REVIEW ARTICLE

Newest Approaches to Treatment of Pelvic

Inflammatory Disease: A Review of Recent
Randomized Clinical Trials
Catherine L. Haggerty and Roberta B. Ness
University of Pittsburgh, Pittsburgh, Pennsylvania

(See the editorial commentary by Eschenbach on pages 9613)

Pelvic inflammatory disease (PID), the infection and

inflammation of a womans upper genital tract, is a
frequent cause of infertility, ectopic pregnancy, and
chronic pelvic pain among women of childbearing age
[1]. Surveillance data are sparse but suggest that PID
is diagnosed in general practice in 1.7% of women aged
1646 years in the United Kingdom annually and in
8% of US women and 15% of Swedish women in
their lifetime, with 11 million US women treated annually [26]. PID is thought to occur when microorganisms, frequently Chlamydia trachomatis or Neisseria
gonorrhoeae, ascend from the lower genital tract and
infect the uterus, fallopian tubes, and ovaries [7]. How-

Received 30 June 2006; accepted 6 November 2006; electronically published

15 February 2007.
Reprints or correspondence: Dr. Catherine L. Haggerty, Dept. of Reproductive
Epidemiology, 130 DeSoto St., 516B Parran Hall, University of Pittsburgh, Pittsburgh,
PA 15261 (haggerty@pitt.edu).
Clinical Infectious Diseases 2007; 44:95360
 2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4407-0011$15.00
DOI: 10.1086/512191

ever, PID has a multimicrobial etiology, and up to 70%

of cases are nongonococcal and nonchlamydial. Anaerobic gram-negative rods, Mycoplasma genitalium,
and bacterial vaginosis are also associated with PID
[812].
Because of its polymicrobial nature, PID is treated
with antibiotics covering a broad spectrum of pathogens. Guidelines of the Centers for Disease Control and
Prevention recommend outpatient treatment of PID
with ofloxacin, levofloxacin, ceftriaxone plus doxycycline, or cefoxitin and probenecid plus doxycycline, all
with optional metronidazole for full coverage against
anaerobes and bacterial vaginosis (table 1) [13]. In a
meta-analysis of 34 treatment trials published primarily
between 1985 and 1992, 4 inpatient regimens and 1
outpatient regimen were found to have pooled clinical
cure rates ranging from 92% to 95% and microbiological cure rates ranging from 91% to 100% [14].
These inpatient regimens included the following drugs:
clindamycin and aminoglycoside (clinical cure rate,
92%; microbiological cure rate, 97%); cefoxitin and
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Treatment of pelvic inflammatory disease (PID) should provide high rates of clinical and microbiological cure
for a range of pathogens and should ultimately prevent reproductive morbidity. Between 1992 and 2006, 5
randomized clinical trials of moxifloxacin (1 trial), ofloxacin (1 trial), clindamycin-ciprofloxacin (1 trial), and
azithromycin (2 trials) treatment among women with mild to moderate PID were found to have clinical cure
rates of 90%97%. Trials of ofloxacin and clindamycin-ciprofloxacin reported rates of cure of Neisseria gonorrhoeae and Chlamydia trachomatis infection of 100%, although microbiological cure data for other pathogens
were not presented. One azithromycin trial reported a 98% eradication of C. trachomatis, N. gonorrhoeae,
Mycoplasma hominis, and anaerobes. Moxifloxacin exhibited high eradication rates for N. gonorrhoeae, C.
trachomatis, M. hominis, Mycobacterium genitalium, and gram-negative anaerobes. Clinical cure rates from 2
doxycycline-metronidazole trials were low (35% and 55%). Although a handful of studies have shown that
monotherapies for PID achieve high rates of clinical cure, the efficacy of these regimens in treating anaerobic
PID and in preventing adverse reproductive sequelae is not fully elucidated.

Table 1. 2006 US Centers for Disease Control and Preventionrecommended outpatient regimens for the treatment
of pelvic inflammatory disease.
Drug

Dosage

Ofloxacin
Levofloxacin

400 mg po twice per day for 14 days

500 mg po once daily for 14 days

Ceftriaxone plus doxycycline

250 mg im in a single dose and 100 mg po twice

per day for 14 days

Cefoxitin plus probenecid plus doxycycline

2 g im in a single dose, 1 g po administered concurrently in a single dose, and 100 mg po

twice per day for 14 days

Other parenteral third-generation cephalosporin (e.g., ceftizoxime

or cefotaxime) plus doxycycline

100 mg po twice per day for 14 days

Metronidazole

Added to any of the above regimens; 500 mg po

twice per day for 14 days

NOTE. Adapted from [13].

