Recommendations and rationale for the treatment of pelvic inflammatory disease_2009.pdf

7/30/2019 Recommendations and rationale for the treatment of pelvic inflammatory disease_2009.pdf

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Expert Rev. Anti Inect. Ther. 9(1), (2011)62

Review Jaiyeoba, Lazenby & Soper

without lower abdominal pain and symptoms noted in Box1. Aphysical examination should be perormed to assess the abdo-men or tenderness. Vaginal secretions examination should beperormed to assess or the presence o BV. Microscopy o the

vaginal secretions (wet mount) should be examined or the pres-ence o leukocytes as well as clue cells and trichomonads. Thecervical canal should be examined or the presence o yellow orgreen mucopus and riability, and testing or C. trachomatisandN. gonorrhoeaeshould be perormed. A bimanual pelvic exami-nation should be perormed to assess or pelvic organ tendernessand or evidence o a pelvic mass, which might suggest a TOA.

Other ancillary tests that can be perormed in diagnosing PIDinclude a complete blood count, erythrocyte sedimentation rate orC-reactive protein test. These tests are recommended or patientswith clinically severe PID. Imaging studies are most helpul whenruling out competing dierential diagnoses such as the use opelvic ultrasonography to rule out symptomatic ovarian cystsand computed tomography to rule out appendicitis. Pelvic ultra-sonography has limited sensitivity or the diagnosis o PID, butthe specifc fnding o thickened uid-flled tubes by ultrasonog-raphy supports the diagnosis o upper genital tract inammation.Pelvic ultrasonography should be perormed in patients requiringhospitalization or those with a pelvic mass noted on bimanualpelvic examination to urther characterize what could be a TOA.

Women with evidence o lower genital tract inection (N. gon-orrhoeae, C. trachomatis, Trichomonas vaginalis or BV) andcervicovaginal inammation and no pelvic organ tenderness canbe treated or an uncomplicated lower genital tract inection orcervicitis (Box2)[10]. For those with lower genital tract inamma-

tion and pelvic organ tenderness, treatment or the syndromicdiagnosis o PID is required. Most women with PID are clinicallymild or moderate cases and can be treated as outpatients. Womenwith severe PID or those meeting the criteria noted in Box3 shouldbe considered or hospitalization and inpatient parenteral therapy.

Treatment

Cervicitis

As mentioned previously, women with a clinical diagnosis o cer-vicitis oten test positive or C. trachomatis, N. gonorrhoeaeandT. vaginalisor have evidence o BV. It is known that up to 27%o these women will have histologic evidence o endometritis [9],

thereore we must be confdent that the choice o antibiotic therapy

or the treatment o cervicitis also covers endometritis (diagnosedin some women with mucopurulent cervicitis and no pelvic organtenderness during bimanual exam). The antibiotic regimen shouldnot only treat the potential pathogens noted but also result in a reso-lution o their endometritis. Fortunately, Eckert et al., showed that ashort course o an oral antibiotic regimen consisting o single-dosecefxime 400 mg, single-dose azithromycin 1 g and metronidazole500 mg twice daily or 7 days was highly eective (89%) in leading

to the resolution o histologic endometritis(Box2) [10]

. Metronidazolemay be withheld i no evidence o BV or T. vaginalisis present.

Mild-to-moderate PID

Most cases o PID (diagnosed in women with evidence o lowergenital tract inammation and pelvic organ tenderness but nomass) have mild-to-moderate disease. These patients can saelybe treated as outpatients. Treatment o PID should provide highrates o clinical and microbiologic cure or N. gonorrhoeaeandC. trachomatis, even in the presence o negative endocervicalscreening or these organisms. It should also provide coverageor the polymicrobial ora ound associated with BV[8,1114] .

