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Pelvic Inflammatory Disease Evaluation and Management

Pelvic Inflammatory Disease Evaluation and Management

INFECTION PRACTICE POINTS Pelvic inflammatory disease Evaluation and Management

Dear FOGSIANs,

The theme of FOGSI this year is “We for Stree”. I would like to thank every FOGSIAN who has helped making every woman Safer, Stronger and Smarter. Through various academic and social programs FOGSI aims to uplift the quality of care that is given to every woman who comes to us.

TOG IPP ( Practice Points) is one such conclave that brings to light some of challenging health issues like Vaginitis, Pelvic inflammatory disease (PID) and Urogenital .

I would like to thank Zuventus for their contributions towards the TOG IPP Conclave.

We, as clinical practitioners are always busy, therefore the TOG IPP that is released has been a quick and easy way to update you with the latest evidence in the field of Infections. This year we ask all FOGSIANs to focus on the Stree and help make them safer, smarter and stronger.

Select FOGSIANs across India came together to deliberate and create these practice points. I am sure that you will appreciate the efforts which has gone into preparing the Infection Practice Points and find them useful in your day to day practice.

Best wishes!

Dr. Nandita Palshetkar MD, FCPS, FICOG President 2019 - Federation of Obstetrics & Gynecological Societies of India (FOGSI)

1 Pelvic inflammatory disease Evaluation and Management

FOGSI President : Dr. Nandita Palshetkar Moderators : Dr. Rishma Dhillon Pai, Dr. Pratik Tambe Panelists : Dr. Nozer Sheriar, Dr. Dibyendu Banerjee, Dr. Shyamal Sett, Dr. Madhuri Patel, Dr. Anshu Jindal, Dr. Seema Mehta, Dr. Adarsh Bhargava, Dr. Rakhi Singh, Dr. Pragya Mishra, Dr. Arun Nayak, Dr. Parzan Mistry, Dr. Bipin Pandit, Dr. Nita Mishra Clinical Reporter : Dr. Ritu Hinduja

From left to right: Dr. Nita Mishra, Dr. Pratik Tambe, Dr. Rakhi Singh, Dr. Parzan Mistry, Dr. Rishma Dhillon Pai, Dr. Nandita Palshetkar, Dr. Anshu Jindal, Dr. Shyamal Sett, Dr. Pragya Mishra, Dr. Madhuri Patel, Dr. Ritu Joshi

This is an independent publication owned by Science Integra®. The advice, opinion, statements, materials and other information expressed and contained in this book are solely those of the experts in the relevant field. The contents including text, graphics and images of the book are meant for educational and informational purposes only. Although great care has been taken in compiling and checking the information, neither Zuventus © 2020 or Science Integra shall be responsible/ liable in any way for the present and/or continued accuracy of the information or for any errors, omissions or inaccuracies in this publications whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. Opinions expressed do not necessarily reflect the views of Zuventus. The information in this book is meant only to supplement and not to replace the practice guidelines set by International, National Associations and Government bodies. The author/s, Doctors, sponsor and publisher advise readers to take full responsibility before practicing any of the suggested guidelines described in this book, be sure not to take risks beyond your level of experience, aptitude, training, and comfort level. These of course are only opinions of our experts and not recommendations or guidelines and are only meant to give the readers a systematic flow 2 chart to follow, using your own expertise to make final judgements. Any unauthorized reproduction or distribution of this publication is illegal. Pelvic inflammatory disease Evaluation and Management

Definition • C. trachomatis is the commonest identified cause accounting for 14%–35% of cases, Pelvic inflammatory disease (PID) refers to acute whilst , anaerobes and infection of the upper genital tract structures other organisms commonly found in the in women, involving any or all of the , may also be implicated fallopian tubes and ovaries and may involve the neighboring pelvic organs.1 • genitalium has been associated with upper genital tract infections in women Mild-to-moderate PID is defined as the absence and is a very likely cause of PID of a tubo-ovarian . Severe disease is • Genital tuberculosis is one of the causes of defined as severe systemic symptoms or the PID in India5 presence of tubo-ovarian abscess.2 Introduction • The insertion of an intrauterine device (IUD) increases the risk of developing PID • Pelvic infection is one of the most common, but only for 4–6 weeks after insertion. This serious infections in non-pregnant women risk is probably highest in women with pre- or reproductive age3 existing gonorrhoea or C. trachomatis3 • Pelvic infection are usually the result of infection ascending from the endocervix causes causing , , • Neisseria and , , tubo-ovarian trachomatis are identified as the causative abscess and/or pelvic peritonitis3 agents of PID • PID is reported to occur in 1% of the 15- • Gardnerella vaginalis, anaerobes and 25 year age group of young adults around the world and affects around 24%–32% of other organisms commonly found in the women in India4 vagina may also be implicated • In developed countries, the annual incidence • Mycoplasma genitalium has been is estimated to be 10–13 per 1000 women, associated with upper genital tract with 20 per 1000 women being in the age infections in women and is a very likely group of 20–24 years4 cause of PID 3 Cause of PID • Insertion of an IUD increases the risk and • Neisseria gonorrhea and Chlamydia is highest in women with pre-existing trachomatis (C. trachomatis) have been gonorrhoea or C. trachomatis identified as the causative agents

3 4,6,8,9 Risk factors Figure 1. Flow diagram of causes of primary and secondary pelvic inflammatory disease7 • Instrumentation of the uterus / interruption of the cervical barrier Pelvic inflamatory disease »» Termination of , insertion of IUD within the past 4 months,

hysterosalpingography, In vitro Primary Secondary

fertilization, intrauterine insemination Typical (IUI), hysteroscopy infections • C. trachomatic Genito- Colonic IUD • N. gonorrhoea urinary • Young < 25 years

• Menstruating women Diverticulitis Atypical Appendicitis infection Actino- • Multiple sexual partners Crohn’s eg- TB disease Infected Salmonella Colorectal endomet- Preforation • Recent new partners Carcinoma rioma