FLUOROQUINOLONE TRIALS
Table 2 provides a summary of the randomized clinical trials
of treatment for PID published between 1992 and 2006. In
general, these recent treatment trials have focused on monotherapies, which are believed to increase compliance. One randomized trial comparing ofloxacin with cefoxitin plus doxycycline among 249 women with clinically suspected PID
reported high rates of clinical cure or improvement (95% vs.
93%) and eradication of N. gonorrhoeae (100% in both groups)
[16]. Ofloxacin was associated with greater eradication of C.
trachomatis (100% vs. 88%) and a lower prevalence of adverse
effects (7% vs. 15%) [16]. Although anaerobes, aerobes, and
mycoplasmal species were obtained from culture for some
women, data about eradication of pathogens were not presented
[16]. Thus, it is impossible to determine from this study the
microbiological efficacy of ofloxacin in treating PID due to
anaerobic species.
Two nonrandomized studies of laparoscopically confirmed
954 CID 2007:44 (1 April) Haggerty and Ness

salpingitis similarly support the efficacy of ofloxacin for the

treatment of gonococcal and chlamydial PID by demonstrating
that ofloxacin, administered every 12 h intravenously followed
by a 10- to 14-day oral regimen, was associated with a gonococcal cure rate of 100% [23, 24], a chlamydial cure rate of
almost 100% [23, 24], and a clinical cure rate of 98% [24].
However, although all patients with anaerobic bacteria cultured
at study admission were considered to be clinically cured at
follow-up in one of these studies [24], follow-up anaerobic
cultures were not reported, and therefore, microbiological cure
of anaerobes cannot be determined.
Because the lack of anaerobic coverage with ofloxacin is a
concern, emphasized by the high rate of treatment failure
among patients with nongonococcal, nonchlamydial PID [16],
the Centers for Disease Control and Prevention suggests the
optional addition of metronidazole [13]. Alternatively, a randomized clinical trial of 131 women with laparoscopically confirmed PID investigated the regimen of another fluoroquinolone, ciprofloxacin, plus clindamycin [17]. In this study,
clindamycin-ciprofloxacin was found to be as effective as ceftriaxone plus doxycycline for the clinical cure of PID (97% vs.
95%) and C. trachomatis eradication (100% in both groups)
[17]. N. gonorrhoeae was less prevalent; it was found in only 2
women who were treated with clindamycin plus ciprofloxacin,
and 1 of these women achieved microbiological cure (a cure
rate of 50%). Although aerobic and anaerobic isolates were
frequently identified before treatment, no comparisons of microbiological cure for these pathogens were presented.
In the most recent fluoroquinolone randomized clinical trial
by Ross et al. [18], moxifloxacin was found to have high rates
of clinical resolution (90%) and microbiological cure. The microbiological cure rate was 100% for N. gonorrhoeae, Mycoplasma hominis, M. genitalium, Escherichia coli, and other gramnegative anaerobes. Although the eradication rate of C.
trachomatis was lower (89%), it was slightly higher than that

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doxycycline (clinical cure rate, 93%; microbiological cure rate,

98%); cefotetan and doxycycline (clinical cure rate, 94%; microbiological cure rate, 100%); and ciprofloxacin (clinical cure
rate, 94%; microbiological cure rate, 96%) [15]. A fifth inpatient regimen, which included metronidazole and doxycycline,
was found to have much lower rates of clinical and microbiological cure (75% and 71%, respectively) [14]. These low efficacy rates are likely attributable to the poor coverage of this
latter combination against N. gonorrhoeae [15]. One outpatient
regimen (cefoxitin, probenecid, and doxycycline) was included
in this meta-analysis and was found to have a pooled clinical
cure rate of 95% and a microbiological cure rate of 91% [14].
Since the publication of this meta-analysis, additional studies
of PID treatment have been conducted, including several new
monotherapies. Here, we summarize and evaluate these recent
randomized clinical trials.

