and management of Chlamydia trachomatis infections. Morb Mortal Wkly Rep 1993; 42 (RR-12): 1-102.
2. Blomer A, Bruch K, Klose U. Ofloxacin in the treatment of gonococcal and chlamydial urethritis. Clin Ther 1988; 10: 263-265.
3. Hooton TM, Batteiger SE, Judson FN, Spruance SL, Stamm WE. Ofloaxcin versus doxycycline for treatment of cervical infection with Chlamydia trachomatis. Antimicrob Agents Chemother 1992; 36: 1144-1146.
4. Nakata K, Maeda H, Fuji A, Arakawa S, Umezu K, Kamidano S. In vitro and in vivo activities of sparfloxacin and other quinolones and tetracyclines against Chlamydia trachomatis. Antimicrob Agents Chemother 1992; 36: 188-190.
5. Martin D, Jones RB, Johnson AB. A Phase II study of trovafloxacin for the treatment of Chlamydia trachomatis infections. J Antimicrob Chemother 1997; 39: in press.
6. Nielson IK, Engdahl E, Larson T. No effect of single dose ofloxacin on postoperative infection rate after first-trimester abortion. Acta Obstet et Gynecol Scand 1993; 72: 556-559.
7. Carlin EM, Barton SF. Azithromycin as the first-line treatment of non-gonococcal urethritis (NGU): a study of follow-up rates, contact attendance and patients' treatment preference. Int J STD AIDS 1996; 7: 185-189.
8. Stamm WE, Hicks CB, Martin DH et al. Azithromycin for empirical treatment of the non-gonococcal urethritis syndrome in men: a randomized double-blind study. JAMA 1995; 274: 545-149.

Screening: Using evidence on chlamydia

RA Moore DSc Editor, Bandolier
As chlamydial infection is often asymptomatic, especially in women, approaches to treating it are often on a population basis, and that amounts to screening. Screening has had a bad press, partly because screening programmes (of which there are over 300 in the UK) have often been started without the considerable thought and testing needed to show that the screening works and can be effective.
Screening programme effectiveness is a combination both of test accuracy and therapeutic effectiveness. But it has to be recognised that there are disadvantages to screening. It has been said that `all screening programmes do harm; some can also do good'. And a screening programme is just that - a programme rather than just a test or just a treatment, and as programmes they need good management to be effective and efficient in the long term.

Screening for chlamydial infection

A literature review[1] has examined the question of the prevalence of chlamydial infection in women in the UK. The figures ranged from about 2-12%, with a weighted mean average of 5.3%. How good does a test have to be to reliably detect chlamydial infection in this population? That depends on a treatment threshold, but if, for instance, one was content that an 80% chance of a woman having the infection was good enough to commence treatment, then the answer is a likelihood ratio of about 100.
A brief survey of recently published papers on diagnosis of chlamydia indicates that clinical guidelines and cytological are ineffective,[2] as is leucocyte esterase dipstick testing of urine.[3] But a number of other test methods that use amplification techniques on urine do have the required performance.[4]
Treatment is effective. Both a single dose of azithromycin and a seven-day regimen of doxycycline gave high rates of cure (above 90%) in nine randomised trials. But drop-outs were high, and this may reflect the population of people inevitably included in such trials (younger, STD patients) or in part general non-compliance with seven-day regimens.[5,6]
There has been a randomised trial of screening that shows that it can be effective.[7] The trial involved 2,600 women at high risk (7%), which included those in the following categories: age <=24; black race; nulligravid; douching; >=2 sexual partners. These high-risk women were randomised to screen plus treatment, or to usual care (patient characteristics were similar at baseline). In the following 12 months, PID occurred in 9/1009 of those who were screened and treated and 33/1598 of those who were given usual care. This is an NNT 85 (95%CI 48 - 375), with a reduction of about 60% in relative risk.

Performance

In any complex organisation, and especially for screening programmes, performance is the key, and it depends on a number of factors:
Performance = motivation x competence
barriers

A good strategy is to assume that people are well motivated, then to ensure that they have the necessary skills (competence) and knock down the barriers that can hinder performance. Those barriers can include inaccessible information, information overload, information irrelevance and insufficient time.