• Past history of sexually transmitted TB: tuberculosis; IUD: intrauterine device. infections (STIs) in the patient or their • Infection of the fallopian tubes initially partner affects the mucosa, but • No h/o of contraception use may rapidly become transmural. This

• Living in an area of high prevalence of PID inflammation, which appears to be mediated by complement, may increase in intensity • use (forgotten) with subsequent infections • Poor menstrual hygiene • Inflammation may extend to uninfected • parametrial structures, including the • However, in Indian scenarios the common- bowel est causes are abortions, puerperal sepsis • Infection may extend via spillage of and IUD insertions purulent materials from the fallopian tubes Pathogenesis of PID4,6,8,9 or via lymphatic spread beyond the to produce acute and acute • Ascending perihepatitis (Fitz-Hugh−Curtis syndrome) • Hematogenous Other factors responsible for influencing • Local spread occurrence of PID are:

Most cases of PID occur in 2 stages. • Cervical mucus provides a functional 1. Acquisition of a vaginal or cervical infection, barrier against upward spread, but vaginal which is often sexually transmitted and may inflammation and hormonal changes that be asymptomatic occur during ovulation and menstruation decrease the efficacy of this barrier 2. Direct ascent of microorganisms from the vagina or to the upper genital tract, • Antibiotic treatment of sexually transmitted with infection and inflammation of these infections can also disrupt the balance of structures endogenous flora in the lower genital tract,

4 causing normally nonpathogenic organisms • Fever (>38°C) in moderate to severe to overgrow and ascend disease

• Opening of the cervix during menstruation, A recent study conducted in Indian women along with retrograde menstrual flow, may with PID demonstrated as also facilitate ascent of microorganisms shown in Figure 2 below.10

• Intercourse may contribute to the ascent Figure 2. Signs and symptoms in studied cases of infection through rhythmic uterine

contractions occurring during orgasm. 68 70 58 Bacteria may also be carried along with 60 52 50 48 38 sperm into the uterus and fallopian tubes 40 30 3,9 22 20 12

Clinical features % of patients 10 PID should be considered in a patient with the 0 clinical signs and/or symptoms as below. Malaise 3 Symptoms Low backache Low grade fever PID may be symptomatic or asymptomatic. The Lower abdominal pain following features are suggestive of a diagnosis of PID: Centre for Disease Control and 11 • Lower abdominal pain which is typically Prevention (CDC) Criteria for PID bilateral (but can be unilateral) Table 1. PID diagnostic criteria per 2015 CDC guidelines Minimal • Cervical motion tenderness • Abnormal vaginal or cervical discharge clinical • Uterine tenderness which is often purulent criteriaa • Adnexal tenderness • Deep dyspareunia particularly of recent • Oral temperature greater than 101°F (38.3°C) • Abnormal cervical mucopurulent discharge onset or cervical friability • Abundant white blood cells on microscopic • Abnormal , including post Additional evaluation of vaginal fluid coital bleeding, inter-menstrual bleeding criteriab • Elevated erythrocyte sedimentation rate and menorrhagia • Elevated C-reactive protein • Laboratory documentation of cervical • Secondary dysmenorrhoea infection with Neisseria gonorrhoea or • Abnormal vaginal or cervical discharge – as • Endometrial biopsy with histopathologic a result of associated , endometritis evidence of endometritis or bacterial vaginosis • Transvaginal ultrasound or magnetic Specific resonance imaging showing thickened, fluid- 3 Physical signs criteriac filled tubes with or without free pelvic fluid or • Lower abdominal tenderness which is tubo-ovarian complex, or • Doppler studies suggesting pelvic infection usually bilateral • Laparoscopic findings consistent with PID Notes: Reproduced from CDC. 2015 Sexually Transmitted Diseases • Adnexal tenderness on bimanual vaginal Treatment Guidelines. Atlanta, GA: Department of Health and Human examination – a tender mass is sometimes Services; 2015. aInitiate treatment if one or more of these criteria are met. present bIn addition to one or more minimal criteria, one or more of the additional criteria increases specificity of the diagnosis of PID. c • Cervical motion tenderness on bimanual One or more of these criteria provides the most specific diagnosis of PID. Abbreviations: CDC, US Centers for Disease Control and Prevention; PID, pelvic inflammatory vaginal examination disease.

5 Vaginal pH assessing gloves as easy quick diagnosis tool Vaginal infections may be associated with PID and now assessing vaginal infections with gloves is an easy diagnostic tool Rationale for use • A move away from normal vaginal pH especially pH≥5.0 may be suggestive of altered and PID • In such situations, the clinical signs and symptoms may not be obvious and the patient may present with only a vaginal discharge • In such a clinical scenario, a simple digital vaginal assessment using specially developed gloves can be utilized Procedure • Wash and dry your hands • Insert your right hand in the glove • Insert your forefinger in the vagina for a few seconds and take out • Immediately press together your forefinger find the thumb, making sure the absorbing pad is pressed against the pH indicator 3.5 4.0 4.5 5.0 5.5 6.0 The normal vaginal pH is between 3.8 and 4.5. An altered vaginal pH is indicative of vaginal infection pH ≤ 4.5 < 4.5 > 4.5 ≥ 5.0 + (white, thick, clumpy + (white/grey, thin, clumpy + (Greenish-yellow, frothy Vaginal discharge +/- discharge) discharge) discharge) Malodour - - + + Itching - + - + Burning - + - + Normal Bacterial vaginosis

Diagnosis • Culture of vaginal secretions: Culture- Blood agar and McConkeys agar at 370C Laboratory evaluation8 for 24 hours. Blood culture plays no role in • Urine pregnancy test (always rule out diagnosis of PID ectopic) • DNA probes: Gonorrhea and chlamydia • CBC: WBC > 10000/microl (<50% cases- not probes (recovery rates of 5%–56%) have a amongst the diagnostic criteria’s) high specificity of 100% on diagnosis • Nucleic Acid Amplification Test (NAAT)- • ESR> 40mm/hr positive supports diagnosis, however • CRP: Elevated CRP> 60 mg/l negative NAAT does not exclude the • Vaginal smear: Abundant WBC on vaginal diagnosis. Performed 3–6 months after Rx smears (>10 WBC/hpf , >1 WBC/ epithelial to rule out reinfection cell) absence of endocervical or vaginal pus • PCR cells is a good negative predictive value • Chlamydia Antibodies: IgG and IgM (95%) but presence has a low positive • Test for other infections: Syphilis, HIV and predictive value of 17%) UTI