of the comparator regimen (86%) [18]. Further, the eradication

rate for N. gonorrhoeae was much higher (100%, compared
with 82%) and the rate of drug-related adverse events was lower
(23%, compared with 31%) among women treated with
moxifloxacin.
AZITHROMYCIN TRIALS

DOXYCYCLINE AND METRONIDAZOLE TRIALS

A few studies have further examined the outpatient combination regimen of doxycycline and metronidazole. In a randomized clinical trial of 40 patients with laparoscopically
confirmed salpingitis, combined doxycycline-metronidazole
treatment exhibited a low clinical cure rate of 35%, with a 50%
clinical improvement rate [21]. The low efficacy of this regimen

INPATIENT MEROPENEM TRIAL

Most randomized clinical trials of monotherapy for PID have
been conducted among women with mild to moderate PID
who were treated as outpatients. In a study of 84 women hospitalized because of PID, meropenem, which has demonstrated
in vitro activity against a broad spectrum of gram-negative and
gram-positive aerobic and anaerobic bacteria, was found to be
associated with high rates of clinical response and microbiological cure that were relatively similar to those found with
treatment with clindamycin plus gentamicin (clinical response
rate, 88% vs. 90%; microbiological cure rate, 88% vs. 86%)
[22]. However, only 37% of patients had cultures performed
after treatment and were included in comparisons of microbiological cure. Further studies are needed to confirm the use
of this well-tolerated [22] broad-spectrum inpatient monotherapy regimen for the treatment of PID.
DISCUSSION
Among the recent trials of treatment for PID, regimens including ofloxacin, moxifloxacin, azithromycin, and clindamycin-ciprofloxacin all yielded high rates of clinical cure and
eradication of N. gonorrhoeae and C. trachomatis, although microbiological cure data among women with PID due to anaerobes are limited. This is attributable, in part, to the complexity of studying PID due to anaerobes, because the organisms
may be present as commensal bacteria in the lower genital tract,
and transcervical sampling of the endometrium may result in
contamination of endometrial biopsy specimens by vaginal or
cervical microorganisms. However, we have previously demonstrated that contamination likely does not account for the
relationships between bacterial vaginosisassociated microorganisms and acute endometritis. In the PID Evaluation and
Clinical Health (PEACH) study, we have shown that anaerobic
gram-negative bacteria are associated with acute endometritis
independent of bacterial vaginosis [9]. Furthermore, anaerobic
gram-negative rods and anaerobic gram-positive coccibut
not other organisms frequent among women with bacterial
vaginosis (e.g., Gardnerella vaginalis and M. hominis)are associated with acute endometritis [9]. Another barrier to the
study of microbiological cure of PID is the lack of 100% corTreatment of Pelvic Inflammatory Disease CID 2007:44 (1 April) 955

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Also of interest because of its association with enhanced compliance, single-dose or short-duration azithromycin in the
treatment of PID has been examined in a handful of studies.
Not surprisingly, compliance with single-dose azithromycin
therapy has been reported to be 100% [25]. In a randomized
clinical trial from India of 165 women with clinically suspected
PID, a kit containing 1 tablet of fluconazole (150 mg), 1 tablet
of azithromycin (1 g), and 2 tablets of secnidazole (2 g) was
associated with a PID clinical cure rate of 93%, which is similar
to that found among a group treated with ciprofloxacin plus
tinidazole for 7 days (clinical cure rate, 96%) and better than
that found among women treated with doxycycline plus metronidazole for 1 week (clinical cure rate, 91%) [19]. However,
although this trial showed high rates of clinical cure, data on
microbiological cure were not presented. In a randomized clinical trial in the United Kingdom that compared azithromycin
monotherapy, azithromycin plus metronidazole, and standard
21-day regimens of metronidazole-doxycycline-cefoxitin-probenecid or doxycycline-amoxicillin-clavulanate among 300 patients with PID, azithromycin was found to have a high rate
of clinical success, similar to that of other regimens (97% for
azithromycin monotherapy, compared with 96% for azithromycin-metronidazole and 95% for a comparator regimen) [20].
Moreover, azithromycin provided excellent rates of eradication
of C. trachomatis, N. gonorrhoeae, M. hominis, and anaerobes
[20]. Complicating the interpretation of this study, however,
was the combining of 2 different trials in the analyses. In 1
trial, 500 mg of azithromycin was administered intravenously
on day 1, followed by 250 mg of oral azithromycin for 6 days.
In the other trial, the intravenous protocol was conducted for
2 days, followed by oral azithromycin therapy for 5 days. The
comparator regimens in each trial differed as well. Therefore,
the optimal azithromycin regimen cannot be determined. Furthermore, the dropout rate at the final follow-up visit was
extremely high (78%), and this reduces the validity and generalizability of the microbiological cure evaluation.

