Doxycycline Compared with Azithromycin for Treating Women with Genital Chlamydia trachomatis Infections: An Incremental Cost-Effectiveness Analysis

Methods

Structure of the Decision Model: The Basic Tree

Figure 1 shows the decision model used in our analysis. We calculated health outcomes and costs for two hypothetical cohorts of 100 000 nonpregnant women of child-bearing age who had laboratory-confirmed, uncomplicated cervical chlamydial infections. One cohort was treated with the doxycycline strategy, and the other cohort was treated with the azithromycin strategy. The doxycycline strategy consisted of oral doxycycline, 100 mg twice daily for 7 days; the azithromycin strategy consisted of 1 g of azithromycin in a sachet formulation administered as a single oral dose. The doxycycline and azithromycin management strategies were identical in all other respects. The subtrees of Figure 1 (identified by the curly braces) represent the risk for adverse antibiotic reactions, pelvic inflammatory disease and its sequelae, and sequelae of chlamydia in new sexual partners and neonates that occur with both treatment strategies.

We defined antibiotic reactions as adverse occurrences resulting from antibiotic therapy. Minor reactions to oral doxycycline included nausea, vomiting, diarrhea, abdominal pain, esophagitis, mild hypersensitivity reactions, photosensitivity, and oral and vaginal candidiasis [17-21]. Minor reactions to azithromycin included nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, fatigue, somnolence, palpitations, mild hypersensitivity reactions, and vaginal candidiasis [9-15, 22]. Major reactions to oral doxycycline included enterocolitis, pericarditis, anaphylaxis (including angioedema), the Stevens-Johnson syndrome, severe urticarial reactions, and a lupus-like syndrome [19-21]. Major reactions to azithromycin included anaphylaxis (including angioedema), cholestatic jaundice, and interstitial nephritis [9-1522, 23]. The true frequency of major reactions associated with azithromycin is unknown because of limited experience with this drug; we therefore assumed that major reactions to azithromycin occurred with the same frequency as reactions to doxycycline.

We defined chlamydia sequelae as conditions that occurred as a result of persistent cervical C. trachomatis infection. We defined minor sequelae of chlamydial infection and antibiotic reactions as self-limited conditions that could be managed solely on an outpatient basis, whereas major sequelae and reactions were outcomes that could potentially lead to hospitalization or substantial future morbidity. We classified urethritis in a male partner and neonatal conjunctivitis as minor sequelae of chlamydial infection and considered pelvic inflammatory disease, infertility, chronic pelvic pain, ectopic pregnancy, epididymitis in a male partner, and neonatal pneumonia to be major sequelae.

Probability Estimates

The probability estimates used in the model Table 1 were obtained from a review of the literature and from a survey of experts using a modified Delphi method. Thirteen physicians expert in managing C. trachomatis infection and its sequelae (specialists in obstetrics and gynecology, pediatrics, and infectious disease, including faculty members of medical schools and physicians practicing in public health clinic settings) were surveyed about their estimates for an extensive set of epidemiologic and clinical variables. For each variable, we determined a best estimate and a range of plausible values representing the degree of uncertainty surrounding the variable. We determined the effectiveness of doxycycline in curing uncomplicated cervical chlamydial infections in a routine clinical setting by combining estimates of compliance with estimates of cure rates at various levels of compliance. Compliance with a 1-week, twice-daily doxycycline regimen was categorized into four levels by the number of pills taken. We assumed that 70% of patients would take 12 to 14 pills and that 96% of these patients would be cured of C. trachomatis infection; 20% would take 7 to 11 pills and 80% would be cured; 5% would take 3 to 6 pills and 40% would be cured; and 5% would take 1 to 2 pills and 10% would be cured. From these estimates, we calculated that the overall baseline estimate of doxycycline effectiveness would be 85.7% (0.70 × 0.96 + 0.20 × 0.80 + 0.05 × 0.40 + 0.05 × 0.10 = 0.857).