6 Transvaginal ultrasound Endoscopy and laparoscopy • Predictor: Thickened >5 mm fluid filled • Not routinely recommended as first line tubes, indistinct borders, moderate to large investigations fluid filled in pouch of Douglas, multiple • When imaging not definitive cysts in ovaries. Cogwheel appearance of • When no relief of symptoms after post tubes on cross section outpatient treatment CT scan • Tubal wall edema, hyperemia, exudates • Not better than USG • Direct visualization of tubo-ovarian abscess • Fitz-Hugh-Curtis Syndrome • Materials obtained simultaneously for histology and culture

Clinical diagnosis of PID: Flowchart12

Pelvic inflamatory disease Suspicious (suspected) of PID (Subclinical) YES No

Treat Mild/ Severe moderate symptoms/ Does the patient have one or more of the following symptoms systemically minimum criteria on pelvic examination unwell • Cervical motion tenderness Consider OR alternative Outpatient diagnosis if Inpatient • Uterine Tenderness management symptoms management OR persist • Adnexal Tenderness • Additional Criteria Clinical No clinical • Oral Temp > 38.3 °C improvement improvement • Abnormal Cervical or vaginal mucopurulent discharge • Preesence of abuntant numbers of WBC on saline of vaginal fluid or cervical fluid Test for proof Other diagnosis • Elevated ESR of cure suspected • Elevated CRP • Laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis or M. genitalium

Clinical No clinical improvement or suspicion improvement of tubo-ovarian abscess

Pelvis scan/TVS

PID diagnosis Other diagnosis confirmed suspected

Consider CT/ Treat diagnostic laparoscopy if clinical Test for proof of deterioration cure *Severe is any patient who is systemically unwell, the rest are mild and moderate

7 Complications3,9 • The Fitz-Hugh-Curtis syndrome comprises right upper quadrant pain associated with • The main complications of PID include tubo- perihepatitis which occurs in some women ovarian and pelvic peritonitis with PID, especially by C. trachomatis • A tubo-ovarian abscess should be suspected • PID is uncommon in pregnancy, but has in patients who are systemically unwell and/ been associated with an increase in both or have severe maternal and fetal morbidity, therefore »» The palpation of an , or parenteral therapy is advised lack of response to therapy, should • Women with HIV may have more severe prompt pelvic imaging with ultrasound, symptoms associated with PID but respond computed tomography (CT) or magnetic well to antibiotic therapy, although resonance imaging (MRI) parenteral regimens may be required »» Tubo-ovarian abscess is an indication • In women with an contraceptive IUD for hospital admission for parenteral in situ, consider removing the IUD since this antimicrobial therapy, with appropriate may be associated with better short-term anaerobic cover and to monitor for signs improvement in symptoms and signs of rupture or sepsis »» The decision to remove the IUD needs 13 Staging of PID to be balanced against the risk of idsog stages pregnancy in those who have had otherwise unprotected intercourse in Stage 1 the preceding 7 days • Women who fulfill the CDC major »» Emergency hormonal contraception diagnostic criteria and ≥1 of its minor following removal of an IUD may be criteria, but who do not have overt appropriate for some women in this peritonitis and who do not have situation prior documented STD upper tract infections complications of pid Stage 2 • Tubo-ovarian abscesses and pelvic • The above said criteria plus peritonitis peritonitis–indication for hospital admission for parenteral antimicrobial Stage 3 therapy, with appropriate anaerobic • Women with demonstrable tubo-ovarian cover complex or tubo-ovarian abscess • Fitz-Hugh-Curtis Syndrome evident on physical or ultrasonographic • Maternal and fetal morbidity in examination pregnancy Stage 4 • HIV women may have severe symptoms • Women with ruptured tubo-ovarian • Consider removal of in situ IUD for abscesses improving symptoms and signs IDSOG: Infectious Diseases Society for Obstetrics and • Septicaemia

8 Differential diagnosis9,14 AAP recommends The of lower • The American Academy of Pediatrics abdominal pain in a young woman (AAP) recommends at least one includes: preventive health visit per year • Ectopic pregnancy • The AAP, American Medical Association • Acute appendicitis and Society for Adolescent Medicine • recommend that physicians discuss • Irritable Bowel Syndrome (and less sexuality with youth as part of routine commonly, other gastrointestinal healthcare disorders) • Complications of an such as rupture or torsion • According to the Society for Adolescent • Medicine, “Confidentiality protection • Functional pain (pain of unknown is an essential component of health care physical origin) for adolescents because it is consistent with their development of maturity and autonomy and without it, some adolescents 15 PID in adolescents will forgo care” • Adolescents and young adults 15– • The AAP has endorsed a position paper 24 years of age represent approximately by the Society for Adolescent Health and 25% of the sexually active population, but Medicine supporting the use of expedited account for nearly half of all new sexually partner therapy (EPT) as a treatment option transmitted infection (STI) cases for heterosexual sex partners of adolescents • Adolescents have the highest incidence with gonorrhea and chlamydia when other of Neisseria gonorrhea and Chlamydia partner treatment methods are impractical trachomatis among any sexually active age or unsuccessful group Counselling and prevention of • This population also has an elevated risk adolescent PID15 of subsequent STIs after initial PID, thus • Make right choices putting them at increased risk of associated • Prevention of disease reproductive health sequelae such as • Adolescent education infertility, ectopic pregnancy and chronic • Menstrual hygiene abdominal pain • School and college education • Meeting adolescents where they interact • Adolescent friendly clinics with healthcare professionals: Talking 9 to adolescents about sex in a confidential Management manner, screening appropriately, notifying Aim of management is: patients with positive results and treating • Symptomatic relief both the patients and their partners to • Treatment of acute condition prevent reinfection should be the standard • Prevention of sequelae of care