was replicated in an observational study in the United Kingdom

involving 135 women with PID, in which only 55% experienced
a clinical cure 2 or 4 weeks after treatment [26]. The addition
of ceftriaxone to this regimen resulted in a higher but still
suboptimal cure rate of 72% [26]. Because combined doxycycline-metronidazole provides poor coverage against N. gonorrhoeae and was also associated with the lowest pooled clinical
and microbiological cure rates in the meta-analysis conducted
by Walker et al. [14], this is not considered to be an optimal
regimen for treatment of PID.

Regimen

Cefoxitin (2 g im) followed by Dox (100 mg twice daily po for 10

days)

1993 Ofloxacin (400 mg twice daily po for 10 days)

Year

Ross et al. [18]

Moxifloxacin

Comparator: ofloxacin (400 mg twice daily) plus Mtz (500 mg twice

daily)

2006 Moxifloxacin (400 mg once daily for 14 days)

Comparator: ceftriaxone (250 mg im, single dose) and Dox (100 mg,
1 capsule twice daily) and placebo (2 capsules 3 times daily for
equivalent diseases of Clin) for 14 days

Arredondo et al. [17] 1996 Clin (300 mg, 2 capsules 3 times daily) and Cpfx (250 mg, 1 tablet
twice daily) for 14 days

Clin and Cpfx

Martens et al. [16]

Ofloxacin

Drug, study

1 patient withdrew because of AEs

1 patient withdrew because of AEs

100% C. trachomatis eradication; 2 women

with results positive for N. gonorrhoeae, 1
of whom was microbiologically cured; of
women with both C. trachomatis and N.
gonorrhoeae infection, all had negative results after treatment
100% C. trachomatis and N. gonorrhoeae
eradication

262/289 (91) 82% overall bacteriological success rate;

82% eradication of N. gonorrhoeae, 86%
eradication of C. trachomatis, and 100%
eradication of M. hominis, M. genitalium,
E. coli, and other gram-positive anaerobes;
50% eradication of other gram-negative
anaerobes

AEs led to discontinuation in 20% of patients

248/275 (90) 88% overall bacteriological success rate;

AEs led to discontinuation in 14% of patients
100% eradication of N. gonorrhoeae, 89%
eradication of C. trachomatis, and
75%100% eradication of Mycobacterium
hominis, Mycobacterium genitalium, Escherichia coli, Streptococcus, and other gramnegative anaerobes; 0% eradication of
other gram-positive anaerobes

61/64 (95)

65/67 (97)

15% rate of AEs; overall, 12 patients did not

comply with study drug regimen; no difference in compliance between treatment
regimens

112/121 (93) 100% N. gonorrhoeae and 88% C. trachomatis eradication

AEs and compliance

7% rate of AEs

Microbiological cure rate(s)

122/128 (95) 100% Neisseria gonorrhoeae and Chlamydia

trachomatis eradication

Clinical cure,
proportion of
patients (%)

Table 2. Randomized clinical trials since 1992 for the treatment of pelvic inflammatory disease.

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25% rate of AEs causing 2 discontinuations

Eradication rate at end of treatment was 24/

24 (100%) for C. trachomatis, 6/6 (100%)
for N. gonorrhoeae, 10/12 (83%) for M.
hominis, and 9/9 (100%) for anaerobes

16% rate of AEs

AEs in 1 patient, without discontinuation

AEs resulted in discontinuation in 2 patients

Comparator: Clin (900 mg iv) plus gentamicin (1.5 mg/kg, following a 166/184 (90) 86% eradication of N. gonorrhoeae, anaerloading dose of 2.0 mg/kg, iv every 8 h for 210 days)
obes, and aerobes

Not reported

Not reported

37% rate of AEs causing 6 discontinuations

13% rate of AEs

9/20 (45)

7/20 (35)

Eradication rate at end of treatment was 30/

30 (100%) for C. trachomatis, 5/5 (100%)
for N. gonorrhoeae, 9/11 (82%) for M.
hominis, and 7/7 (100%) for anaerobes