The Pelvic Inammatory Disease Evaluation and Clinical HealthRandomized Trial (PEACH) provides the best guidance regardingthe antibiotic therapy o women with mild-to-moderate PID. Inthis large, multicentered, prospective randomized trial, a single doseo intramuscular ceoxitin administered with probenecid, ollowedwith 14 days o oral doxycycline, resulted in a similar short-termcure rate (both >98%) in outpatients when compared with multipleparenteral doses o ceoxitin and oral doxycycline in inpatients.There was no dierence in the long-term outcomes o ertility andectopic pregnancies between the two groups. Although two-thirdso the PEACH participants had BV, concurrent metronidazole wasnot administered. This suggests that a single dose o ceoxitin,which has good activity against Gram-negative anaerobes, and

multiple doses o doxycycline, despite suboptimal activity against

Box 1. Symptoms in women with clinicallysuspected pelvic infammatory disease.

Abdominal pain

Abnormal discharge

Intermenstrual bleeding Postcoital bleeding

Fever

Urinary requency

Lower back pain

Nausea/vomiting

Data taken rom [50,51].

Box 2. Outpatient antibiotic regimen or cervicitis.

Cefxime 400 mg orally in a single dosePlusAzithromycin 1 g orally in a single dosePlus

Metronidazole 500 mg orally twice daily or 7 days i bacterialvaginosis or Trichomonas vaginalis is present

Data taken rom [10].

Box 3. Criteria or hospitalization in women withpelvic infammatory disease.

Surgical emergencies (e.g., appendicitis) cannot be excluded

Patient is pregnant

Patient does not respond clinically to oral antibiotic therapy

Patient is unable to ollow or tolerate an outpatientoral regimen

Patient has severe illness, nausea and vomiting or high ever

Patient has a tuboovarian abscess

Data rom [52].


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www.expert-reviews.com 63

ReviewRecommendations & rationale or the treatment o pelvic infammatory disease

anaerobic bacteria, are sufcient or clinical cure and apparentlydo not adversely aect long-term outcome comparatively[15]. TheCDC-recommended regimens allow substitution o ceoxitin withother extended-spectrum cephalosporins such as cetriaxone, ceti-zoxime and ceotaxime. The CDC-recommended regimens alsoallow the clinician discretion to extend the anaerobic coverage byprescribing oral metronidazole in addition to the aorementioneddoxycycline (Box4).

Severe PID & TOAWomen with clinically severe PID or who meet the criteria notedin Box3, or both, should be considered or hospitalization and inpa-tient parenteral therapy. These patients are most likely have non-chlamydial polymicrobial PID or, less commonly, acute gonococcalPID. Imaging should be considered in hospitalized patients to eval-uate or other diseases and/or abscess. Women hospitalized withsevere PID may have TOA, and imagingwith pelvic ultrasonography or computedtomography is recommended [16]. Although75% o women with TOA will respond toantibiotic therapy alone, some will ail to

respond and require surgical intervention [17].The need or surgical intervention is relatedto the size o the TOA with 60% o thosewith abscesses 10 cm or greater in diameter,30% o those measuring 79 cm, and only15% o those 46 cm in diameter needingsurgery [17]. Patients who ail to respondto antibiotic treatment within 4872 h, ascharacterized by persistent ever and increas-ing leukocytosis, should be considered orsurgical drainage. Drainage o TOA canbe eected by laparotomy, laparoscopy or

image-guided percutaneous routes.

Proper antimicrobial therapy o pelvic abscesses includes anantibiotic regimen with activity against anaerobic bacteria suchas Bacteroides ragilisand Prevatella bivius,which areb-lactamaseproducing. In addition, the antimicrobial regimen should havegood coverage or E. coli, a common and predominant isolate rom

patients with ruptured TOA and a well-recognized cause o Gram-negative sepsis. Regimens recommended or this clinical scenarioinclude the combination regimens o clindamycin with gentamicin,ceotetan or ceoxitin with doxycycline, and ampicillin/sulbactamwith doxycycline (Box5)[18].