9 Information, explanation and advice around 30% of women following PID for the patient6 »» PID increases the relative risk of a • Rest is advised for those with severe subsequent pregnancy being an disease ectopic, but the absolute risk of ectopic • Appropriate analgesia should be provided pregnancy remains low at around 1% • Patients should be advised to avoid oral Admission for parenteral therapy, observation, or genital intercourse until they and their further investigation and/or possible surgical partner(s), have completed their treatment intervention should be considered in the • A detailed explanation of their condition following situations: with particular emphasis on the long term • Diagnostic uncertainty implications for the health of themselves • Lack of response to oral therapy and their partner(s) should be provided • Clinically severe disease • Appropriate information should include: • Presence of a tubo-ovarian abscess »» Fertility is usually well preserved in • Intolerance to oral therapy women with first-episode of PID who • Pregnancy receive prompt appropriate antimicrobial therapy Recommended regimens9 »» The risk of impaired fertility increases • Broad spectrum antibiotic therapy significantly with each subsequent is required to cover N. gonorrhoeae, episode of PID (approximately doubling C. trachomatis and anaerobic infection with each new presentation) • It is also desirable to include microbiological »» The risk of impaired fertility is increased cover for other possible pathogens (M. in clinically more severe PID and chronic genitalium, streptococci, staphylococci, E. coli, pelvic pain of varying severity affecting H. influenzae) General advice • Rest is advised for those with severe disease (Evidence level IV, C) • If there is a possibility that the patient could be pregnant, a pregnancy test should be performed (Evidence level IV, C) • Appropriate analgesia should be provided (Evidence level IV, C) • Intravenous therapy is recommended for patients with more severe clinical disease • Oral or genital intercourse should be avoided until treatment completion to avoid reinfection Admission for parenteral therapy, observation, further investigation and/or possible surgical intervention should be considered in the following situations: • Diagnostic uncertainty • Lack of response to oral therapy • Clinically severe disease • Presence of a tubo-ovarian abscess • Intolerance to oral therapy • Pregnancy

10 recommended regimens

Choice of treatment regimen should be influenced by the following:

• Mild and moderate cases should be treated as outpatients with oral therapy (Evidence level Ib, A)

• Intravenous therapy, when given, should be continued until 24 h after clinical improvement and then switched to oral therapy (Evidence level IV, C)

• Dosage recommendations may need to be adjusted depending on local licensing regulations and the availability of drug formulations, e.g. may be dosed at 400 or 500 mg

• The optimal duration of treatment is not known but most clinical trials report a response to 10–14 days of therapy

Outpatient regimens9 Inpatient regimens9 First line therapy • IV/IM ceftriaxone 1 g once daily + IV doxycycline 100 mg • IM ceftriaxone 500 mg single dose followed by twice daily (oral doxycycline may be used if tolerated) followed by • Oral doxycycline 100 mg twice daily plus metronidazole »» Oral doxycycline 100 mg twice daily + oral 500 mg twice daily for 14 days (Evidence level Ia, A) metronidazole 500 mg twice daily to complete Second line therapy 14 days (Evidence level Ia, A) • Oral ofloxacin 400 mg twice daily plus oral metronidazole • IV 900 mg three times daily plus 500 mg twice daily for 14 days (ofloxacin may be replaced IM/IV gentamicin (3–6 mg/kg as a single daily dose with by levofloxacin 500 mg once daily) (Evidence level Ib, A) renal monitoring) followed by »» Either (oral clindamycin 450 mg four times daily to • Oral 400 mg once daily for 14 days (Evidence complete 14 days) or (oral doxycycline 100mg twice level Ia, A) daily plus oral metronidazole 500 mg twice daily to complete 14 days) (Evidence level Ia, A) Alternative regimens9 The evidence for alternative regimens is less robust than the regimens above. • IV ofloxacin 400 mg twice daily plus IV metronidazole 500 mg three times daily for 14 days (Evidence level Ib,A) • IM ceftriaxone 500 mg single dose plus oral azithromycin 1 g single dose followed by a second dose of oral azithromycin 1 g after one week (Evidence level Ib, A) Where the above regimens are not available antibiotic therapy should be given for 14 days and attempt to cover: • N. gonorrhoeae, e.g. cephalosporins • C. trachomatis, e.g. tetracyclines, macrolides • Anaerobic bacteria, e.g. metronidazole