Evaluation of the Use of Medical Services

We estimated the use of medical services by patients with chlamydia sequelae on the basis of a review of the literature and expert opinion (Appendix). We asked expert respondents to detail the nature and quantity of services and resources used to treat patients with chlamydia sequelae (that is, physician visits, hospitalizations, diagnostic tests, surgical procedures, and medical therapy).

Cost Estimates

Our analysis was done from the perspective of a payer and was confined to assessing direct medical costs resulting from sequelae of C. trachomatis infections (Table 2). We intended the primary analysis to be applicable to many settings in which patients would be screened and treated for chlamydial infections. For the primary analysis, 1993 payments and allowed charges for medical services (diagnostic tests, physician services, and hospital care) were obtained from Colorado Blue Cross and Blue Shield. We used Blue Cross and Blue Shield payments to estimate the cost of hospital services and used Blue Cross and Blue Shield-allowed charges to estimate the cost of outpatient and physician services. Allowed charges and actual payments are a reasonable proxy for medical costs and should not be confused with the nominal charges of hospitals and physicians.

We used the average wholesale price (AWP) to estimate antibiotic acquisition costs in the primary analysis. Although the term “wholesale” is used in its name, the AWP is actually a price suggested by the manufacturer to the pharmaceutical retailer [48]. We chose to use the AWP because it is a standardized national source for pharmaceutical pricing and because it may overstate the antibiotic cost differential between the azithromycin strategy and the doxycycline strategy, thereby biasing the model in favor of the doxycycline strategy.

We determined the costs associated with each medical outcome by aggregating the various cost elements (Appendix). To adjust for time-related preferences in this analysis, costs were discounted at a rate of 5% per year for complications that would probably occur after 1 year of infection (ectopic pregnancy, chronic pelvic pain, and infertility). We then calculated the total discounted cost of each management strategy by adding the costs of each associated outcome.

We also did a secondary analysis in which we modeled cost estimates for a public health clinic. Colorado Medicaid reimbursements were used to estimate the cost of inpatient, outpatient, and physician services. Estimates of antibiotic costs were based on the acquisition prices of federally supported public clinics. Because the results of the secondary analysis were almost identical to those of the more general primary analysis, we present only the results of the primary analysis.

Health Outcomes

For each management strategy, we summed major antibiotic reactions and major chlamydia sequelae to calculate total major complications. Minor antibiotic reactions and minor chlamydia sequelae were added to determine total minor complications. For our analysis, all major complications were considered to be of equal importance, and similarly, all minor complications to be of equal importance. There is controversy over which technique should be used to measure preferences and quality of life [49]. Because there is no standard technique for measuring utilities, we did not attempt to present quality-adjusted outcome measures.

Although experts agree that financial costs must be discounted for time effects, there is controversy about whether nonfinancial health benefits should be discounted [50]. Thus, we ran the model with health outcomes both undiscounted and discounted at a 5% rate for complications that would probably occur after 1 year of infection (ectopic pregnancy, chronic pelvic pain, and infertility). Because the results were similar with both methods, we present the results with health outcomes undiscounted.

Cost-Effectiveness

We used incremental cost-effectiveness ratios to compare the cost-effectiveness of two alternative interventions when one intervention was more effective but also more expensive than the other. The incremental cost-effectiveness ratio is the additional cost of a more expensive but more effective intervention above that of a less expensive but less effective intervention divided by the differences in effectiveness. This ratio allows assessment of the cost per unit benefit of switching from one treatment strategy to a second treatment strategy. Incremental cost-effectiveness was used to compare management alternatives when the azithromycin strategy was more effective in preventing disease sequelae but was more expensive than the doxycycline strategy (that is, [cost_azithromycin strategy − cost_doxycycline strategy]/[effectiveness_azithromycin strategy − effectiveness_doxycycline strategy]) and was expressed as the ratio of the extra dollar cost incurred per additional major complication prevented.

