A randomized double-blind comparison of moxifloxacin and doxycycline/metronidazole/ciprofloxacin in the treatment of acute,uncomplicated pelvic inflammatory disease

Abstract

This multicentre, double-blind study was undertaken to demonstrate non-inferiority of once-daily oral moxifloxacin compared with combination therapy in the management of acute, uncomplicated pelvic inflammatory disease (PID). Women aged ≥18 years with PID were randomized to receive moxifloxacin (400 mg once daily) for 14 days or comparator treatment (doxycycline [100 mg twice daily] plus metronidazole [400 mg three times daily] for 14 days, plus one single 500-mg ciprofloxacin dose). Of the 434 valid per protocol (PP) patients, the overall clinical success rates at 2–14 days post-therapy were 96.6% (moxifloxacin) and 98.0% (comparator); moxifloxacin was non-inferior to the comparator regimen both in the PP (95% confidence interval [CI]: −4.5, 1.6) and intent-to-treat (95% CI: −5.8, 6.9) populations. Clinical success rates at 21–35 days post-therapy were 93.8% (166/177; data missing for 47 patients) for moxifloxacin and 91.3% (147/161; data missing for 37 patients) for the comparator. Bacteriological success rates at 2–14 days post-therapy were 92.5% (moxifloxacin) and 88.2% (comparator). Once-daily dosing and proven efficacy suggest that moxifloxacin may be of value in acute, uncomplicated PID.

Keywords

ciprofloxacin doxycycline metronidazole moxifloxacin pelvic inflammatory disease

INTRODUCTION

In sexually active women, pelvic inflammatory disease (PID) is a common and serious complication of sexually transmitted infections. Delays in initiating appropriate treatment may lead to infertility, ectopic pregnancy, chronic pelvic pain and other serious sequelae.^1–3 Acute PID is difficult to diagnose because signs and symptoms vary widely, from acute to asymptomatic, and even when present they lack sensitivity and specificity.^1,3 Its treatment is also challenging as several pathogens may be involved, either alone or in combination. Neisseria gonorrhoeae and Chlamydia trachomatis have been identified as causative agents while Mycoplasma genitalium, Gardnerella vaginalis and other common genital-tract bacteria have also been implicated.^1,4–9

In view of the difficulty of diagnosis and the potential risk to reproductive health caused by PID, guidelines recommend maintaining a low threshold for the diagnosis of PID. Empiric treatment is also recommended as the prevention of long-term sequelae is directly linked with the prompt administration of broad-spectrum antibiotic therapy.^1–3,8 Because of the polymicrobial nature of PID and the difficulty in obtaining cultures from upper genital tract sites, multidrug regimens have gained acceptance as the current standard treatment for this condition.^1–3,10

At the time the present study was implemented, the Centers for Disease Control and Prevention (CDC) recommended that therapeutic regimens for PID included an agent with broad-spectrum efficacy against N. gonorrhoeae, other aerobes and anaerobes plus an antichlamydial agent.¹¹ However, since then, antimicrobial-resistant strains of N. gonorrhoeae have emerged, leading to changes in national guidelines. In the USA, for example, following the spread of fluoroquinolone-resistant N. gonorrhoeae, fluoroquinolones are recommended only for use in the treatment of PID when parenteral cephalosporin therapy is not feasible and the community prevalence and risk of gonorrhoea is low.¹⁰ European and some local guidelines on PID have also been updated to take into account the increase in fluoroquinolone-resistant N. gonorrhoeae.^1–2 These, too, support the use of fluoroquinolones in patients with PID at low risk of gonococcal infection.

The fluoroquinolone, moxifloxacin, has an extended spectrum of activity against Gram-positive cocci, aerobic and intracellular bacteria, atypical organisms such as Mycoplasma and Chlamydia, and anaerobic bacteria.^12–14 It also has a convenient once-daily dosing regimen. The purpose of this study was to compare the efficacy and safety of once-daily oral moxifloxacin with a combination of doxycycline plus metronidazole plus a single dose of ciprofloxacin, in the treatment of acute, uncomplicated PID.