185/211 (88) 88% eradication of N. gonorrhoeae, anaerobes, and aerobes

1997 Meropenem (500 mg iv every 8 h for 210 days)

Pefloxacin (800 mg daily) plus Mtz (500 mg every 8 h) for 1014

days

1993 Dox (200 mg first day followed by 100 mg daily) and Mtz (500 mg
every 8 h) for 1014 days

Minor AEs noted in 30% of patients; compliance rate, 87%

Minor AEs noted in 19% of patients; compliance rate, 94%

Minor AEs noted in 13% of patients; compliance rate, 92%

Not reported

Not reported

Not reported

101/105 (96) Eradication rate at end of treatment was 24/ 30% rate of AEs causing 4 discontinuations
25 (96%) for C. trachomatis, 5/5 (100%) for
N. gonorrhoeae, 15/18 (83%) for M. hominis, and 11/11 (100%) for anaerobes

Comparators: Mtz (500 mg iv 3 times daily for 1 day) plus Dox (100 88/93 (95)
mg po twice daily for 14 days) plus cefoxitin (2 g im 4 times daily)
plus probenecid (1 g po single dose) or Dox (100 mg po twice
daily for 21 days) plus amoxicillin-clavulanate (1 g iv 3 times daily
for 5 days) plus amoxicillin-clavulanate (500 mg po 3 times daily)

Azithromycin (500 mg iv for 12 days followed by 250 mg po for

56 days) plus Mtz (500 mg iv 3 times daily for 12 days, plus
400500 mg po 3 times daily for 1011 days)

99/102 (97)

42/46 (91)

Comparator: Dox (100 mg) twice daily and Mtz (200 mg) 3 times
daily for 7 days

2003 Azithromycin (500 mg iv for 12 days followed by 250 mg po for

56 days)

47/49 (96)

Comparator: Cpfx (500 mg) and tinidazole (600 mg) twice daily for 7
days

2003 Kit containing 1 tablet of fluconazole (150 mg), 1 tablet of azithromy- 43/46 (93)
cin (1 g), and 2 tablets of secnidazole (2 g)

NOTE. AE, adverse event; Clin, clindamycin; Cpfx, ciprofloxacin; Dox, doxycycline; Mtz, metronidazole.

Hemsell et al. [22]

Meropenem

Witte et al. [21]

Dox-Mtz

Bevan et al. [20]

Malhotra et al. [19]

Azithromycin

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958 CID 2007:44 (1 April) Haggerty and Ness

clinically suspected mild to moderate PID treated with the standard antibiotic regimen of doxycycline and cefoxitin, endometritis and upper genital tract gonococcal and chlamydial infection were not associated with reproductive morbidity [37].
One interpretation is that these antibiotics that are used to treat
modern-day mild to moderate chlamydial and gonococcal PID
limited to the uterus are so effective that reproductive morbidity
is not elevated among women with treated endometritis. However, despite the high rates of clinical cure and eradication of
N. gonorrhoeae and C. trachomatis observed in the PEACH
study at 30 days after treatment [38], rates of infertility (17%)
[38], recurrent PID (14%) [38], and chronic pelvic pain (37%)
[39] were distressingly elevated over the course of follow-up.
This suggests a need to discover and provide coverage against
all possible damaging PID pathogens and also to focus on longterm morbidity in treatment efficacy evaluations.
It is possible that women with nongonococcal PID may be
more likely to experience adverse sequelae. In the PEACH study,
we reported that women with nongonococcal bacteria identified
in the endometrium were generally more likely to experience
reproductive morbidity than were women with gonococcal infection. Infertility rates were 13% for women with N. gonorrhoeae identified, 19% for women with C. trachomatis identified, 22% for women with anaerobic bacteria identified, 27%
for women with U. urealyticum identified, and 17% for women
with M. hominis identified; chronic pelvic pain rates were 27%
for women with N. gonorrhoeae identified, 21% for women
with C. trachomatis identified, 33% for women with anaerobic
bacteria identified, 41% for women with U. urealyticum identified, and 54% for women with M. hominis identified. Similarly, in a study by Brunham et al. [40] of 50 women with
laparoscopically confirmed salpingitis, 54% of women with
nongonococcal infections had future adverse reproductive outcomes, compared with none of the women with gonococcal
infections. Collectively, the PEACH study [37] and the study
by Brunham et al. [40] suggest that, although these regimens
may have high short-term clinical and microbiological cure
rates, the standard antibiotic regimens of doxycycline-cefoxitin
[37], doxycycline-clindamycin [40], and doxycycline-metronidazole [40] may not be optimal for the prevention of adverse
sequelae among women with nongonococcal PID.
Animal models may provide insight into better regimens for
the treatment of nongonococcal PID. Rapid single-dose oral
azithromycin therapy has been found to prevent infertility in
a mouse model of chlamydial salpingitis [41]. Similarly, azithromycin was found to be more effective than doxycycline in
the microbiological cure of C. trachomatis infection and the
prevention of immunopathological upper reproductive tract
damage in a macaque model of PID [42]. Studies of reproductive sequelae following various PID treatment regimens in
humans are needed.

