ICMR Antimicrobial Guidelines for Infections in Obstetrics and Gynaecology

Indian Council of Medical Research, Department of Health Research has issued the ICMR Antimicrobial Guidelines for Infections in Obstetrics and Gynaecology. Following are the major recommendations :

Purpose

The purpose of these guidelines is to ensure appropriate antimicrobial prophylaxis and treatment while at the same time limiting unnecessary use of antibiotics. Common gynaecological conditions which need treatment with antibiotics are pelvic inflammatory disease, bacterial vaginosis, vaginal candidiasis, vaginal trichomoniasis. Serious conditions include surgical site infection (SSI), puerperal sepsis and septic abortion. Antibiotic prophylaxis in surgical procedures reduces colonization by microorganisms introduced at surgery to a level which the patient’s immune system can overcome. Prophylactic antibiotics should be safe, inexpensive and effective against organisms likely to be encountered. Adequate serum and tissue levels should be present before an incision is made and therapeutic levels should be maintained during surgery and for a few hours after it is over.

Case definition:

Infectious complications following obstetric & gynaecologic surgery (eg caesarean section and hysterectomy) include SSI, urinary tract infection, endometritis, vaginal cuff cellulitis, perineal infection, and septicaemia.

Surgical Site Infection (SSI): These are defined by the centre for disease control, USA (CDC) and may be superficial, deep or involving organ/space.

i) Superficial incisional SSI: It occurs within 30 days after operation and involves only skin and subcutaneous tissue of the incision with at least one of the following:

• Purulent drainage, with or without laboratory confirmation, from the superficial incision


• Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision


• At least one of the following: pain or tenderness, localised swelling, redness, or heat


• Diagnosis of superficial incisional SSI made by a surgeon or attending physician.

ii) Deep incisional SSI: It occurs within 30 days after operation if no implant is left or within one year if implant is in place. The infection appears related to the operation and involves deep soft tissue (e.g. fascia, muscle) of the incision with at least one of the following:

• Purulent drainage from deep incision but not from organ/space component of surgical site


• A deep incision dehisces spontaneously or is deliberately opened plus at least one of the following features: fever (>38°C), localised pain or tenderness (unless culture-negative)


• An abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathological or radiological examination


• Diagnosis of deep incisional SSI made by a surgeon or attending physician

iii) Organ/space SSI: It occurs within 30 days after the operation if no implant is left in place or within one year if implant is in place. The infection appears related to the operation and involves any part of anatomy (e.g., organs and spaces) other than the incision which was opened or manipulated during an operation and at least one of the following:

• Purulent drainage from a drain that is placed through a stab wound into organ/space


• Organisms isolated from an aseptically obtained culture of fluid or tissue in organ/ space


• An abscess or other evidence of infection involving the organ/space found on direct examination, during reoperation, or by histopathological or radiological examination


• Diagnosis of organ/space SSI made by a surgeon or attending physician.

Puerperal sepsis: It is defined as “Infection of the genital tract occurring between rupture of membranes or labour and the 42nd day postpartum with 2 or more of the following”:

• Pelvic pain


• Pyrexia i.e. oral temperature 38.5°C or higher on any occasion


• Abnormal vaginal discharge , e.g. presence of pus or discharge with foul odour


• Delay in the rate of reduction of the size of the uterus (<2cm/day during the first 8 days)

Pelvic inflammatory disease (PID) comprises inflammatory disorders of upper genital tract, including endometritis, salpingitis, tubo-ovarian abscess, or pelvic peritonitis. The symptoms include fever, pelvic pain, dyspareunia and abnormal vaginal discharge. The diagnosis of PID would be likely in the presence of features listed below

• Sexually active young women


• Symptoms of pelvic or lower abdominal pain


• Presence of cervical motion tenderness OR uterine tenderness OR adnexal tenderness on clinical examination.


• No other cause identified for the above symptoms and signs

Vaginitis & cervicitis: comprises a spectrum of inflammatory disorders of the lower female genital tract characterised by vaginal discharge, odor, pruritus, and dyspareunia.

Common Pathogens:

The common organisms causing sepsis in the puerperium are mostly from endogenous microbiota of vagina and include streptococci (Group B), enterococci, lactobacilli, diphtheroids, Escherichia coli, genital mycoplasma, , Bacteroides sp and other anaerobes.