11 CDC’s treatment recommendations9,16 reliable therapy against extended-spectrum β-lactamase producers, their substitution in Treatments are generally targeted toward the causative pathogens. Anaerobic coverage is place of cephalosporins appears to reduce indicated if tubo-ovarian abscess is present. emergence of the latter pathogens • Their use may also curtail the emergence Oral treatment regimens for pelvic inflammatory disease Ceftriaxone 250 mg IM in a single dose of other resistant pathogens such as PLUS difficile and vancomycin- Doxycycline 100 mg orally twice a day for 14 days WITH or WITHOUT resistant enterococci Metronidazole 500 mg orally twice a day for 14 days • Sulbactam is combined with either ampicillin OR or cefoperazone 2 g IM in a single dose and Probenecid, 1 g orally administered concurrently in a single dose Evidence for efficacy of Amoxycillin PLUS Doxycycline 100 mg orally twice a day for 14 days + in PID WITH or WITHOUT In women with PID with 3 days of treatment, Metronidazole 500 mg orally twice a day for 14 days more patients in the amoxycillin/clavulanic OR Other parenteral third-generation cephalosporin acid group showed diminution of symptoms (e.g., ceftizoxime or cefotaxime) of pain and discharge (p≤0.05) compared to PLUS the triple combination group (oral ampicillin, Doxycycline 100 mg orally twice a day for 14 days WITH or WITHOUT intramuscular gentamicin and metronidazole Metronidazole 500 mg orally twice a day for 14 days tablets/pessaries). Adapted from Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010 [published correction appears in MMWR Morb Mortal Wkly Rep. 2011;60(1):18]. MMWR Recomm Complete cure or satisfactory improvement Rep. 2010;59(RR-12):66. was recorded at the end of treatment. Parenteral treatment regimens for pelvic inflammatory disease BETA-LACTAM Regimen A • Oral amoxycillin/clavulanic acid Cefotetan 2 g IV every 12 hours OR reduces symptoms and is a convenient Cefoxitin 2 g IV every six hours alternative to the triple drug regimen PLUS for the treatment of PID Doxycycline 100 mg orally or IV every 12 hours Regimen B Clindamycin 900 mg IV every eight hours Patients admitted with severe PID and/or PLUS Gentamicin: Loading dose IV or IM (2 mg per kg), followed tubo–ovarian abscess are recommended by a maintenance dose (1.5 mg per kg) every eight hours; a to be discharged on a broad-spectrum oral single daily dose (3 to 5 mg per kg) can be substituted Alternative regimen antimicrobial regimen to complete a 14-day Ampicillin/sulbactam 3 g IV every six hours course. Owing to excellent polymicrobial PLUS coverage, the oral regimens recommended Doxycycline 100 mg orally or IV every 12 hours for discharge include /clavulanate β-lactam/β-lactamase inhibitor (875 mg twice daily) or the combination of combinations trimethoprim/sulfamethoxazole (160/800 mg • Although, β-Lactam/β-lactamase inhibitor twice daily) and metronidazole (500 mg twice combinations generally, do not constitute daily).20,21

12 The most frequently recommended treatment to eradicate these organisms are:22 Cefoperazone + Sulbactam • The addition of sulbactam to either 1. Amoxicillin and Clavulanic acid 2–3 g/day + ampicillin or cefoperazone does not doxycycline (200 mg/day) compromise the safety of these β-lactam 2. Amoxicillin and Clavulanic acid 2–3 g/ day + antibiotics26,27 ofloxacin (400 mg/day) • Sulbactam/cefoperazone is effective When PID is associated with risk factors such and safe for the treatment of moderate- as IUD, hysterosalpingography, D and C, to-severe bacterial infections caused post-partum and post abortion, the bacteria mainly by β-lactamase—producing usually isolated is Enterobacteriaceae, organisms26,27 anaerobes, Haemophilus and streptococcus. The initial recommended treatment is Evidences favouring Cefoperazone + therefore amoxicillin with clavulanic acid Sulbactam combination 2–3 g/day+ofloxacin 200 mg i.v. twice every Cefoperazone is safe and effective for the 24 hours. treatment of common obstetric and gynecologic Beigi, et al has shown that Amoxicillin/Clavulanic infections.28 acid plus doxycycline has acceptable efficacy.23 • Symptomatic cures were achieved in 91% Amoxicillin/clavulanate in combination with of patients and 96% of isolated pathogens doxycycline was associated with excellent clinical were eradicated during the therapy cure rates of 95% in the treatment of PID. The • Adverse drug-related reactions occurred in microbiologic cure rates were also observed only 4% of the patients (Table 2) to be excellent (>95%) for N. gonorrhoeae, Intravenous administration of sulbactam/ C. trachomatis, M. hominis and anaerobes.24 cefoperazone to patients with various kinds of Moreover, Amoxicillin/Clavulanic acid combina- gynecological infectious diseases demonstrated tion was considered as a satisfactory alternative a clinical and bacteriological efficiency rate of to the -aminoside metronidazole 100% and 75%, respectively. No remarkable combination in the treatment of upper genital side effects were observed, except for 1 buccal infections in women.25 exanthema and 1 genital candidiasis detected Cefoperazone + Sulbactam during the course of drug administration.29 combination for PID Sulbactam/cefoperazone combination demonst- • Sulbactam–cefoperazone has been used rated an effectiveness rate of 91.7%.30 in several nosocomial infections, including Combined sulbactam/cefoperazone covers a mild-to-moderate and severe nosocomial much wider range than cefoperazone only.31 , intra-abdominal infections, Reports have revealed that combined including biliary sepsis, intra-abdominal sulbactam/cefoperazone administered at a abscesses, pelvic inflammatory disease, daily dosage of 2 g in two divided doses is gynecological infections, sepsis, infections considered to be a highly effective antibiotic with in burn patients and infections in febrile clinical efficacy in obstetric and gynecological neutropenic patients26,27 infections.32

13 The efficacy rate was 100% for all conditions due to single or mixed infection, due to aerobic Gram- • Cefoperazone is safe and effective for negative, -positive or anaerobic bacteria. In a the treatment of common obstetric and study, patients with Obstetric and Gynecologic gynaecologic infections Infections (post cesarean section endometritis, • Sulbactam/cefoperazone combination post-hysterectomy cuff, pelvic cellulitis, or both, demonstrated high efficacy rate in acute salpingitis and endometritis after vaginal delivery or incomplete abortion) demonstrated infections caused by β-lactamase good clinical response (92%) to cefoperazone. producing organisms Cefoperazone appeared to be as effective as • The efficacy rate of sulbactam/ clindamycin-gentamicin and was observed cefoperazone was reported to be 100% to be safe and efficacious in women with for all infections due to single or mixed polymicrobial pelvic infections.33, 34 infection, due to aerobic Gram-negative, In the treatment of 31 cases of gynecological -positive or anaerobic bacteria infections, the clinical efficacy of sulbactam/ cefoperazone was assessed as excellent in 9 cases and effective in 22 cases.35 Treatment in pregnancy31