References

1. Stokes T. Screening for chlamydia in general practice: a literature review and summary of the evidence. J Public Health Med 1997; 19: 222-232.
2. Sellors J, Howard M, Pickard L et al. Chlamydial cervicitis: testing the practice guidelines for presumptive diagnosis. Can Med Assoc J 1998; 158: 41-46.
3. Marrazzo J, White CL, Krekeler B et al. Community-based urine screening for Chlamydia trachomatis with a ligase chain reaction. Ann Intern Med 1997; 127: 796-803.
4. Goessens W, Moulton JW, vand der Meijden W et al. Comparison of three commercially available amplification assays for detection of Chlamydia trachomatis in first-void urine. J Clin Microbiol 1997; 35: 2628-2633.
5. Haddix AC, Hillia SD, Kassler WJ. The cost effectiveness of azithromycin for Chlamydia trachomatis infections in women. Sex Transm Dis 1995; 22: 274-280.
6. Lea AP, Lamb HM. Azithromycin: A pharmacoeconomic review of its use as a single-dose regimen in the treatment of uncomplicated urogenital Chlamydia trachomatis infections in women. Pharmacoeconomics 1997; 12: 596-611.
7. Scholes D, Stergachis A, Heidrich F et al. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. New Engl J Med 1996; 334: 1362-1366.

Economic issues in chlamydial infection

Mo Malek PhD Professor of Health Policy and Management, Chairman of Department of Management,University of St Andrews
The economic issues of chlamydial infection can be tackled at macro and micro levels. Ideally these two levels of analysis will complement each other and inform the conduct of the health policy and management of the disease as well as the strategies for resource allocation.
At macro level there is the question of the burden of chlamydia infection - ie, what is the economic and social burden of chlamydia from the viewpoint of society as a whole and from the viewpoint of the individual? In general, there are two methods of answering this question:

Prevalence approach

The prevalence approach estimates the cost of chlamydia in a particular year for all patients with chlamydial infection by identifying all the direct and indirect costs attributable to chlamydia in that year and multiplying this by the prevalence rate of the infection.
The prevalence method has the advantage of being easy to estimate from existing secondary data sources.

Incidence approach

The incidence approach calculates the lifetime costs of chlamydia for a cohort of people from onset of the disease to death, using the likely outcomes of chlamydia. This approach has the advantage of allowing the impact of intervention strategies over time to be assessed. However, it is very difficult to get the necessary data, since it requires estimates about disease progression.

The problems with the available evidence

All available published studies have used the prevalence approach to estimate the burden of chlamydia in different countries. All these studies are sensitive with regards to the prevalence rate, the choice of the cost categories, the perspective of the study, and the time horizon perceived as relevant by the investigators.
In the USA chlamydia is seen as the most common and costly of all STDs, with approximately 4 million new cases occurring each year at an estimated cost of $2.4 billion.[1]
There are obvious limitations on cost-of-illness studies such as those mentioned above, they concentrate only on the cost side of chlamydia and say nothing about the effectiveness of the practical treatment and prevention strategies and this leads us to the second level of the analysis of the economic issues - ie, cost-effective management of chlamydia.
Issues are varied, but theoretically it should be possible to find a cost-effective, evidence-based method of management. Broadly speaking the problems arise at two sequential stages: detection and treatment.

Detection alternatives

This includes decisions such as:
The decision to screen rests on answering two questions:
i) Is it worth it?
ii) From what do we get the most value?
Answering these questions requires knowledge of the costs and benefits of such screening to identify a threshold prevalence above which screening would be economically cost-effective, and then ranking possible testing strategies in order of their cost-effectiveness.
There are a few studies that inform the decision making (with the usual proviso that they should be treated with some caution). For example, it has been suggested that screening women at prevalences of more than 6% and men at prevalences of more than 4% is cost-effective, and screening women appears economically more preferable to screening men. At prevalences of 9% and over, mass therapy becomes more economically viable than both universal and targeted screening programmes.
With regards to selective screening, there is already ample evidence regarding possible risk factors: age, use of the contraceptive pill, marital status, past history of STD, number of partners and so on, are frequently used factors in the literature. It should be possible to quantify the exact contribution of these factors and use the model to evaluate the relative viability of different selective screening strategies.