METHODS

Study design and setting

This prospective, randomized, double-blind multicentre study was designed in accordance with the CONSORT guidelines to illustrate the non-inferiority in terms of clinical efficacy of oral moxifloxacin to doxycycline plus metronidazole plus a single dose of ciprofloxacin, in the treatment of acute, uncomplicated PID. The study protocol was prepared in accordance with the European Guidelines for Good Clinical Practice (1991) and National Rules and Regulations. The study was conducted in accordance with the Declaration of Helsinki.

Treatment and follow-up

Patients enrolled in the study were randomized to receive either oral moxifloxacin (400 mg once daily) for 14 days or comparator treatment (oral doxycycline [100 mg twice daily] plus oral metronidazole [400 mg three times daily] for 14 days, plus one 500-mg oral ciprofloxacin dose).

Patients were asked to return for follow-up evaluations 3–7 days after entry into the study, and then at 2–14 days and 21–35 days post-therapy. At the early follow-up visits, patients were questioned about compliance and side-effects. They underwent clinical examinations during which endocervical, endometrial and laparoscopic samples were collected and the clinical severity score assessed. Biochemical, haematological and microbiological tests were repeated at the 2–14 days and 21–35 days post-therapy visits.

Patients

Women aged at least 18 years and receiving either hospital or outpatient care for uncomplicated acute PID and who were using a reliable form of contraception were enrolled into the study. Women were excluded if they had a positive serological test for syphilis or had evidence of a pelvic abscess on sonographic or laparoscopic examination.

All patients were questioned about the duration of symptoms and past history of PID. Tenderness was scored at abdominal and pelvic examination according to modifications of previously described grading systems for acute salpingitis.¹⁵ Endocervical/endometrial (and/or laparoscopic) specimens were obtained for assays for N. gonorrhoeae and C. trachomatis. Ligase chain reaction (LCR) testing for both organisms was performed centrally (Covance Central Laboratory, Geneva, Switzerland); endocervical cultures and associated bacteriology were performed locally. In the event of discrepancies (e.g. a positive result by LCR but a negative culture), the positive result was used in the analysis.

Efficacy evaluations

Clinical

Treatment responses were classified according to Thomson et al. ¹⁶ Clinical success was defined as cure (severity score reduced by ≥70% plus normal temperature and leukocyte count) or improvement (severity score reduced <70% but >30% plus normal temperature and leukocyte count). Therapy was considered to have failed if symptoms and signs of infection persisted or worsened, as shown by persistent fever, leukocytosis and/or a reduction in severity score of ≤30%. Clinical efficacy was considered ‘unevaluable’ when a patient could not be assessed.

Bacteriological

When organism(s) had been identified from baseline endometrial/laparoscopic samples, the overall bacteriological response at 2–14 days was categorized as ‘eradication’ if the causative organism(s) was absent at the end of therapy and/or if the patient was clinically cured. The response was categorized as ‘persistence’ if the baseline causative organism(s) persisted and/or the patient clinically failed.

Evaluable populations and outcome measures

The intent-to-treat (ITT) population included all randomized patients receiving at least one dose of study drug. The per protocol (PP) population included patients with a confirmed diagnosis of uncomplicated PID, who received no systemic antimicrobial agents other than study drug for at least three days in the case of clinical failure or ≥80% of study medication in case of success, with adequate documentation of compliance and absence of major protocol violations. The microbiologically valid (MBV) population included PP patients with at least one documented pretherapy causative organism and an appropriate post-therapy bacteriological evaluation.

The primary efficacy measure was clinical response at the end of therapy (2–14 days post-treatment), defined as the proportion of PP patients with clinical cure or improvement. Secondary efficacy parameters included clinical cure rate at the end of therapy, clinical response at follow-up (21–35 days post-treatment) and bacteriological response at the end of therapy and at follow-up. Bacteriological response was based on culture and non-culture results of specimens taken before therapy, after therapy and at follow-up in the MBV population.