• β-Lactam/β-lactamase inhibitor combina- A pregnancy test should be performed in all tions are particularly useful against women suspected of having PID to help exclude mixed infections an ectopic pregnancy. • Owing to excellent polymicrobial coverage, the oral regimen recommended • In an on-going intrauterine pregnancy, PID at discharge is amoxicillin/clavulanate is extremely rare, except in the case of septic (875 mg twice daily) for those with severe abortion. Cervicitis may occur, however and PID is associated with increased maternal and • Amoxicillin and clavulanic acid 2–3 g/day + doxycycline (200 mg/day) or amoxicillin fetal morbidity including pre-term delivery and clavulanic acid 2–3 g/ day + ofloxacin • Treatment regimens will be dependent (400 mg/day) are the most frequently recommended treatment to eradicate upon the organisms isolated. Drugs known N. gonorrhoeae and C. trachomatis to be toxic in pregnancy should be avoided • The initial recommended treatment is e.g.- Tetracyclines amoxicillin with clavulanic acid 2–3 g/day + ofloxacin 200 mg IV twice every • Erythromycin and amoxycillin are not 24 hours for PID associated with risk factors known to be harmful in pregnancy such as IUD, hysterosalpingography D and C, postpartum and post abortion • A combination of cefotaxime, azithromycin • Amoxicillin-clavulanic acid combination and metronidazole for 14 days may be used. is considered as a satisfactory alternative The risks associated with metronidazole are to the penicillin-aminoside metronidazole uncertain but no confirmed associations combination in the treatment of upper with adverse outcomes have been genital infections in women reported

14 Table 2. Results of cefoperazone therapy in patients with obstetric and gynecologic infections No. of patients with clinical response No. of patients with bacteriologic response Type of infection No. of patient studied Cure Improvement Failure Satisfactory Unsatisfactory Undetermined Uterine 65 59 3 3 62 – 3 PID 21 59 1 – 18 – 3 Postoperative 14 11 2 1 13 1 – Miscellaneous* 7 7 – – 7 – – Totals 107 97 6 4 100 1 6 PID: pelvic inflammatory disease; *Chorioamnionitis, septicemia and tubo-ovarian abscess Treatment in a woman with Follow-up of patients31 an intrauterine contraceptive device36 • In the outpatient setting, review at 72 hours is recommended particularly • An intrauterine contraceptive device (IUCD) for those with a moderate or severe may be left in situ in women with clinically clinical presentation mild PID but should be removed in cases of severe disease and, especially, if symptoms • Failure to improve suggests the need have not resolved within 72 hours for further investigations, parenteral Treatment in a woman with HIV36 therapy and / or surgical intervention • Further review four weeks after therapy • Women with PID who are also infected with HIV should be treated with the same may be useful to ensure: antibiotic regimens as women who are HIV »» Adequate clinical response to negative treatment

• Potential interactions between antibiotics »» Compliance with oral antibiotics and anti-retroviral medication need to be »» Screening and treatment of sexual considered on an individual basis. Low CD4 contacts count is an indication for hospitalization » Surgery36 » Awareness of the significance of PID and its sequelae Surgical treatment should be considered in severe cases or where there is clear evidence • If PCR is used as a test of cure, it should of a pelvic abscess. not be repeated before 3 weeks as persistent gonococcal and chlamydial • Laparotomy/laparoscopy may help early DNA may lead to false positive results resolution of the disease by division of adhesions and drainage of pelvic • If microscopy and culture are used as abscesses a test of cure, specimens should be • Ultrasound-guided aspiration of pelvic taken at least 72 hrs after completion of fluid collections is less invasive and may be treatment equally effective • A full screen for all STDs including • It is also possible to perform adhesiolysis Hepatitis B & HIV should be offered for in cases of peri-hepatitis due to chlamydia persistent infections although there is no evidence as to whether this is superior to antibiotic therapy alone

15 Prevention11,37 2) Prevention of recurrent disease Primary prevention • Patients with recurrent PID are at risk for • Patient education greater reproductive sequelae than those • Opportunistic screening who avoid subsequent disease • Secondary prevention • Reports have shown that infertility roughly doubles with each subsequent • Adherence of compliance to treatment episode of PID and that women with • Follow up of treatment recurrent PID were almost two times • Tracing of partner and partner treatment more likely to report infertility and over • Completion of entire antibiotic course four times more likely to report CPP Prevention of PID falls broadly into the following two categories: Notification and treatment of 1) Prevention of the first PID 14 episode male sexual partners Men who have had sexual contact with a woman • Women who have had one episode of PID diagnosed with PID during the 60 days prior to need to prevent STI infection given the her onset of symptoms (or most recent sexual relationship between recurrent STIs, such partner if her last sexual intercourse was >60 as C. trachomatis and infertility days) should be evaluated and treated with • The CDC recommends annual chlamydia regimens that are effective against chlamydia and gonorrhea screening in all sexually and gonorrhea. active women <25 years of age and in • Women should be advised to avoid sexual sexually active women ≥25 years of age intercourse until they and their partners at increased risk (who have a new sex have completed the treatment course partner, those who have more than one • If adequate screening for gonorrhea and sex partner, those whose sex partner chlamydia in the sexual partner(s) is not has concurrent partners, or those with possible, empiric therapy for gonorrhea a sex partner who has an STI) and chlamydia should be prescribed • The CDC also recommends considering Grading of recommendations regular screening for Trichomonas A (Evidence levels Ia, Ib) – Requires at least vaginalis in women receiving care in one randomized controlled trial as part of high STI prevalence settings and women the body of literature of overall good quality engaged in high risk behaviors (such as and consistency addressing the specific sex with multiple partners, exchanging recommendation. sex for money or drugs, use of illicit drugs and prior history of an STI) B (Evidence levels IIa, IIb, III) – Requires availability of well-conducted clinical studies but no randomized clinical trials on the topic of • Women who test positive for an STI should recommendation. be rescreened for STIs 3 months after STI C (Evidence IV) – Requires evidence from treatment, particularly if they reside in expert committee reports or opinions and/or STI-prevalent communities and/or new clinical experience of respected authorities. behavioral risks are identified at the follow- Indicates absence of directly-applicable studies up visit of good quality. 16 summary

• Pelvic inflammatory disease (PID) refers therapy, with appropriate anaerobic to acute infection of the upper genital coverage tract structures in women, involving • Fitz-Hugh-Curtis Syndrome any or all of the uterus, fallopian tubes and ovaries and may involve the • Maternal and fetal morbidity in neighbouring pelvic organs pregnancy