Treatment alternatives

When a drug regimen is chosen, there are concerns about toxicity, cost, compliance and the potential effect on the microbial environment.[2] The three conventional and most often cited effective antimicrobial agents in treatment of chlamydial infections are:
However, a disquieting observation has been that some isolates of chlamydia demonstrate in vitro or in vivo resistance to tetracyclines[3,4] and to erythromycin.[5]
Azithromycin has been a major advance in the treatment of CT and in studies with reasonable follow-up, azithromycin has provided efficacy equivalent to that of doxycycline with a single oral dose. Effectiveness would be even better taking into account the compliance issues.
The issue therefore boils down to the comparative cost of alternative regimens. From a global perspective, drug costs contribute minimally to the overall cost of prevention and management of STDs in general, and chlamydia in particular.[6,7,8,9] In this respect, unit acquisition costs become almost irrelevant in the comparison of the alternative therapies. The issues become more concentrated on compliance and failure rates. For example, the standard doxycycline regimen (100 mg twice daily for seven days) costs $0.50-$2 in the USA compared with azithromycin (1 g sachet) which costs $9.50 - a cost differential of around $8 per patient.
However, one does not need to conduct a sophisticated cost-effectiveness analysis to show that prescribing azithromycin will make both clinical and economic sense.

Conclusion

The methodology for economic evaluation of the therapeutic options available for treatment of chlamydia has largely been concentrated at the rather short-term, narrow view of costs and outcomes.
Where the methodology has been performing less satisfactorily has been due to the quality of the medical and epidemiological information. As is usually the case, we also have been subjected to short-term budgetary considerations, for which unfortunately there is unlikely to be a cure.

References

1. Hillis S, Black C, Newhall J et al. New Opportunities for Chlamydia Prevention: Application of Science to Public Health Practice. Sex Transm Dis 1995; 22: 197-202.
2. Bowie WR. Sexually Transmissible Diseases. In: TM Speight, HG Holford (eds). Avery's Drug Treatment, 4th Edition. Auckland: Adis International Ltd, 1997, 1545-1581.
3. Shepard MK, Jones RB. Recovery of Chlamydia trachomatis from endometrial and fallopian tube biopsies in women with infertility of tubal origin. Fertil Steril 1989; 52: 232-238.
4. Jones RB, Van der Pol B, Martin DH et al. Partial characterisationing of Chlamydia trachomatis isolates resistant to multiple antibiotics. J Infect Dis 1990; 162: 1309-1315.
5. Mourad A, Sweet RL, Sugg N et al. Relative resistance to erythromycin in Chlamydia trachomatis. Antimicrob Agents Chemother 1980; 18: 696-698.
6. Genc M, Ruusuvaara L, Mardh PA. An economic evaluation of screening for Chlamydia trachomatis in adolescent males. JAMA 1993; 270: 2057-2064.
7. Haddix AC, Hillis SD, Kassler WJ. The cost-effectiveness of single dose therapy for Chlamydia trachomatis infection in women. In: Orfila J, Byrne GI, Chernesky MA et al (eds). Eighth International Symposium on Human Chlamydial Infections. Bologna: Societa Editrice Esculapio, 1994, 55-58.
8. Begley CE, McGill L, Smith PB. The incremental cost of screening diagnosis, and treatment of gonorrhoea and chlamydia in a family planning clinic. Sex Transm Dis 1989; 16: 63-67.
9. Netleman MD, Jones RB, Roberts SD et al. Cost-effectiveness of culturing for Chlamydia trachomatis: a study in a clinic for sexually transmitted diseases. Ann Intern Med 1986; 105: 189-196.