Expert commentary

Treatment o PID should take into account the short-term goalso clinical and microbiological cure and the long-term goals oprevention o inertility, ectopic pregnancy, recurrent inectionand chronic pelvic pain. Optimal antimicrobial regimens shouldbe well tolerated with little to no gastrointestinal side eects and

tailored or compliance, or example, single- to short-course regi-mens administered once a day or even less requently i possible.Oral therapy is preerred over parenteral therapy or reasons oconvenience and cost as well as to avoid the pain o needle injec-tion. Cost is an important consideration and relative expense othe antimicrobials under consideration is noted in TaBle 1.

Several quinolone antimicrobials (e.g., moxioxacin, ciprooxa-cin and ooxacin) alone or in combination with other agents havebeen studied and shown to be eective in the treatment o PID[1922]. However, ciprooxacin appeared less eective in clearingBV-associated microorganisms rom the endometrium despite thepatients clinical cure [20]. This causes some concern that persistentanaerobic inection could lead to a relapse o endometritis andsalpingitis. In addition, owing to increasingN. gonorrhoeaeresis-tance, quinolone use is no longer recommended or the treatmentoN. gonorrhoeaein the USA and thereore cannot be considereda primary monotherapy option or the treatment o PID in areaswith quinolone-resistant N. gonorrhoeae(QRNG) [23,24]. In areaswhere QRNG is uncommon, moxioxacin is an antibiotic thatshould be considered or the treatment o acute PID.

Box 5. The April 2007 CDC updated parenteral regimens.

Recommended regimen ACeotetan 2 g intravenously every 12 hOr

Ceoxitin 2 g intravenously every 6 hPlusDoxycycline 100 mg orally or intravenously every 12 hRecommended regimen BClindamycin 900 mg intravenously every 8 hPlusGentamicin loading dose intravenously or intramuscularly (2 mg/kg o bodyweight),ollowed by a maintenance dose (1.5 mg/kg) every 8 h. Single daily dosing maybe substitutedAlternative regimenAmpicillin/sulbactam 3 g intravenously every 6 hPlusDoxycycline 100 mg orally or intravenously every 12 h


Box 4. The April 2007 CDC updated recommendedoral regimens.

Cetriaxone 250 mg intramuscularly in a single dosePlusDoxycycline 100 mg orally twice a day or 14 daysWith or withoutMetronidazole 500 mg orally twice a day or 14 daysOrCeoxitin 2 g intramuscularly in a single dose andProbenecid 1 g orally administered concurrently in a single dosePlusDoxycycline 100 mg orally twice a day or 14 daysWith or withoutMetronidazole 500 mg orally twice a day or 14 daysOrOther parenteral third-generation cephalosporins (e.g., cetizoximeor ceotaxime)PlusDoxycycline 100 mg orally twice a day or 14 daysWith or withoutMetronidazole 500 mg orally twice a day or 14 days



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Moxioxacin has been ound in three randomized controlledtrials to be an eective and well-tolerated oral treatment in womenwith acute PID [25]. Ross et al. ound that moxioxacin once-dailymonotherapy was as clinically and bacteriologically eective astwice-a-day ooxacinmetronidazole combination [22]. Heystecket al. also demonstrated the efcacy o moxioxacin monother-apy in a comparative study with a combination o doxycycline,

metronidazole and ciprooxacin [26].

Moxioxacin rapidly penetrates uter-ine tissue where it remains in high con-centrations and is suiciently high toeliminate the principal pathogens o PID[27]. In addition, Bradshawet al. reported

that moxioxacin was able to eradicateM. genitalium in patients who had ailedazithromycin treatment [28,29]. Thus, mox-ioxacin represents a useul addition to thetreatment armamentarium or acute PIDin women.