• Neisseria gonorrhea and Chlamydia • HIV women may have severe symptoms trachomatis are identified as the • Consider removal of in situ IUD for causative agents. Gardnerella vaginalis, improving symptoms and signs anaerobes and other organisms commonly found in the vagina may also • Septicaemia be implicated. Mycoplasma genitalium Differential diagnosis for lower has been associated with upper genital abdominal pain in young women include tract infections in women and is a very likely cause of PID • Ectopic pregnancy

Risk factors for PID • Acute appendicitis

• Instrumentation of the uterus/ • Endometriosis interruption of the cervical barrier • Irritable bowel syndrome (and less • Young < 25 years commonly, other gastrointestinal • Menstruating women disorders)

• Multiple sexual partners • Complications of an ovarian cyst such as • Recent new partners rupture or torsion

• No h/o of contraception use • Urinary tract infection

• Living in an area of high prevalence of • Functional pain (pain of unknown PID physical origin) • Tampons use (forgotten) PID in adolescents • Poor menstrual hygiene • The American Academy of Pediatrics • Bacterial vaginosis (AAP) recommends at least one • Abortions, puerperal sepsis and IUD preventive health visit per year insertions in Indian scenario • The AAP, American Medical Association Complications of PID and Society for Adolescent Medicine • Tubo-ovarian abscesses and pelvic recommend that physicians discuss peritonitis– indication for hospital sexuality with youth as part of routine admission for parenteral antimicrobial healthcare

17 summary

• According to the Society for Adolescent • Intravenous therapy, when given, should Medicine, “Confidentiality protection is be continued until 24 h after clinical an essential component of health care improvement and then switched to oral for adolescents because it is consistent (Evidence level IV, C) with their development of maturity • Dosage recommendations may need to and autonomy and without it, some be adjusted depending on local licensing regulations and the availability of drug adolescents will forgo care” formulations • The AAP has endorsed a position paper • The optimal duration of treatment is not by the Society for Adolescent Health and known but most clinical trials report a Medicine supporting the use of EPT as a response to 10–14 days of therapy treatment option for heterosexual sex For treatment of PID in Indian population partners of adolescents with gonorrhea NACO has recommended Yellow Kit – KIT 6 and chlamydia when in the other partner 1. Tab Cefixime 400 X 1 tab treatment methods are impractical or 2. Tab Metronidazole 400 mg X ( 1 BD for unsuccessful 14 days) General advice on management 3. Tab Doxycycline 100 mg ( 1 BD for 14 • Rest is advised for those with severe days) disease (Evidence level IV, C) β-lactam/β-lactamase inhibitor combinations for PID • If there is a possibility that the patient could be pregnant, a pregnancy test • β-Lactam/β-lactamase inhibitor combi- nations are particularly useful against should be performed (Evidence level IV, mixed infections C) • β-Lactamase inhibitors when combined • Appropriate analgesia should be with certain β-lactam antibiotics, provided (Evidence level IV, C) augment the potency of these against • Intravenous therapy is recommended β-lactamase-producing bacteria for patients with more severe clinical Amoxycillin + clavulanic acid in PID disease • Owing to excellent polymicrobial • Oral or genital intercourse should be coverage, the oral regimen avoided until treatment completion to recommended at discharge is avoid reinfection amoxicillin/clavulanate (875 mg twice Recommended regimen daily) for those with severe PID

• Mild and moderate cases should be • Amoxicillin and clavulanic acid 2–3 g/day treated as outpatients with oral therapy +doxycycline (200 mg/day) or amoxicillin (Evidence level Ib, A) and clavulanic acid 2–3 g/ day+ofloxacin

18 summary

(400 mg/day) are the most frequently compromise the safety of these β-lactam recommended treatment to eradicate antibiotics N. gonorrhoeae and C. trachomatis • Sulbactam/cefoperazone is effective • The initial recommended treatment and safe for the treatment of moderate- is amoxicillin with clavulanic acid to-severe bacterial infections caused 2–3 g/day +ofloxacin 200 mg i.v. twice mainly by β-lactamase—producing every 24 hours for PID associated organisms with risk factors such as IUD, hysterosalpingography, D and C, • The efficacy rate of sulbactam/ postpartum, post abortion cefoperazone was reported to be 100% Cefoperazone + sulbactam combination for all infections due to single or mixed

• The addition of sulbactam to either infection, due to aerobic Gram-negative, ampicillin or cefoperazone does not -positive or anaerobic bacteria