Sensitivity Analysis

Rates of chlamydia sequelae, antibiotic reactions, antibiotic effectiveness, and costs of antibiotics and chlamydia sequelae were varied over a plausible range of values as determined from the literature and estimated by experts. We used univariate sensitivity analysis to calculate the effect of these changes on health outcomes, costs, and cost-effectiveness for all model variables. We also did a multivariate sensitivity analysis, combining the most extreme estimates for each chlamydia sequela variable selected so that the relative cost-effectiveness of the doxycycline strategy would be maximized.

Results

Base-Case Analysis: Health Outcomes and Costs

The health outcomes and dollar costs for the two hypothetical cohorts of 100 000 women with cervical chlamydial infections who were treated with the alternative treatment strategies are shown in Table 3. When we used the base-case estimates Table 1 and Table 2, the azithromycin strategy incurred fewer major and minor sequelae of C. trachomatis infection and was less expensive than the doxycycline strategy. The azithromycin strategy incurred 938 major complications (major chlamydia sequelae plus major antibiotic reactions) and 15 715 minor complications (minor chlamydia sequelae plus minor antibiotic reactions) per 100 000 patients compared with 3330 major complications and 25 706 minor complications incurred with the doxycycline strategy. In the base-case analysis, the azithromycin strategy cost $39.51 per patient and the doxycycline strategy cost $69.07 per patient.

Univariate Sensitivity Analysis

The superiority of the azithromycin strategy over the doxycycline strategy for preventing major and minor complications was insensitive to changes in any variable assumption throughout the plausible ranges shown in Table 1. Results were also insensitive to variation of any cost estimate, including a 30% reduction in the baseline costs of treating patients with cervical chlamydia sequelae. The relative cost of the two strategies was sensitive only to variation in the effectiveness of doxycycline in curing cervical chlamydial infection.

Figure 2 shows the incremental cost-effectiveness of the azithromycin strategy relative to the doxycycline strategy as the overall rate of doxycycline effectiveness was varied. This sensitivity analysis is presented over a broader range (0.80 to 0.94) than that listed in Table 1 (0.80 to 0.90) to allow assessment of management decisions for individual patients in whom compliance with doxycycline and doxycycline effectiveness can therefore be predicted to be significantly better than those estimated for the general population. At rates of doxycycline effectiveness less than 0.93, the azithromycin strategy prevented more major and minor complications and cost less than the doxycycline strategy. For rates of doxycycline effectiveness greater than 0.93, the azithromycin strategy still prevented more major and minor complications but cost more than the doxycycline strategy.

Multivariate Sensitivity Analysis

Because model results were relatively insensitive to univariate sensitivity analysis, we created a scenario in which the desirability of the doxycycline strategy was maximally enhanced relative to the azithromycin strategy. This model used the most conservative plausible estimates from published data and expert opinion for 11 assumptions: the highest rate of doxycycline effectiveness (0.90); the lowest rates of pelvic inflammatory disease in patients with persistent lower genital tract chlamydial infection (0.08), hospitalization for symptomatic pelvic inflammatory disease (0.08), pelvic inflammatory disease sequelae (0.08 for infertility, 0.05 for ectopic pregnancy, and 0.08 for chronic pelvic pain), infected partner sequelae (0.35 for urethritis and 0.01 for epididymitis), and infected neonatal sequelae (0.15 for conjunctivitis and 0.03 for pneumonia); and the lowest number of infected partners per infected female patient (0.75).

Under these assumptions, the azithromycin strategy still resulted in fewer major complications (440) and minor complications (14 431) per 100 000 women treated than did the doxycycline strategy (1100 and 19 579, respectively), but it was more costly, with an incremental cost-effectiveness of $521 per additional major complication prevented. Its incremental cost-effectiveness was $521 per additional major complication prevented. However, if the antibiotic cost-differential was less than $9.80 ($15.31 for the azithromycin regimen compared with $5.51 for the baseline doxycycline regimen), the azithromycin strategy was cheaper and more effective, even under these extreme conditions.