Owing to persistent concern about thecurrent outpatient antimicrobial regimenslacking comprehensive coverage o anaero-bic bacteria, metronidazole has been sug-gested as an addition to doxycycline, par-ticularly or those women with PID and

BV. However, the combination o doxycy-cline and metronidazole has been associ-ated with low clinical and microbiologicalcure rates o 75 and 71%, respectively, orPID [24,30]. These observations suggestthat the combination o doxycycline andmetronidazole is a suboptimal choice oran oral antibiotic regimen used to treatPID [24,31]. The low efcacy rates may bedue to the poor coverage o these drugsagainst N. gonorrhoeae, and the additiono an eective anti-gonoccocal antibioticto the regimen should improve the efcacyrates. Piyadigamage et al. demonstratedthat by adding cetriaxone to doxycyclineand metronidazole, there was a signifcantclinical cure rate improvement rom 55 to72% [31].

Azithromycin provides excellent cover-age o chlamydia and moderate-to-goodcoverage or a range o aerobic and anaero-bic bacteria, including Gram-negativeanaerobes [30,32]. It is also at least 100-oldmore active in vitro againstM. genitaliumthan the quinolones or tetracyclines [33,34].

Although not included in the updatedCDC 2007 guidelines or treatment oPID, several studies suggest that azithromy-cin can be used or the treatment o acutePID [30,32]. In a randomized controlled

trial, cure rates o azithromycin or chlamydial inections, con-comitant gonorrhea and gonorrhea only were high (95.8, 84.2and 98.2%, respectively) [35]. Another randomized trial com-paring the efcacy and saety o azithromycin as monotherapyor combined with metronidazole showed cure rates o 97.6 and95.5%, respectively[36]. Malhotraet al. reported a clinical curerate o 93% among those given a one-time dose o uconazole,

azithromycin and secnidazole [37]. In the macaque animal model,

Table 1. Cost o requently used antibiotics in the treatment o pelvicinfammatory disease.

Drug Regimen dose Regimen cost

Azithromycin 500 mg p.o. one dose

ollowed by 250 mgq.d. 7 days

Tablets: 250 mg (eight tablets)

US$26.40

Amoxicillin/clavulanate 875 mg p.o. q 12 hor 12 days

Tablets: 875125 mg(24 tablets) US$38.40

Ampicillin /sulbactam 3 g iv. q 6 h or 48 h iv. vial: (2 g:1 g) or 48 hUS$80

Cetriaxone 1 g iv. q 12 h or 48 h iv. vial: (250 mg) US$3;iv. vial: (2 g) or 48 h US$18.28

Cefxime 400 mg p.o. one dose Tablets: 400 mg (one tablet)US$11

Ceoxitin 2 g im. one dose (mild-to-

moderate PID)2 g iv. q 6 h or 48 h insevere PID

iv. vial: (1 g/50 ml)

US$11.23

US$22.46 or 2 g doseUS$179.68 or 48 h

Ceotetan 2 g iv. q 12 h or 48 h iv. vial: (2 g) US$28.45

US$113.8 or 48 h

Clindamycin 900 mg iv. q 8 h iv. vial: (900 mg) US$13.28

US$79.68 or 48 h

Doxycycline 100 mg p.o. q 12 h or 14 days100 mg iv. q 12 h in severe PID

Capsule: 100 mg (28 capsules)US$12.13

Gentamicin Loading dose 2 mg/kg iv.ollowed by maintenance dose(1.5 mg/kg) q 8 h single q.d.

Dosing may be substituted by4.5 mg/kg iv. q.d.

Solution: 10 mg/ml (25 vials,2 ml) US$125

Metronidazole 500 mg p.o. q 12 h or 14 days Tablets: 500 mg (28 tablets)US$12.12

Probenecid 1 g p.o. administeredconcurrently with ceoxitin

Tablets: 500 mg (two tablets)US$1.17

Trimethoprim/sulamethoxazole

160/800 mg p.o. q 12 h or12 days

Tablets: 160800 mg(24 tablets) US$16

Ciprooxacin 500 mg p.o. q 12 h Tablets: 500 mg (28 tablets)US$11

Levooxacin 500 mg p.o. q.d. Tablets: 500 mg (14 tablets)US$236.60

Moxioxacin 400 mg p.o. or iv. q.d. Tablets: 400 mg (14 tablets)US$225.60

Approximate retail price rom [101].Average wholesale price rom [102].im.: Intramuscularly; iv.: Intravenously; PID: Pelvic inammatory disease; p.o.: Orally; q: Every; q.d.: Daily.