References 9. Ross J, Guaschino S, Cusini M, et al. 2017 European guideline for the management of pelvic inflammatory disease. Int J 1. Wiesenfeld HC. Pelvic inflammatory disease: Treatment in STD AIDS. 2018; 29(2):108–114. adults and adolescents. UpToDate. Uptodate.com. 2019 10. Gopchade CA. Pelvic Inflammatory Disease in Women of [cited 6 August 2019]. Available from: https://www.uptodate. Child Bearing age Group: A Prospective Study. Annals of com/contents/pelvic-inflammatory-disease-treatment-in- International Medical and Dental Research. 2018; 4 (2): DOI: adults-and-adolescents. 10.21276/aimdr.2018.4.2.OG7 2. Ross J. Pelvic inflammatory disease. BMJ Clin Evid. 2013; 11. Das BB, Ronda J, Trent M et al. Pelvic inflammatory disease: 2013: 1606. Improving awareness, prevention and treatment. Infect 3. Ross J, Cole M, Evans C et al. United Kingdom National Drug Resist. 2016; 9: 191–7. Guideline for the Management of Pelvic Inflammatory 12. Diagnostic Imaging Pathways - Pelvic Inflammatory Disease (2019 Interim Update). PID Guideline Disease (Suspected). 2014. Available on: http://www. 4. Vanamala VG et al. Pelvic inflammatory disease and the imagingpathways.health.wa.gov.au/index.php/imaging- risk factors. Int J Reprod Contracept Obstet Gynecol. 2018; pathways/obstetric-gynaecological/pelvic-inflammatory-dis 7(9):3572–75 ease?tmpl=component&format=pdf Assessed on: 9th Aug 2019 5. Grace GA, Devaleenal DB, Natrajan M. Genital tuberculosis 13. Hemsel DL, Ledger WJ, Martens M, et al. Concerns regarding in females. Indian J Med Res. 2017; 145(4):425–36. the Centers for Disease Control’s published guidelines 6. Dayal S, Singh A, Chaturvedi V, et al. Pattern of pelvic for pelvic inflammatory disease. Clin Infect Dis. 2001; inflammatory disease in women who attended the tertiary 32(1):103–7. care hospital among the rural population of North India. 14. BMJ Best Practice. Pelvic inflammatory disease. 2018 Muller J Med Sci Res 2016;7:100–4. 15. Schneider K et al. Adolescents and Young Adults: Targeting 7. Smith J, Daley FC, Shakur A et al. Causes and complications the Unique Challenges of This High Risk Group. DOI: http:// of female pelvic inflammatory disease: a multimodal imaging dx.doi.org/10.5772/intechopen.86251 review. ECR 2018 / C-1945 doi: 10.1594/ecr2018/C-1945 16. Workowski KA, Berman S; Centers for Disease Control and 8. Kristi A Tough DeSapri, Pelvic Inflammatory Disease. Prevention (CDC).Sexually transmitted diseases treatment Medscape. 2019. Available on: https://emedicine.medscape. guidelines, 2010. MMWR Recomm Rep. 2010; 59(RR-12): com/article/256448-overview 1-110.

19 17. NACO. STI/RTI syndromic case management. Available on: 28. Strausbaugh LJ, Llorens AS. Cefoperazone therapy for http://naco.gov.in/sites/default/files/Syndromic%20Poster_ obstetric and gynecologic infections. Rev Infect Dis. 1983; REDUCED.pdf 5 Suppl 1:S154–60.

18. Lee N, Yuen KY, Kumana CR. Clinical role of beta- 29. Saito Y, Tachizaki T, Maki M. [Clinical and bacteriological lactam/beta-lactamase inhibitor combinations. Drugs. efficiency of sulbactam/cefoperazone in gynecological 2003;63(14):1511–24. infectious diseases]. [Article in Japanese] Jpn J Antibiot. 19. Uri FI, Sartawi SA, Dajani YF, et al. Amoxycillin/clavulanic 1984; 37(10):1919–24. acid (augmentin) compared with triple drug therapy for 30. Chimura T, Inoue K, Morisaki N. [Clinical evaluation of pelvic inflammatory disease. Int J Gynaecol Obstet. 1992; sulbactam/cefoperazone for infections in the field of 38(1):41–3. obstetrics and gynecology]. [Article in Japanese]. Jpn J 20. Jaiyeoba O, Lazenby G, Soper DE. Recommendations and Antibiot. 1984; 37(10):1928–33. rationale for the treatment of pelvic inflammatory disease. Expert Rev Anti Infect Ther. 2011; 9(1):61–70. 31. Domon H, Kodama M, Sato H, et al. [Clinical evaluation of 21. Soper DE. Pelvic inflammatory disease. Obstet Gynecol. sulbactam/cefoperazone in obstetric and gynecological 2010; 116(2 Pt 1):419–28. infection]. [Article in Japanese] Jpn J Antibiot. 1984; 37(10):1925–7. 22. Quentin R, Lansac J. Pelvic inflammatory disease: Medical treatment. Eur J Obstet Gynecol Reprod Biol. 2000; 32. Kohara T, Matsui Y, Noda M, et al. [Experience with sulbactam/ 92(2):189–92. cefoperazone in the field of obstetrics and gynecology]. 23. Beigi RH, Wiesenfeld HC. Pelvic inflammatory disease: New [Article in Japanese] Jpn J Antibiot. 1984; 37(10):1934–8. diagnostic criteria and treatment. Obstet Gynecol Clin North 33. Kubota K. [Fundamental and clinical studies of sulbactam/ Am. 2003; 30(4):777–93. cefoperazone in obstetrics and gynecology]. [Article in 24. Sweet RL. Treatment strategies for pelvic inflammatory Japanese] Jpn J Antibiot. 1984; 37(11):2234–42. disease. Expert Opin Pharmacother. 2009; 10(5):823–37. 34. Gilstrap LC 3rd, St Clair PJ, Gibbs RS, et al. Cefoperazone 25. Buisson P, Mulard C, Baudet J, et al. [Treatment of upper versus clindamycin plus gentamicin for obstetric and genital infections in women. Multicenter study of the gynecologic infections. Antimicrob Agents Chemother. comparative efficacy and tolerance of an amoxicillin- 1986; 30(5):808-9. clavulanic acid combination and of a triple antibiotic 35. Obata I, Ryu F, Imagawa N, et al. [Clinical studies on combination]. [Article in French] Rev Fr Gynecol Obstet. 1989; 84(10):699–703. sulbactam/cefoperazone in the field of obstetrics and gynecology]. [Article in Japanese]. Jpn J Antibiot. 1984; 26. Akova M. Sulbactam-containing beta-lactamase inhibitor 37(12):2478–94. combinations. Clin Microbiol Infect. 2008; 14 Suppl 1:185–8. 36. ICOG FOGSI Recommendations for Good Clinical Practice. Management of Acute Pelvic Inflammatory Disease. 2009 27. Li JT, Lu Y, Hou J, et al. Sulbactam/cefoperazone versus cefotaxime for the treatment of moderate-to-severe 37. Pelvic Inflammatory Disease: Guidelines for Prevention and bacterial infections: Results of a randomized, controlled Management. 1991 // 40(RR-5);1-25 Available on: https:// clinical trial. Clin Infect Dis. 1997; 24(3):498–505. www.cdc.gov/mmwr/preview/mmwrhtml/00031002.htm

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TOG-IPP-PID Booklet/02/01/2019-20 For the use of a registered medical practitioner or a hospital or a laboratory only.

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