Discussion

Our decision-analysis model used the best available data to compare the cost-effectiveness of azithromycin with that of doxycycline for women with laboratory-confirmed, uncomplicated cervical C. trachomatis infections. The azithromycin strategy was the strategy of choice under our set of baseline assumptions because it incurred fewer major and minor complications and was less expensive than the doxycycline strategy. The superiority of the azithromycin strategy was robust, although, under some assumptions, the azithromycin strategy resulted in reduced complications at modest increase in cost. Despite this general trend, what holds on average may not be appropriate for all situations, and when the degree of doxycycline compliance and effectiveness for a specific patient or setting is estimated to be significantly greater than that for the population as a whole (for example, for a patient previously known to be compliant or a patient in an observed setting, such as a hospital), the doxycycline strategy may be preferable to the azithromycin strategy.

These results specifically apply to women of childbearing age who have laboratory-confirmed chlamydial infection. Our analysis does not address and is not necessarily generalizable to the treatment of men, nor does it refer to empiric treatment of conditions associated with an increased prevalence of C. trachomatis infection. Our analysis is also limited to settings in which both treatments are initiated by the health care provider (such as directly observed administration of single-dose azithromycin or provision of the full course of doxycycline in which the initial dose is directly administered by the provider and the remaining 13 doses are given to the patient to be taken in the next 7 days).

All clinical models and decisions are necessarily limited by the use of imperfect data and simplifying assumptions. The baseline probabilities used, although imperfect, represent the best estimates currently available from the literature and experts. The superiority of the azithromycin strategy over the doxycycline strategy in preventing major and minor complications was insensitive to changes in any variable assumptions, indicating the greater effectiveness of azithromycin when compliance with drug therapy is likely to be imperfect. The relative cost of the two strategies was sensitive to only one variable: the effectiveness of doxycycline in curing cervical chlamydial infections.

Estimates of the clinical effectiveness of any antibiotic regimen must incorporate compliance measures as well as estimates of treatment efficacy associated with various levels of compliance. Because our model considers provider administration of the single azithromycin dose, the effectiveness of azithromycin will not be altered by patient compliance and should be similar to the efficacy reported in clinical trials. In contrast, the effectiveness of doxycycline is significantly influenced by patient compliance. Previous health economic analyses of chlamydia screening and treatment programs [34-36, 51-53] used baseline estimates of doxycycline efficacy ranging from 0.90 to 1.00. Few studies have explicitly estimated compliance; in studies that have considered compliance, estimates of efficiency range from 0.50 to 1.00 [37, 38, 54]. Generally, in studies in which compliance was estimated [37, 38, 54], treatment was assumed to have failed in noncompliant patients.

In our study, we considered various compliance levels based on the number of pills taken by the patient, as well as the probable effectiveness of doxycycline therapy at various levels of compliance. Estimates of the proportion of patients and degree of efficacy associated with each of these compliance levels produced a calculated baseline rate of doxycycline effectiveness of 0.857 and a sensitivity analysis range of 0.80 to 0.90. We obtained estimates of doxycycline compliance from studies of patients treated for C. trachomatis infection [6], Neisseria gonorrhoeae infection [5, 6], and pelvic inflammatory disease [7]. Although data on doxycycline efficacy in patients with cervical chlamydia who complete the full standard 7-day regimen are well established [9, 17, 18], estimates of doxycycline efficacy for C. trachomatis infection at less than the recommended regimen (100 mg orally, twice daily for 7 days) are based on limited published data [25, 47] and expert opinion.

There are probably patient subsets and individual patients whose compliance rates are both lower and higher than our estimates. In addition, strategies may exist for improving overall compliance rates and, therefore, doxycycline effectiveness. Such strategies might include better patient education and drug packaging or more effective telephone follow-up and other quality management programs. Because the half-life of doxycycline is greater than 12 hours [19], twice-daily treatment may be less important than therapy duration in achieving high rates of chlamydia cure. As long as the acquisition cost of doxycycline therapy remains substantially less than that of azithromycin therapy, further study of doxycycline compliance and efficacy associated with various degrees of compliance should be a priority.