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azithromycin was more eective in eradicating chlamydial organ-isms rom the upper and lower reproductive tract tissues thandoxycycline, and also exerted a signifcant anti-inammatoryeect [38]. Azithromycins advantages over doxycycline includesingle-dose administration and ewer side eects [30]. However,

N. gonorrhoeaeresistance to azithromycin has been reported andthe higher 2 g dose recommended to treat this pathogen is associ-ated with signifcant gastrointestinal side eects. Despite theseconcerns, multidose regimens o azithromycin monotherapy reli-ably eradicated N. gonorrhoeaewhen isolated in women with PIDin the studies cited. Savaris et al., in a randomized controlledtrial conducted in Brazil, showed that when combined with ce-triaxone, 1 g o azithromycin weekly or 2 weeks was equivalentto cetriaxone plus a 14-day course o doxycycline or treatingmild PID [39]. The discussion on azithromycin would be incom-plete without discussing azithromycin ailure in the treatment oM. genitalium urethritis.A total o15% o patients experienced

treatment ailure with azithromycin versus 55% treatment ailurewith doxycycline [40]. Azithromycin treatment ailure o 1530%has also been reported in patients withM. genitalium urethritisin Australia and the use o moxioxacin in these cases resultedin rapid symptom resolution and eradicated the inection [28,29].

Given the above commentary, it appears that optimal regi-mens or the treatment o mild-to-moderate PID should includean antibiotic with reliable activity against N. gonorrhoeaein addi-tion to an antibiotic with reliable activity against C. trachomatisand M. genitalium. There is not a single agent with these char-acteristics so only combination therapy can be recommendedor the treatment o PID. Given the increasing concern aboutM. genitalium as an etiologic agent or PID, coverage o thismicroorganism is desirable [11]. Finally, broad-spectrum cover-age o the BV-associated microorganisms appears less important[15,24]. In act, the combination o doxycycline with metroni-dazole appears to be inerior and thereore one might consideravoiding it.

The extended-spectrum cephalosporinsoer excellent coverage oN. gonorrhoeae.For the reasons o convenience, cost and easeo administration, oral cefxime 400 mg ina single dose is our frst extended cephalo-sporin o choice. Cetriaxone 250 mg intra-muscularly in a single dose is our second

choice owing to the act that, unlike ceoxi-tin, it does not require the addition o oralprobenecid. However, it should be pointedout that both o these cephalosporins ailto cover the Gram-negative anaerobes otenassociated with BV that ceoxitin covers.Ceoxitin is high on our list but given theneed to split the intramuscular dose intotwo 1 g intramuscular injections plus theneed to add oral probenecid, this is a lessattractive alternative. These choices reliablytreat a gonococcal inection. Optimally,

one would use cefxime or cetriaxone in

those women with PID and no BV present, but opt or ceoxitin,owing to its superior anaerobic coverage in the presence o PIDwith concurrent BV(Box6).

The second antibiotic should be either doxycycline or azithro-mycin owing to their eectiveness against C. trachomatisand

M. genitalium. Doxycycline has been studied in the gold stan-dard o PID studies, the PEACH study, and along with ceoxitinhas been shown to be highly efcacious. However, doxycyclinerequires a twice-a-day dosing regimen or 14 days, making com-pliance improbable. Azithromycin, on the other hand, can bedosed in either a single daily dose (500 mg ollowed by 250 mgdaily) or 1 week or in two single doses (1 g each) 1 week apart. Inaddition, azithromycin appears to work more efciently in eradi-catingin vitro inection and has the added beneft o a signifcantanti-inammatory eect [38]. Moreover, there is some concernabout persistent M. genitalium inection ollowing doxycycline[11,14]. Given these observations, azithromycin appears to be the