Statistical analysis

Treatment arm comparability was checked for the ITT and PP populations by using a two-way analysis of variance using cluster of centres and treatment as factors, or by using the Cochran–Mantel–Haenszel test stratified by cluster of centres for categorical variables.

For clinical efficacy analyses of equivalence, a two-sided 95% confidence interval (CI) was calculated using Mantel–Haenszel weighting. If the lower limit of this CI was greater than −10%, moxifloxacin therapy was considered statistically non-inferior to the comparator regimen.

Safety data (including laboratory tests) were analysed using descriptive statistics. Data management was carried out by Parexel (Berlin, Germany).

RESULTS

A total of 686 women were enrolled in 43 centres from 14 countries between March 1997 and June 1998. Baseline characteristics of the ITT and PP populations according to treatment arm are shown in Table 1.

Table 1

Baseline characteristics of the ITT and PP populations by treatment arm

	ITT population		PP population
	Moxifloxacin (n = 343)	Comparator (n = 326)	Moxifloxacin (n = 232)	Comparator (n = 202)
Age (years), mean ± SD	29.0 ± 7.3	28.2 ± 7.2	29.1 ± 7.2	28.5 ± 7.0
Nulliparity*, n (%)	85 (24.8)	84 (25.8)	54 (23.3)	47 (23.3)
≥1 abortion*, n (%)	99 (28.9)	84 (25.8)	73 (31.5)	52 (25.7)
History of previous PID, n (%)	52 (15.2)	63 (19.3)	41 (17.7)	48 (23.8)
History of other sexually transmitted disease, n (%)	12 (3.5)	22 (6.8)	12 (5.2)	22 (10.9)
Protected sex or abstinence, n (%)	172 (50.1)	166 (50.9)	108 (46.6)	103 (51.0)
Hospitalization prior to entry, n (%)	57 (16.6)	46 (14.1)	35 (15.1)	33 (16.3)
Days between onset of abdominal/pelvic pain and randomization, n (%)
<4	136 (39.7)	141 (43.3)	97 (41.8)	90 (44.6)
4–7	101 (29.4)	74 (22.7)	68 (29.3)	42 (20.8)
>7	106 (30.9)	111 (34.0)	67 (28.9)	70 (34.7)
Abdominal/pelvic score, mean ± SD	14.5 ± 6.0	14.5 ± 5.8	14.1 ± 5.8	14.4 ± 5.8
Abnormal laparoscopic findings, n (%)	64 (18.7)	64 (19.6)	50 (21.6)	52 (25.7)
Body temperature^† (°C), mean ± SD	37.3 ± 0.7	37.2 ± 0.7	37.3 ± 0.7	37.2 ± 0.7
White blood count^‡ (Giga/L), mean ± SD	7.8 ± 3.4	7.8 ± 3.4	7.8 ± 3.1	8.0 ± 3.4
Erythrocyte sedimentation rate^§ (mm/hour), mean ± SD	22.6 ± 16.3	20.2 ± 13.3	22.1 ± 14.9	20.2 ± 14.0
C-reactive protein** (mg/dL), mean ± SD	2.5 ± 5.7	2.0 ± 4.5	2.4 ± 5.5	2.0 ± 4.3

*Information missing in two ITT patients of the comparator group

^†Documented in 341 and 325 patients of moxifloxacin and comparator groups, respectively, in the ITT population, and in 230 and 201, respectively, in the PP population

^‡Documented in 332 and 320 patients of moxifloxacin and comparator groups, respectively, in the ITT population, and in 229 and 199, respectively, in the PP population

^§Documented in 75 and 77 patients of moxifloxacin and comparator groups, respectively, in the ITT population, and in 57 and 60, respectively, in the PP population

**Documented in 306 and 300 patients of moxifloxacin and comparator groups, respectively, in the ITT population, and in 215 and 192, respectively, in the PP population