Following a CS – Organisms to cover would be Staphylococci, Streptococci, Enterococci, Lactobacilli, Diptheroids, E.coli, Anaerobic streptococci, Bacteroides and Fusobacterium spp. A meta-analyses showed that prophylaxis is definitely recommended and reduces fever, endometritis, SSI, UTI etc [Hofmeyr GJ, Smaill F. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev 2002; 3: CD000933]

The common organisms causing sepsis in gynaecologic surgery are polymicrobial and include enterococci, aerobic gram negative bacilli, gram positive cocci, Bacteroides spp and other anaerobes. Antibiotic resistant organisms include methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE), and extendedspectrum beta-lactamase-producing organisms. For majority of SSI, the endogenous flora of the vagina or the skin are responsible. Aerobic gram positive cocci, like staphylococci, are causative agents in majority of the cases but faecal flora (Enterobacter spp and E coli) may also contribute when the incision is near the perineum or groin.

Multicenter, randomized, double blind, active- and placebo-controlled study compared single doses of ampicillin, cefazolin, and placebo administered to women undergoing elective total abdominal hysterectomy at two centers in Thailand. The study found a significantly lower rate of infection, including superficial and deep SSIs, urinary tract infections, vaginal cuff infection, and pneumonia, with cefazolin (10.3%) compared with placebo (26.9%) and ampicillin (22.6%).[Chongsomchai C, Lumbiganon P, Thinkhamrop J et al. Placebo-controlled, double-blind, randomized study of prophylactic antibiotics in elective abdominal hysterectomy. J Hosp Infect 2002; 52:302–306.]

The staphylococci may be MSSA (methicillin senstitive Staphylococcus aureus) or MRSA, the latter more likely when the patient is referred after treatment at some other health care facility. During procedures like hysterectomy, which involve opening of the vaginal cuff, the surgical site may be exposed to a variety of anaerobes and aerobes from the vaginal microflora. There is evidence that the cervical region and surrounding uppermost part of vagina has less number of anaerobes and aerobes of proteobacteria which are responsible for majority of infections.

Common pathogens causing pelvic inflammatory disease (PID) are, C. trachomatis, N. gonorrhoeae, Bacteroides, peptostreptococci, mycoplasma, Gardnerella vaginalis, Haemophilus influenzae, enteric Gram-negative rods, Streptococcus agalactiae and anaerobes. Common pathogens causing vaginitis are candida species, Trichomonas vaginalis and organisms causing bacterial vaginosis like Gardnerella, peptostreptococci, Bacteroides, anaerobes, ureaplasma and mycoplasma. Common pathogens causing cervicitis are chlamydia and N. gonorrhoeae.

Investigations:

Blood culture and other samples are guided by clinical suspicion of focus of infection, such as mid-stream urine, vaginal swab, cervical swab, throat swab, placental swabs, sputum, cerebrospinal fluid, epidural site swab, caesarean section or episiotomy site wound swabs should be obtained prior to starting antibiotics. Antibiotics should be given as soon as possible. Results of laboratory tests should be checked and the microbiologist consulted to ensure optimum antimicrobial therapy.

Resistance pattern of common pathogens: in % susceptible (ICMR data 2014)

Enterobacteriaceae

Amikacin	53
Cefepime	17
Cefoperazone/Sulbacta m	40
Cefotaxime	13
Ceftazidime	14
Chloramphenicol	72
Ciprofloxacin	35
Colistin*	96
Gentamicin	46
Imipenem	71
Meropenem	46
Piperacillin/Tazobactam	42
Tetracycline	55
Ertapenem	48

Staphylococcus aureus

Ciprofloxacin	68
Erythromycin	58
Clindamycin	68
Cefoxitin	51
Netilmicin	99
Vancomycin	100
Teicoplanin	100

Pseudomonas aeruginosa

Amikacin	93
Ceftazidime	68
Cefepime	51
Pip-taz	99
Imipenem	83
Cefoperazone	68
Meropenem	70
Cefo-sulbactam	56
Colistin	100
Ciprofloxacin	80

Acinetobacter baumannii

Amikacin	18
Cefepime	2
Cefoperazone/Sulbacta m	10
Cefotaxime	6
Ceftazidime	2
Chloramphenicol	26
Ciprofloxacin	10
Colistin	100
Imipenem	41
Meropenem	46
Piperacillin/Tazobactam	11
Tetracycline	32
Tobramycin	36
Ampicillin/Sulbactam	21
Ertapenem	0
Gentamicin	18

Antibiotic prophylaxis regimens:

I. Obstetrics:

a. Vaginal Delivery: Antibiotics are not routinely recommended. Women who do not know their Group B streptococcus (GBS) status are given antibiotics in situations mentioned in table II.