superior choice.Finally, we have to ask ourselves, how important is it to cover theanaerobic bacteria associated with BV and isolated rom the uppergenital tracts o women with PID? The antibiotics discussed abovehave modest activity against these microorganisms. The antibiotic,ceoxitin, with the best coverage against Gram-negative anaerobes,is administered in a single dose. Antibiotic regimens prospectivelystudied with little to no activity against anaerobic bacteria haveuniormly perormed well, while regimens containing metronida-zole and doxycycline, which should enhance anaerobic coverage,have perormed comparatively poorly. This leads us to suggest thatdual therapy with an extended-spectrum cephalosporin and doxy-cycline or azithromycin is an excellent regimen or the treatmento women with PID who can be treated as outpatients.

Women with clinically severe PID should be considered orimaging to evaluate or TOA. As mentioned earlier, antibioticregimens recommended or clinically severe disease should cover

Box 6. Outpatient antibiotic regimen or treatment omild-to-moderate pelvic infammatory disease.

Recommended oral regimenCefxime 400 mg orally in a single dosePlusAzithromycin 500 mg orally ollowed by 250 mg orally daily or a total o 7 daysOrDoxycycline 100 mg orally twice daily or 14 daysAlternative regimenCetriaxone 250 mg intramuscularly in a single dosePlusAzithromycin 500 mg orally ollowed by 250 mg orally daily or a total o 7 daysOrDoxycycline 100 mg orally twice daily or 14 daysPreerred regimen i concurrent bacterial vaginosis inectionCeoxitin 2 g intramuscularly in a single dose andProbenecid 1 g orally administered concurrently in a single dosePlusAzithromycin 500 mg orally ollowed by 250 mg orally daily or a total o 7 daysOrDoxycycline 100 mg orally twice daily or 14 days


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Gram-negative aerobic and anaerobic bacteria. I a TOA is pres-ent, regimens should have the ability to penetrate abscess cavitieswhile remaining stable in an acidic, hypoxic abscess environment.

Although regimens containing an aminoglycoside have beenused eectively in women with pelvic abscesses, this class o anti-

biotic has its activity signifcantly reduced at low pH, low oxygentension and in the presence o drug-binding purulent debris [41].McNeeley et al. showed that the combination o clindamycinand gentamicin was associated with a signifcantly lower curerate (47%) than the combination o clindamycin/ampicillin/gen-tamicin (87.5%) when used to treat patients with TOA[42]. Forthese reasons, an extended-spectrum cephalosporin, or exam-ple, cetriaxone, may be a better choice to combine with eitherclindamycin or metronidazole in treating women with severePID with or without a TOA. Not only do extended-spectrumcephalosporins maintain their activity in an abscess environment,but they have a much higher serum level to MIC ratio than the

aminoglycosides(Box7)

.Clindamycin is actively transported into polymorphonuclearleukocytes and macrophages and is present in relatively high con-centrations compared with peak serum levels in experimentalabscesses [43]. Clindamycin has long been used in combinationtherapy or PID because o its activity against anaerobes and con-tinues to be recommended in the treatment o PID on the basis oearlier studies and previously successul experience, but resistanceto clindamycin has recently been observed among isolates recov-ered rom the lower genital tract [44]. Among nonpregnant womenwith BV, 17% o isolates demonstrated clindamycin resistance atbaseline, a rate that increased to 53% ater clindamycin therapy.Although there are no data indicating that these observations

o resistance are associated with PID treatment ailures withclindamycin-based regimens, there is concern that resistance toclindamycin may be on the rise [45]. Clinicians should be awareo bacterial resistance when selecting antimicrobial therapy. Inthis light, renewed interest has been ocused on ampicillin/sul-

bactam or metronidazole which, in contrast to clindamycin, doesnot appear to have the same problems with selective pressure ormicrobial resistance [46].