ITT = intent-to-treat; PP = per protocol; SD = standard deviation

The majority (96.8%) of patients in the PP population were sexually active. A minority of patients in each treatment group (PP population) were 40 years of age or older (n = 43 [9.9%]). A comparison of the two study groups revealed no significant differences in age, parity or prior history of PID or other sexually transmitted diseases. Treatment arms were also comparable for clinical and laboratory variables at the time of enrolment in both the PP and the ITT populations (Table 1). Laparoscopy was performed in 102 patients (23.5%) in the PP population, showing abnormal findings in all cases, the most common being hyperaemia (86.4%) or oedema (60.2%) of the tube. Ultrasonography was performed in all PP patients and showed abnormalities in 99 (22.8%) of them, mainly thickening of the tubal wall.

Pathogenic organisms were detected in 106/669 (15.8%) of ITT patients and in 74/434 (17.1%) of PP patients. The incidence of mono- and polymicrobial infections is shown in Table 2. The majority of organisms were C. trachomatis and N. gonorrhoeae (all other organisms cultured were not considered pathogenic if not isolated from endometrial/laparoscopic material). These two species were detected, either alone or in combination, in 84 and 54 patients of the ITT and PP groups, respectively, with no significant difference between the treatment groups (Table 2). None of the N. gonorrhoeae isolates were resistant to fluoroquinolones in vitro.

Table 2

Incidence of isolation of Chlamydia trachomatis, Neisseria gonorrhoeae and other causative organisms at study enrolment

	ITT population		PP population
	Moxifloxacin	Comparator	Moxifloxacin	Comparator
Organisms*	(n = 343) No. (%)	(n = 326) No. (%)	(n = 232) No. (%)	(n = 202) No. (%)
Total number of patients identified with causative organisms	56 (16.3)	50 (15.3)	40 (17.2)	34 (16.8)
Monomicrobial infection	26 (7.6)	19 (5.8)	21 (9.1)	16 (7.9)
Polymicrobial infection	30 (8.7)	31 (9.5)	20 (8.6)	18 (8.9)
Chlamydia trachomatis alone	7 (2.0)	8 (2.5)	5 (2.2)	5 (2.5)
Neisseria gonorrhoeae alone	9 (2.6)	5 (1.5)	7 (3.0)	5 (2.5)
Both organisms present	28 (8.2)	27 (8.3)	17 (7.3)	15 (7.4)
Gram-positive aerobic organisms	4 (1.2)	6 (1.8)	4 (1.7)	5 (2.5)
Other Gram-negative aerobic organisms	7 (2.0)	5 (1.5)	6 (2.6)	5 (2.5)
Anaerobic organisms	2 (0.6)	2 (0.6)	2 (0.9)	1 (0.5)

*When not specified, multiple organisms may be present in the same patient

ITT = intent-to-treat; PP = per protocol

Clinical efficacy

Based on the clinical success criterion at 2–14 days post-therapy, moxifloxacin was non-inferior to the comparator regimen in both the PP (95% CI −4.5, 1.6) and ITT (95% CI −5.8, 6.9) populations (Table 3). At 21–35 days post-therapy, when clinical failures at 2–14 days post-therapy examination were carried forward, clinical success rates were also similar in the two treatment groups (95% CI −3.8, 7.4 and −5.8, 9.1 in the PP and ITT analyses, respectively; Table 3). The majority of patients assessed as clinical success at 2–14 days post-therapy were also clinically cured in each treatment group and study population. The moxifloxacin and comparator regimens resulted in similar clinical cure rates (95% CI −9.2, 5.1 and −7.5, 7.0 in the PP and ITT analyses, respectively; Table 3). This was confirmed by calculation of the abdominal/pelvic severity score at 2–14 days post-therapy: mean (SD) values were 1.8 (2.9) and 1.2 (2.4) in both treatment groups for PP and ITT populations, respectively. Similar severity score values were observed at 21–35 days post-therapy (data not shown).