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relation between the microbiological makeup of the endometrium and fallopian tube and the unlikelihood of determining
the microbiological flora of the fallopian tube after treatment.
Despite the challenges facing the study of PID due to anaerobic
organisms as a result of the fact that only one-third to onehalf of PID cases are attributed to N. gonorrhoeae and/or C.
trachomatis and the fact that bacterial vaginosis, anaerobic
gram-negative rods, and mycoplasmal bacteria have been identified among women with PID [9, 10, 12, 27, 28], the microbiological efficacy of treatment regimens for both chlamydial
and/or gonococcal and nonchlamydial and/or nongonococcal
PID should be determined. Unfortunately, previous trials of
metronidazole showed it to have limited efficacy, perhaps because poor tolerability limits adherence. Indeed, the highest
rates of adverse effects and study discontinuation in the randomized clinical trials reviewed herein occurred in women who
were assigned to comparator regimens containing metronidazole [1820]. This fact underscores the need for research on
agents for the treatment of PID that are bactericidal for anaerobes. Regimens with shorter duration and monotherapy regimens are promising and may increase compliance and decrease
sequelae. However, there is currently limited evidence for the
recommendation of alternative therapies for the treatment of
anaerobic PID. Although azithromycin provides coverage
against a range of anaerobic and aerobic pathogens (including
black-pigmented gram-negative rods) [20, 29], fluoroquinolones, including ofloxacin, have generally been found to have
limited activity against anaerobes [30, 31]. In a recent trial of
moxifloxacin versus ofloxacin plus metronidazole, moxifloxacin was found to be as clinically efficacious as ofloxacin plus
metronidazole and to exhibit similar cure rates for C. trachomatis and Mycoplasma and better cure rates for N. gonorrhoeae
and gram-negative anaerobes [18]. However, women treated
with moxifloxacin experienced a worse cure rate for grampositive anaerobes [18]. Alternatively, a study has shown azithromycin to be effective for the treatment of anaerobic PID [20].
Clinical cure rates and eradication of anaerobes are similar
among women whose PID is treated with azithromycin alone
and women treated with combination azithromycin-metronidazole (clinical cure rate, 97% vs. 96%; anaerobe eradication
rate, 100% vs. 100%) [20]. This initial study is promising, and
further work may support the use of azithromycin monotherapy for the treatment of anaerobic PID. However, neither azithromycin nor quinolones are optimal for the treatment of gonococcal PID, because increasing drug resistance is being
reported [3236].
Treatment efficacy in the studies reviewed was restricted to
short-term clinical and microbiological cure. There are limited
data on the efficacy of any PID treatment regimen in the prevention of adverse reproductive sequelae. From the PEACH
study, we have previously reported that, among women with

In summary, a focus on reproductive and gynecologic morbidity, rather than on short-term clinical and microbiological
cure, is greatly needed. Whether currently prescribed PID antibiotic regimens are effective in the prevention of subsequent
reproductive morbidity is largely unknown. Arguably, longterm PID sequelae represent the most important treatment outcomes. Ultimately, microbe-specific and optimized treatment
needs to preserve fertility following PID and also prevent recurrent and persistent infection, ectopic pregnancy, and chronic
pain, improving the long-term prognosis for women who have
PID.

17.

18.

19.

20.

Acknowledgments
Potential conflicts of interest. C.L.H. and R.B.N.: no conflicts.
21.

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24.

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27.
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