For the reasons noted earlier, we recommend metronidazole orclindamycin in combination with cetriaxone as our regimen ochoice. Other antimicrobials with similar broad-spectrum cov-erage and activity within the hostile environment o the abscessinclude b-lactam agents with b-lactamase inhibitors (e.g., ampi-cillin/sulbactam, ticarcillin/clavulanate and piperacillin/tazo-bactam) and the carbapenems (e.g., ertapenem, merepenem andimipenem/cilistatin). O these alternative choices, we recommendertapenem owing to our ability to dose it once a day. Finally,

or those women with an immediate hypersensitivity to penicil-lin, we would recommend the combination o a quinolone (e.g.,ciprooxacin or levooxacin) plus metronidazole. It would beimportant to test or N. gonorrhoeaeby culture in these patients assusceptibility to quinolones would need to be ascertained (Box7).

Patients admitted with severe PID and/or TOA should bedischarged on a broad-spectrum oral antimicrobial regimen tocomplete a 14-day course. Recommended oral regimens or dis-charge include amoxicillin/clavulanate (875 mg twice daily) orthe combination o trimethoprim/sulamethoxazole (160/800 mgtwice daily) and metronidazole (500 mg twice daily), owing toexcellent polymicrobial coverage.

The most severe orm o clinical PID-ruptured TOA should beconsidered in patients with PID presentingwith an acute abdomen and signs o septicshock. TOAs in patients undergoing medi-cal management o PID may rupture andrequire emergent surgical therapy. Surgicalexploration with extirpation o the involvedadnexa and drainage o purulent locula-tions is liesaving. Hysterectomy is usuallynot necessary[47,48].

Conclusion

Optimal therapy or PID must take into

consideration the severity o disease, thepolymicrobial etiology o disease, the avail-ability and costs o the antimicrobials,and their ease o administration. For thisreason we recommend regimens or usein the treatment o those women who arecandidates or outpatient therapy that canbe administered as single or inrequent oraldoses. Cefxime or a similar oral extended-spectrum cephalosporin can be used tocover the gonococcus, while azithromycincan be recommended to cover chlamydia

and M. genitalium. Both agents together

Box 7. Inpatient parenteral antibiotic regimens or treatment osevere pelvic infammatory disease and tuboovarian abscess.

Recommended regimen

Cetriaxone 1 g intravenously every 12 hPlusMetronidazole 500 mg intravenously every 6 hOrClindamycin 900 mg intravenously every 8 hAlternative regimensErtapenem 1 g intravenously dailyOr

Piperacillin/tazobactam 3.375 g intravenously every 6 hOrTicarcillin/clavulanate 300 mg/kg/day intravenously in divided doses every 4 hOrAmpicillin/sulbactam 3 g intravenously every 6 hAlternative regimen or penicillin-allergic patients

Levooxacin 500 mg orally once daily or 14 daysOrCiprooxacin 400 mg intravenously every 12 hPlusMetronidazole 500 mg intravenously every 6 h

Intravenous antibiotics can be switched to oral antibiotics ater 4872 h o therapy or based onclinical judgment.I Chlamydia positive, add either azithromycin or doxycycline.Culture or quinolone-resistant Neisseria gonorrhoeae is required i the quinolones are used.


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appear to have satisactory anaerobic coverage to render womenwith the clinical diagnosis o mild-to-moderate PID asymptomatic.Moxioxacin is a good alternative regimen or acute PID but it iscostly, and its use should be restricted to areas were gonococcalPID is uncommon. Gonococcal culture and sensitivity testing isrequired to ensure N. gonorrhoeaeis sensitive to moxioxacin. Arepeat gonococcal test is also required post-treatment to document

eradication o the pathogen.

Women with more severe disease, partic-ularly in the context o an associated TOA,must have the non-sexually transmittedmicroorganisms covered. This will includeanaerobic bacteria and aerobic Gram-

negative bacteria, especially E. coli. Inaddition, broad-spectrum therapy shouldinclude those microorganisms commonlyassociated with BV. A combination o par-enteral cetriaxone and metronidazole orclindamycin provides this coverage.