Table 3

Summary of clinical efficacy results

	ITT population*			PP population
	Moxifloxacin n/No. (%)	Comparator n/No. (%)	95% CI	Moxifloxacin n/No. (%)	Comparator n/No. (%)	95% CI
Day 2–14 post-therapy
Clinical success^†	264/343 (77.0)	250/326 (76.7)	−5.8, 6.9	224/232 (96.6)	198/202 (98.0)	−4.5, 1.6
Clinical cure	222/343 (64.7)	212/326 (65.0)	−7.5, 7.0	189/232 (81.5)	168/202 (83.2)	−9.2, 5.1
Day 21–35 post-therapy
Clinical success^‡	206/343 (60.1)	191/326 (58.6)	−5.8, 9.1	166/177^§ (93.8)	147/161^§ (91.3)	−3.8, 7.4

*Indeterminate and missing cases counted as non-successes

^†Clinical cure and improvement combined

^‡Clinical failures at day 2–14 post-therapy carried forward for follow-up

^§Forty-eight and 37 missing cases in the moxifloxacin and comparator groups, respectively. Missing data are excluded for calculation of the 95% CI

ITT = intent-to-treat; PP = per protocol; CI = confidence interval

Clinical success rates were similar in patients with either mono- or polymicrobial infections. In the PP population, all patients (100%) in both treatment arms with either monomicrobial or polymicrobial infections achieved clinical success. In the ITT population, clinical success rates in patients with monomicrobial infections were 84.6% (22/26) for moxifloxacin and 94.7% (18/19) for the comparator. Clinical success rates in patients with polymicrobial infections were 80.0% (24/30) for moxifloxacin and 77.4% (24/31) for comparator.

In the subgroup of patients with abnormal laparoscopic findings at enrolment, a descriptive analysis of the PP population showed that clinical success occurred in 98.0% (49/50) of moxifloxacin-treated patients and 100% (52/52) of comparator-treated patients; similar figures were observed in the ITT population.

Bacteriological response

In the MBV population, overall bacteriological success rates at 2–14 days post-therapy were similar in the two treatment groups (moxyfloxacin: 92.5%, comparator 88.2%; P = 0.52). Chlamydial eradication rates were 95.5% (21/22) in the moxifloxacin-treated group and 17/19 (89.5%) in the comparator group. Gonococcal eradication rates were 91.7% (22/24), in the moxifloxacin-treated group and 90.0% (18/20) in the comparator group. In the moxifloxacin group (n = 40), there was persistence of N. gonorrhoeae (n = 2) and C. trachomatis (n = 1). In the comparator group (n = 34), there was persistence of N. gonorrhoeae (n = 2), C. trachomatis (n = 2), Escherichia coli (n = 2), Streptococcus agalactiae (n = 1) and Enterococcus faecalis (n = 1).

Safety analysis

Adverse events considered by the investigator as remotely, possibly or probably related to the study drug were reported in a similar number of patients in the two groups (P = 0.14 for any adverse event) (Table 4). No treatment-related differences were detected in the analysis of vital signs, and no major differences were seen in the analyses of laboratory parameters between the treatment groups.

Table 4

Incidence of drug-related adverse events occurring in ≥2% of patients in either treatment group

	Moxifloxacin (n = 343)	Comparator (n = 326)
	No. (%)	No. (%)
Any adverse event	151 (44.0)	162 (49.7)
Any gastrointestinal event*	100 (29.2)	149 (45.7)
Diarrhoea	26 (7.6)	24 (7.4)
Nausea	57 (16.6)	79 (24.2)
Nausea and vomiting	4 (1.2)	10 (3.1)
Vomiting	13 (3.8)	36 (11.0)
Other adverse events
Abdominal pain	8 (2.3)	18 (5.5)
Asthenia	17 (5.0)	11 (3.4)
Headache	16 (4.7)	20 (6.1)
Leukopaenia	11 (3.2)	11 (3.4)
Dizziness	18 (5.2)	10 (3.1)
Rash	8 (2.3)	10 (3.1)
Pruritis	4 (1.2)	10 (3.1)
Vaginal moniliasis	10 (2.9)	11 (3.4)