In general, our model is conservative with regard to the cost-effectiveness of the azithromycin strategy. First, the analysis considers only the relatively limited direct medical costs of a persistent cervical chlamydial infection. Consideration of nonmedical direct costs (travel costs incurred in the course of receiving medical care, additional out-of-pocket costs of care), indirect costs (work and productivity losses and the reduction in quality of life resulting from infertility or chronic pelvic pain), and intangible costs (pain and suffering) would further increase the benefits of the azithromycin strategy relative to the doxycycline strategy. One study [1] estimated that the indirect costs of genital chlamydial infections were approximately equal to the direct costs. If indirect costs of this magnitude were included in our model, the azithromycin strategy would be less expensive under all sets of assumptions, including the most extreme scenarios.

Second, we assumed that all patients managed as outpatients would be seen at a physician's office; thus, we did not account for more expensive physician and hospital service fees for the proportion of patients seen in emergency departments. Furthermore, we assumed that all patients with an acute condition resulting from C. trachomatis infection would already be established patients of the physician caring for them. To the extent that some patients would not be previously known to the physician, the analysis underestimates the additional costs of establishing medical and administrative records for such new patients.

Third, the morbidity assumptions of the model may also have underestimated the advantages of the azithromycin strategy. The estimated probabilities for sequelae in patients with persistent cervical C. trachomatis infection used in the analysis were generally lower than those used in previously published analyses [1, 34-38, 51-55]. We also did not include the morbidity and costs of several other conditions associated with chlamydial infection (such as the Reiter syndrome; recurrent episodes of pelvic inflammatory disease; male infertility; and the adverse pregnancy outcomes of postpartum endometritis, prematurity, and stillbirth) or the morbidity and costs associated with the transmission of chlamydia to secondary female partners by men who become infected by an female index case.

Fourth, we assumed that only women who develop symptomatic pelvic inflammatory disease were at increased risk for developing late sequelae of pelvic inflammatory disease. However, serologic studies of patients with tubal infertility suggest that a significant proportion of cases of upper genital tract chlamydial infection may be asymptomatic [56]. Prevention of asymptomatic pelvic inflammatory disease was not included as a benefit in our model because it was not known whether early antibiotic treatment prevents this complication. To the extent that the azithromycin strategy prevents proportionately more cases of subclinical pelvic inflammatory disease than the doxycycline strategy, the azithromycin strategy becomes even more desirable relative to the doxycycline strategy.

Finally, we did not consider the potential role of C. trachomatis in facilitating transmission of the human immunodeficiency virus (HIV). Emerging data associate various sexually transmitted diseases, both ulcerative and nonulcerative, with enhanced transmission of HIV, and control of sexually transmitted diseases is increasingly being considered important for prevention of HIV infection [57]. To the extent that azithromycin cures chlamydial infection more effectively than doxycycline, its use may provide important benefits for HIV control, especially in areas in which the prevalence of heterosexual HIV infection is high, such as many cities in the eastern United States.

On the other hand, factors absent from our model might contribute to making the azithromycin strategy less desirable than our analysis predicts. First, the rate of major adverse reactions is less well established for azithromycin than for doxycycline, and newly recognized adverse reactions to azithromycin could reduce the cost-effectiveness of the azithromycin strategy. Second, we did not address the issue of reinfection of a female index patient by a male partner who is infected and does not receive effective treatment. Because baseline cure rates are greater for the azithromycin strategy than for the doxycycline strategy, rates of reinfection with C. trachomatis will decrease the effectiveness of the azithromycin strategy more than it will that of the doxycycline strategy. Third, as noted above, our model considered only provider-administered therapy, with which compliance with azithromycin can be assured. The relative benefit of the azithromycin strategy may be lower in settings in which medication is prescribed, to the extent that more azithromycin than doxycycline prescriptions can be expected to be unfilled because of the greater cost of the former.