It is unclear how long therapy need con-tinue but most studies (Box8) and the CDCrecommendations suggest 14 days. It isunlikely that most patients will adhere tosuch a long regimen ater their symptomsresolve. It is most likely sae to discontinue

antibiotic therapy once the patients ever haslysed, her white blood cell count has nor-malized and her pelvic exam is non-tender,or at most reects mild tenderness.

Five-year view

There are several important areas in whichadditional investigation could provide impor-tant guidance. Despite the revelation o apolymicrobial etiology o acute PID in 1975,we still do not understand the true impor-tance o anaerobic bacteria as etiologic agentso acute PID. Current data suggest that anti-microbial regimens with little to no anaerobiccoverage are highly eective in the treatmento mild-to-moderate PID, even in womenwith concurrent BV. Prospective studiesneed to be perormed that will compare well-tolerated antibiotic regimens with excellentanaerobic coverage with those with little tono such coverage in the treatment o mild-to-moderate PID. In addition, prospectiverandomized trials are required to study oralcefxime versus other parenteral cephalospo-rins. We also understand little with respect

to the need or duration o treatment and therequency o dosing. It would be interestingto see i short courses (


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despite doxycycline therapy and its optimal therapy is unknown.M. genitaliumcould become the next C. trachomatisi widespreadtesting was undertaken, yet commercially available nucleic acidtests are not available. It will be important to defne the epide-miology, sequelae and most eective therapy or this emerging

sexually transmitted inection.It would be preerable to use a single agent that covers all

the potential microbial pathogens, can be administered oncedaily and is inexpensive. Currently, moxioxacin (not avail-able as a generic in the USA) comes closest to being this agentbut quinolone-resistant N. gonorrhoeaeand its cost (US$225.60

or 14 tablets) prevent it rom being embraced in this regard.Continued antibiotic development could provide us with thisagent in the uture.

Financial & competing interests disclosure

The authors have no relevant aliations or nancial involvement with anyorganization or entity with a nancial interest in or nancial confict with

the subject matter or materials discussed in the manuscript. This includes

employment, consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production o this manuscript.

Key issues

Pelvic inammatory disease (PID) is an inection-induced continuum o the emale genital tract capable o causing tubal actor inertilityand ectopic pregnancy.

PID is a polymicrobial inection caused by the sexually transmitted microorganisms Neisseria gonorrhoeae, Chlamydia trachomatis andMycoplasma genitalium.

It is clear that anaerobic bacteria play a signifcant etiologic role in PID complicated by tuboovarian abscess, but it is less clear as towhether these microorganisms can inect and cause inammation in previously undamaged allopian tubes.

Outpatient therapy is recommended or patients with mild-to-moderate PID.

Azithromycin needs urther study to confrm its e ectiveness in the treatment o mild-to-moderate acute PID.

Women with clinically severe PID should be admitted to hospital or imaging to rule out tuboovarian abscess and be started onparenteral therapy utilizing an antibiotic regimen that will remain active within an abscess environment.

Aminoglycosides are inactive in an abscess environment and are thereore o limited use in the treatment o women with clinicallysevere PID and/or tuboovarian abscess.

Fluoroquinolones cannot be recommended to treat PID unless culture or N. gonorrhoeae is perormed to allow susceptibility studies tobe carried out to rule out quinolone-resistant N. gonorrhoeae.

M. genitalium needs to be urther characterized as a sexually transmitted pathogen.

Prospective randomized trials are required to study oral cefxime versus other parenteral cephalosporins.

ReerencesPapers o special note have been highlighted as:

of interest

of considerable interest

1 Centers or Disease Control andPrevention. Sexually transmitted d iseasestreatment guidelines.MMWR55(NoRR-11), 5661 (2006).

2 Rein DB, Kassler WJ, Irwin KL, Rabiee L.Direct medical cost o pelvic inammatorydisease and its sequelae: decreasing, butstill substantial. Obstet. Gynecol. 95,

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