*P = 0.001

DISCUSSION

PID is a condition which, if not treated promptly and appropriately, can have serious consequences. Many patients are treated as outpatients and most are treated empirically to overcome the difficulty in confirming the diagnosis without surgical intervention. A high leukocyte count, elevated (>38°C) body temperature and lower abdominal pain or tenderness elicited on pelvic examination are highly suggestive of the correct initial diagnosis of PID. These symptoms are acknowledged as indirect assessments of response to acute infection, as laparoscopy may be inappropriate in women with mild disease. While the use of clinical criteria to diagnose PID results in marked over-treatment, it is accepted as standard because it reduces the risk of long-term sequelae.^1–3,10,17

Since this study was initiated, treatment guidelines for PID have been amended in many countries. Based on the emergence of quinolone-resistant N. gonorrhoeae, the CDC recommends the use of quinolones in the management of PID only when parenteral cephalosporin therapy is not feasible and the community prevalence and risk of gonorrhoea is low.¹⁰ European guidelines have also been amended. However, these recognize that quinolone therapy is an effective empirical treatment and quinolones are still recommended in PID except where gonococcal PID is suspected. Such cases might include those where the male partner is known to be infected with gonorrhoea, clinically severe PID or where Gram-negative diplococci are identified on a Gram-stained cervical smear.¹ Thus, despite changes in guidelines, the outcomes from this study remain pertinent today.

At the time of study initiation, monotherapy with the fluoroquinolone, ofloxacin, was reported to be as effective as cefoxitin and doxycyline for the treatment of PID.^18–20 Since then, once-daily moxifloxacin has been shown to be as effective as ofloxacin twice daily plus metronidazole.²¹ Moxifloxacin has a spectrum of activity that includes all the important aetiological agents of PID, provides better activity against C. trachomatis than ciprofloxacin and better cover against anaerobes than ofloxacin.^22,23 Here, moxifloxacin was used as monotherapy in comparison with a combination of doxycycline, metronidazole and ciprofloxacin (single dose) in the treatment of acute PID.

The antimicrobial regimens compared were equally effective, with clinical success rates of 96.6% and 98.0% for moxifloxacin and comparator therapy, respectively, in the PP population. The recruitment and retention of sufficient women (i.e. more than 200 patients in each group of the PP population) allowed a 90% power to detect equivalence of the two regimens and a 95% probability of correctly assessing equivalence.

The use of an established system for scoring symptom severity permitted an objective and homogeneous assessment before treatment and the response to therapy at its completion, and at 21–35 days follow-up.^18–20 All the women who were judged to be clinical successes had normal symptom severity scores (value 0, 1 or 2) at their second and third follow-up visits. Furthermore, the follow-up examination (21–35 days post-therapy), for patients with positive chlamydial cultures at baseline, was included to ensure eradication of those organisms.

Indeed, high bacteriological efficacy was noted with both regimens. At 2–14 days post-therapy, chlamydial and gonococcal eradication rates were both over 90% for each treatment. The number of patients in the MBV population is, however, too small to draw definitive conclusions. The overall percentage of patients (17.1% of the PP population) with microbiological documentation was lower than in previous trials,^19,20,24 possibly because only definitely pathogenic bacteria were included in the bacteriological assessment of PID. As a consequence, other microorganisms present in the vagina or cervix that may have been causal, e.g. Enterobacteriaceae spp. or streptococci were excluded. Alternatively, there could have been reproducibility issues with either the assay used to detect C. trachomatis and N. gonorrhoeae ²⁵ or because studies reporting higher rates of isolation of C. trachomatis and N. gonorrhoeae might have been undertaken in populations with a greater proportion of patients at risk of sexually transmitted infections.²⁴