Finally, it is worth considering how future trends in health care delivery may affect the results of our model. For example, expanding infertility therapy benefits for women would make the azithromycin strategy relatively more desirable. Conversely, expansion of routine chlamydia screening in asymptomatic women might enhance the doxycycline strategy by giving some patients with cervical chlamydia who are not cured with initial antibiotic therapy an opportunity to be screened and treated again before developing upper tract disease. Similarly, if current trends toward the reduced use of inpatient services continue, the relative superiority of the azithromycin strategy over the doxycycline strategy would be reduced. Although it is unclear how changes in health care delivery will affect strategies for managing chlamydia, decision models such as the one used in our study will be helpful in evaluating the effect of these changes.

The flexibility of our decision model will also be helpful in evaluating the significance of data from future epidemiologic studies of chlamydial infection and therapy. Prospective studies comparing the field effectiveness of doxycycline with that of azithromycin under routine clinical conditions are a priority for future research and are essential for confirming our estimates. In addition, studies assessing predictors of poor patient compliance with doxycycline therapy will be valuable to clinicians who practice in settings in which fiscal constraints mandate the selective use of azithromycin. Finally, the marginal benefit of azithromycin relative to doxycycline will be reduced for the empiric treatment of women with chlamydia-associated syndromes such as mucopurulent cervicitis, because not all of these patients are infected with C. trachomatis. The preferred treatment strategy for these patients is unclear and is an important area for further investigation [58].

The azithromycin strategy is dominant from the perspective of the entire health care system because it prevents more complications and costs less than the doxycycline strategy. However, from the perspective of the clinic, initial azithromycin therapy is “cost increasing” because the higher cost of initial treatment is borne directly by the clinic, whereas the cost savings are accrued later, often by other components of the health care system, such as insurers. This may be a particular problem for public family planning and sexually transmitted disease clinics, which generally serve low-income patients and have limited budgets. These clinics may have to divert funds from other programs in order to implement the routine use of azithromycin for treatment of chlamydia. Thus, although azithromycin has the potential to have a significant effect on chlamydia control efforts in the United States today, its rapid universal adoption may be limited by practical financial constraints of our current fragmented health care delivery system, in which costs of prevention and costs of sequelae are often borne by different providers.

Appendix: Medical Service Use and Associated Costs

For patients whose condition required hospitalization, we assumed that entry into the hospital required an average of one extended prehospitalization visit ($75.00). We assumed that the attending physician would visit for each day of hospitalization and that the first visit would entail an initial, comprehensive examination ($173.00); the second visit, an intermediate examination ($79.00); and any remaining visits, brief examinations ($55.00). For the last day of hospitalization, a hospital discharge physician fee was assessed ($80.00). A single, limited, postdischarge physician visit was assumed ($35.00). Relevant physician fees for radiologic interpretations, surgical procedures, and anesthesia services were added to the cost of hospitalization for patients who used these services.

Outpatient physician services included comprehensive visits ($127.00), extended visits ($75.00), intermediate visits ($47.00), and limited visits ($35.00). Outpatient microbiology tests included a Gram stain ($5.00) and culture for N. gonorrhoeae ($13.00) and diagnostic testing for C. trachomatis ($25.00). The average wholesale pharmacy cost for empiric treatment of N. gonorrhoeae infection (intramuscular ceftriaxone, 250 mg) was $7.60; the cost for empiric treatment of C. trachomatis infection (oral doxycycline, 100 mg twice daily for 7 days) was $5.51. The average wholesale pharmacy cost for treatment of C. trachomatis infection with 7 days of erythromycin was $6.40.

The average cost for outpatient management of pelvic inflammatory disease was calculated to be $191.55. The following medical services were included in this estimate: an average of 1.0 extended and 1.5 limited follow-up physician visits ($127.50), culture for N. gonorrhoeae ($13.00), and a diagnostic test for C. trachomatis ($25.00). In one third of cases, additional laboratory tests (complete blood count, urinalysis, or pregnancy tests) were considered necessary ($23.00). Empiric treatment included intramuscular ceftriaxone, 250 mg ($7.60), and a 2-week course of doxycycline ($11.02).

The average cost for inpatient management of pelvic inflammatory disease was calculated to be $5259.03. This included a hospital fee for an average stay of 4.0 days ($3975.00), professional fees for primary attending services ($497.00), and an interpretation of an ultrasonogram of the pelvis ($75.00). We estimated that one third of hospitalized patients would require a surgical procedure, thereby incurring an additional hospital fee ($563.00), a surgeon fee ($1100.00), and an anesthesiologist fee ($450.00). All patients received a 10-day course of doxycycline ($7.87) at discharge.

The probability that women with a history of pelvic inflammatory disease who developed tubal infertility would use medical services for evaluation and treatment of their infertility was estimated from data collected in the National Survey of Family Growth, a periodic survey conducted by the National Center for Health Statistics. Data from the 1988 survey indicated that 45% of women with a history of impaired fertility or fecundity who also had a history of pelvic inflammatory disease sought an infertility evaluation. Of women with a history of pelvic inflammatory disease who had an evaluation for infertility, 30% had tubal surgery. Similarly, in the National Center for Health Statistics survey, of the 45% of women who sought medical attention, 12% ultimately received in vitro fertilization treatment (Chandra A. Personal communication). We therefore calculated that 5.4% of all infertile women would receive in vitro fertilization (45% × 12%). We assumed that, on average, each of the 5.4% of women would have two procedures.

We calculated that the average cost for managing a case of tubal infertility would be $5172.68. We assumed that 45% of patients with tubal infertility secondary to pelvic inflammatory disease would seek medical evaluation for their infertility, with an average workup including the following: one extended, three intermediate, and four limited physician visits ($408.00); semen analysis ($42.00); postcoital test ($50.00); endometrial biopsy ($185.00); hormonal laboratory testing ($170.00); ultrasonography of the pelvis ($184.00); and hysterosalpingography ($236.00). We estimated that 75% of patients would have outpatient laparoscopy (including a hospital fee of $1725.00, a surgeon fee of $760.00, and an anesthesiologist fee of $375.00) and that 30% would have tubal surgery (including an outpatient hospital fee of $3056.00, a surgeon fee of $1100.00, and an anesthesiologist fee of $450.00). We further estimated that 12% of patients would have an average of two trials of in vitro fertilization at a cost of $7500.00 per trial. We assumed that, on average, tubal infertility costs would be incurred 5 years after the development of acute pelvic inflammatory disease. Therefore, the total average cost for managing tubal infertility, $6601.80, was discounted at a rate of 5% per year for 5 years to $5172.68.

The average cost for managing a case of ectopic pregnancy was calculated to be $4717.69. We assumed that patients with ectopic pregnancy would be hospitalized for an average of 3.0 days (hospital fee, $3834.00) with professional fees for primary attending physician services ($442.00) and for interpretation of an ultrasonogram of the pelvis ($75.00). We estimated that 95% of patients would have a surgical procedure, thereby incurring a surgeon fee ($1259.00) and an anesthesiologist fee ($499.00). We assumed that, on average, ectopic pregnancy costs would be incurred 5 years after the development of acute pelvic inflammatory disease. Therefore, the total average cost for managing ectopic pregnancy, $6021.10, was discounted at a rate of 5% per year for 5 years to $4717.69.

The average cost for managing a case of chronic pelvic pain was calculated to be $3809.11. We assumed that an average work-up would require the following services: one extended, four intermediate, and five limited physician visits ($490.00); analgesic drug therapy for 6 months ($100.00); and ultrasonography of the pelvis ($184.00). We estimated that 75% of patients would have outpatient laparoscopy (including a hospital fee of $1725.00, a surgeon fee of $760.00, and an anesthesiologist fee of $375.00) and that 30% of patients would have lower-abdominal surgery (including an inpatient hospital fee of $4538.00, an attending physician fee of $387.00, a surgeon fee of $1100.00, and an anesthesiologist fee of $450.00). We assumed that, on average, chronic pelvic pain costs would be incurred 5 years after the development of acute pelvic inflammatory disease. Therefore, the total average cost for managing chronic pelvic pain was discounted at a rate of 5% per year for 5 years to $3809.11.