When conducting this study it was hoped that its findings would translate directly into clinical practice. The recruitment strategy was used in the knowledge that not all women would have microbiological evidence of PID, hence the choice of an antibiotic with broad cover and good efficacy against C. trachomatis and N. gonorrhoeae. Also, the multicentre, multinational design of the study provided a ‘real life’ geographically heterogeneous population with varying access to health care. Study subjects were women who met generally accepted clinical criteria for non-complicated PID and represent the majority of women presenting with PID.¹⁸ Severely ill patients with pelvic abscesses or diffuse peritonitis were excluded and of the total study population, 15% were inpatients. In addition, the baseline mean severity score was 40% of the maximum possible score, and overall low erythrocyte sedimentation rate values were noted, confirming that these were patients with mild-to-moderate PID. As such, these patients were considered suitable candidates for ambulatory therapy and for whom the development of a simple, effective drug regimen for use in an outpatient setting would be of prime importance. This stimulates the question, that with the emergence of quinolone-resistant N. gonorrhoeae, can these findings still translate into clinical practice?

A review of recent literature has revealed that, where reported, the prevalence of N. gonorrhoeae as the causal agent of PID in Europe is low. For example, Bevan et al., reported in 2003 that between 5% and 6% of cases of PID in an English study were due to N. gonorrhoeae and in 2006, Ross et al. reported that 5.1–7.6% of patients recruited to a multinational, multicentre study had N. gonorrhoeae identified as the causal organism for PID.^5,21 In the UK, where the incidence of fluoroquinolone-resistant N. gonorrhoeae in women is 8.7%, those with mild-to-moderate PID at low risk of PID due to N. gonorrhoeae could benefit from fast, effective empiric oral treatment with fluoroquinolones.^5,26 Reassessment of patients within 72 hours of an initial visit, as recommended in national guidelines, would identify non-responders. Therefore, use of an oral therapy such as a fluoroquinolone in women with mild-to-moderate PID in whom infection with fluoroquinolone-resistant N. gonorrhoeae can be excluded is appropriate in an outpatient setting. However, if resistant N. gonorrhoeae is either suspected or proven, then treatment with a fluoroquinolone combined with an appropriate anti-gonococcal antibacterial agent (e.g. a cephalosporin) should be considered. Moxifloxacin has recently been approved in Europe for use in mild-to-moderate PID under these circumstances.²⁷

Adverse events were mild or moderate in intensity and reported at comparable rates in both treatment arms. However, a significantly (P = 0.001) lower proportion of patients taking moxifloxacin reported gastrointestinal events and the overall type and incidence of adverse events noted did not differ from those previously associated with moxifloxacin treatment. A recent recommendation for the restricted use of moxifloxacin tablets in respiratory tract infections due to concerns over aspects of its safety profile (especially hepatotoxicity) has not affected regulator's advice for its use in PID. Indeed, the positive benefit/risk balance of moxifloxacin in PID was noted by the European Medicines Agency in its recent update to the moxifloxacin label.²⁷

CONCLUSION

Moxifloxacin monotherapy given as a 400 mg once-daily oral dose for 14 days was therapeutically equivalent to a combination of doxycycline (100 mg twice daily) plus metronidazole (400 mg three times daily) plus a single dose of ciprofloxacin (500 mg) in the treatment of acute, uncomplicated PID. Moxifloxacin monotherapy was associated with fewer gastrointestinal adverse events than the comparator. The once-daily dosing regimen, which may enhance patient compliance, also supports the use of moxifloxacin as outpatient therapy for patients with PID.

Footnotes

ACKNOWLEDGEMENTS

The authors thank Margherita Tellarini (formerly of Bayer, Italy) for her contribution to this work, Heinz Schmitz (formerly of Bayer, Germany), Peter Reimnitz (Bayer Schering Pharma, Germany) and Sabine Gerstmayr (Parexel, Berlin) for their help with statistical data and Christina Krasemann (formerly of Bayer Pharma, Germany) for bacteriology. They also thank Hans-D Heillmann (formerly of Bayer Pharma, Germany) and Pierre Arvis (Bayer Schering Pharma, France) for their support and critical review of the manuscript.

Sponsorship: Bayer Schering Pharma, Germany, provided financial and logistical support for this trial.

APPENDIX

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