The average cost of managing a case of urethritis in a male partner was estimated to be $82.39, including an intermediate physician visit ($47.00), a Gram stain for N. gonorrhoeae ($5.00), diagnostic testing for C. trachomatis ($25.00), and antibiotic treatment effective against chlamydia ($5.51).

The average cost for outpatient management of epididymitis was calculated to be $206.70. Medical services included one initial extended and one limited follow-up physician visit ($110.00), a urinalysis or urine culture ($11.00), N. gonorrhoeae culture ($13.00), and diagnostic testing for C. trachomatis ($25.00). We estimated that an ultrasonogram or Doppler flow study of the testicles ($220.00) and a urology consultation ($127.00) would be obtained in 10% of patients. Antibiotic treatment effective against N. gonorrhoeae and C. trachomatis ($13.00) was given to all patients.

The average cost of inpatient management of epididymitis was estimated to be $3421.59. This included a hospital fee for an average stay of 3.5 days ($2806.00) and professional fees for primary attending physician services ($469.50) and interpretation of an ultrasonogram of the testicles ($75.00). We estimated that 3% of patients would require a surgical procedure, thereby incurring an additional hospital fee ($563.00), a surgeon fee ($1100.00), and an anesthesiologist fee ($450.00). All patients received a 10-day course of doxycycline ($7.87) at discharge.

To estimate rates of sequelae of chlamydial infection for children born to infected mothers, we assumed a live birth rate in women with persistent chlamydial infection to be 6% per year [59] for 2 years. We assumed that 80% of women would be screened for chlamydial infection as part of their prenatal care and that 80% of those screened would receive a correct diagnosis and treatment. Only women whose chlamydial infections were not detected and cured at the time of prenatal screening and who delivered by the vaginal route (an estimated 80%) were assumed to be at risk for transmitting the infection to their children.

The average cost for outpatient management of a case of neonatal conjunctivitis was estimated to be $81.80. We assumed that evaluation would include a limited physician visit ($35.00), laboratory tests for C. trachomatis and N. gonorrhoeae ($38.00), and treatment with a course of erythromycin ($12.80) for both child and mother.

The average cost for outpatient management of a case of neonatal pneumonia was estimated to be $225.80. We assumed that an average evaluation would include one intermediate and one limited follow-up physician visit ($82.00), laboratory testing ($75.00), and chest radiography ($60.00). All patients and their mothers were treated with a course of erythromycin ($12.80).

The average cost for inpatient management of a case of neonatal pneumonia was calculated to be $3023.80. Costs included a fee for an average hospital stay of 3.0 days ($2523.00), a primary attending physician fee ($442.00), and a fee for interpretation of a chest radiograph ($50.00). All patients and their mothers were treated with a course of erythromycin ($12.80).

The average cost for outpatient management of a minor adverse drug reaction was estimated to be $35.00. We assumed that an average evaluation would include one limited physician visit ($35.00).

The average cost for inpatient management of a case of a major adverse antibiotic reaction was calculated to be $3747.50. Costs included a fee for an average hospital stay of 3.5 days ($3278.00) and a primary attending physician fee ($469.50).

We estimated that in 50% of cases of newly diagnosed pelvic inflammatory disease, neonatal conjunctivitis, and neonatal pneumonia, a male partner would be referred for treatment. We also estimated that in 50% of cases of newly diagnosed urethritis or epididymitis, a female partner would be referred for treatment. The average cost of partner treatment was calculated to be $50.39. We assumed that an average evaluation would include the cost of partner notification ($10.00), a limited physician visit ($35.00), and antibiotic treatment effective against C. trachomatis ($5.51).

Presented in part at the Western Section of the American Federation of Clinical Research, Carmel, California, February 1993, and at the Annual Meeting of the Society of Academic Emergency Medicine, San Francisco, California, May 1993.

Dr. Douglas: Disease Control Service, Denver Department of Public Health, 605 Bannock Street, Denver, CO 80204.

Dr. Schwartz: The Leonard Davis Institute of Health Economics, University of Pennsylvania, 3641 Locust Walk, Suite 210, Philadelphia, PA 19104.