Antibiotic regimens:

• Ampicillin 2 gm I V initial dose followed by 1gm IV 4-6 hrly till delivery for GBS prophylaxis. If allergic, Vancomycin 1 gm IV 12 hrly


• Third / fourth degree perineal tear: Single dose Cefotetan or Cefoxitin 1 gm IV, after sensitivity testing (or clindamycin 600-900 mg IV , if allergic). The alternates are: IV cefuroxime 1.5 gm plus metronidazole 500 mg or IV amoxicillin-clavulanic acid 1.2 gm.

b. Preterm pre-labour rupture of membranes: Ampicillin 2 gm followed by 1 gm IV 4- 6 hourly for 48 hours followed by oral amoxycillin for 5 days PLUS oral erythromycin stearate 250-500 mg 6th hourly for 7 days.

c. Caesarean Delivery: Antibiotic prophylaxis is recommended for all caesareans

• Single dose of first generation cephalosporin, iv Cefazolin, 2 gm, within 60 minutes before incision. Minimum interval before incision should be 15 min, preferably 30 min


• If allergic to Cefazolin, give single dose of iv Clindamycin 600-900 mg + Gentamicin 80 mg

After single dose, therapeutic drug level is maintained for 3-4 hrs; repeat dose if duration of surgery is >3 hrs or blood loss is >1500 ml. Cefazolin prophylaxis is recommended even for those receiving ampicillin during labour for GBS prophylaxis. This is because ampicillin is less effective against MSSA, the chief cause of SSI, due to beta lactamase production. If the patient is already receiving appropriate antibiotics (e.g., for chorioamnionitis), then cefazolin prophylaxis may be omitted.

d. Rescue cervical encerclage: Ampicillin 2 gm IV single dose to reduce the risk of infection due to exposed membranes in the vagina.

II. Gynaecological Surgery

a. Hysterectomy and surgeries for pelvic organ prolapse and/or stress urinary incontinence: All women undergoing laparoscopic / vaginal / abdominal hysterectomy (VH, AH), or surgery for stress urinary incontinence should receive prophylactic antibiotics.

• Single dose of cefazolin 2 gm IV. Dose is 3 gm if weight is >100 kg. The alternate is a second-generation cephalosporin like cefuroxime.


• If allergic to cephalosporins, use Clindamycin 600 mg IV


• Administer 15 to 60 minutes prior to incision. Additional dose is given 3 hours after the initial dose if surgical procedure is lengthy (e.g. >3 hours), or blood loss is >1500 mL


• Give oral metrogyl 500 mg BD x 7 days, starting at least 4 days before surgery, to prevent post-operative vaginal cuff infection if there is evidence of bacterial vaginosis.

b. Other gynaecological procedures:

• Laparoscopy (uterus and/or vagina not entered) / Hysteroscopy / Ectopic pregnancy: Single dose of Cefazolin 1 gm IV (if allergic, use clindamycin 600 mg). Alternate is a second-generation cephalosporin like cefuroxime. Give oral doxycycline 100 mg twice daily for 5 days post-operatively if there is history of PID or if fallopian tubes are dilated at procedure.


• Abortions: Women undergoing an induced abortion (surgical or medical) must receive antibiotics effective against Chlamydia trachomatis and anaerobes. There is no need of antibiotics following curettage for a missed or incomplete abortion. Regimens: doxycycline 100 mg oral twice daily for 7 days, starting on day of abortion, plus metronidazole 800 mg oral at time of abortion OR azithromycin 1 g oral plus metronidazole 800 mg oral at time of abortion


• HSG: oral doxycycline 100 mg prior to procedure, to be continued twice daily for 5 days if there is history of PID or fallopian tubes are found dilated at procedure

III. Emergency area (septic cases)

a. Puerperal sepsis / Septic induced abortion / chorioamnionitis: Inj. Piperacillin + Tazobactam 4.5 gm IV 8 hrly X 7-14 days. If patients have received antibiotics elsewhere OR have septic shock OR are intubated, consider optimum and appropriate antibiotics like Vancomycin , Imipenem and Teicoplanin to cover MRSA. Important to consider and cover C. sordelli and C. perfringens

Table I Antimicrobial spectrum of AMAs:

Antimicrobial drug	Organisms sensitive	Organisms resistant
Ampicillin	Gram positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes, some isolates of Staphylococcus aureus (but not penicillin-resistant or methicillin-resistant strain), and some Enterococci. Gram negative bacteria: Neisseria meningitidis, some strains of Haemophilus influenzae, and Enterobacteriaceae Actinomyces spp.	MSSA, MRSA
Cefazolin	MSSA, Aerobic gram positive (S. aureus, S. epidemidis, S. pyogenes, S. pneumoniae), Aerobic gram negative if not ESBL or CRE (E. coli, Proteus) ESBL: Extended Spectrum Beta Lactamase producing Bacteria CRE: Carbapenem Resistant Enterobacteriaceae	MRSA, Enterococci, anaerobes
Cefuroxime	Aerobic gram positive (pneumococci, S. pyogenes, S. aureus), aerobic Gram negative if not ESBL or CRE (E. coli, H influenzae, K. pnemoniae, N. gonorrhoeae)	MRSA, Enterococci, anaerobes
Cefotetan	Like second generation: additional = anaerobes: Bacteroides
Metronidazole / Tinidazole	Broad array of gut anaerobes, protozoa, and microaerophilic bacteria. Bacteroides spp, Clostridium spp, Prevotella spp, Porphyromonas sp p, Fusobacterium spp, Clostridium spp Also anaerobic protozoa: T. vaginalis, E.histolytica, Giardia lamblia, Blastocystis hominis, Balantidium coli	Propionibacterium acnes, and Lactobacillus spe cies are resistant to metronidazole
Piperacillin + Tazobactum	MSSA, Coagulase negative Staphylococci if Methicillin susceptible, Streptococcus pneumoniae (penicillin susceptible), Streptococcus spp., Haemophilus influenzae, Neisseria gonorrhoeae, Enterobacteriaceae, E. coli, Pseudomonas aeruginosa	MRSA
Clindamycin	Staphylococci, Streptococcus viridans, Streptococcus pyogenes, and Streptococcus pneumoniae Potent activity against anaerobes such as B. fragilis, Clostridium perfringens, Fusobacterium spp, Prevotella melaninogenicus, Peptostreptococcus spp, Actinomyces spp	H. influenzae, enterococci, Neisseria meningitides, Mycopla sma pneumoniae and aerobic g
Vancomycin	MRSA

Table 2 Summarizing use of Anti Microbial Agents (AMA) in Obstetrics & Gynaecology

S. no.	Clinical condition / procedure	Common pathogens	Preferred AMA	Alternate AMA	Comments
1.	Vaginal delivery: For GBS (Group B Streptococcus) prophylaxis in women who do not know their GBS status in the following situations: Preterm labour (< 37 wks) Prolonged rupture of membranes (>18 hrs) Fever during labour or chorioamnionitis History of previous baby with GBS infection Bladder or kidney infection due to GBS	Group B Streptococci	Ampicillin 2 gm IV followed by 1gm IV 4-6 hrly till delivery	Cefazolin 2 g IV followed by 1 g 8 hrly till delivery If allergic, Vancomycin 1 gm IV 12 hrly till delivery	Not recommended routinely for normal vaginal delivery Delivery is considered akin to drainage of an abscess as the fetus and placenta is removed which are the nidus of infection
2.	3rd or 4th degree Perineal tear	Gram positive Staph. aureus, Gram negative Enterobacteria ceae, Anaerobes	Single dose cefoxitin or cefotetan 1gm IV	Single dose Cefazolin 1 gm IV plus metronidazole 500 mg IV OR single dose IV cefuroxime 1.5 gm plus metronidazole 500 mg IV OR single dose IV 1.2 gm amoxicillinclavulanic acid . if allergic, single dose IV clindamycin 600- 900 mg	Prophylaxis is considered to prevent adverse outcomes arising from infection eg fistulas
3.	Preterm pre-labour rupture of membranes	Gram positive GBS Gram negative: Enteric gramnegative bacilli, Ureaplasma, mycoplasma Anaerobes (including G. vaginalis),	IV Ampicillin 2 gm followed by 1 gm 4-6 hourly for 48 hours followed by oral amoxycillin 500 mg 8 hourly for 5 days PLUS oral erythromycin 333 mg 8 hourly for 7 days	If erythromycin 333 mg is not available, use erythromycin stearate 250 mg 6 hourly for 7 days
4.	Caesarean delivery	Gram positive aerobes: GBS, Staphylococci, enterococci, Gram negative Aerobes: E. coli, Klebsiella, Proteus Anaerobic Gram-positive cocci Peptococci, peptostreptoco cci Anaerobic Gramnegative bacilli: Bacteroides, Prevotella spp. Facultatively anaerobic Gram-variable rod: G. vaginalis	Single dose cefazolin 2gm IV Dose is 3gm if patient is >100kg	If allergic, single dose clindamycin 600-900 mg IV + Gentamicin 1.5mg/kg IV	Puerperal endometritis is polymicrobial, (aerobic– anaerobic). These organisms are part of vaginal flora and are introduced into the upper genital tract coincident with vaginal examinations during labour and/or instrumentation during surgery Tita et al showed the addition of 500-mg azithromycin to cefazolin for cesareans (in labor or with membranes ruptured) reduced Endometritis & wound infection significantly (6.1% vs. 12.0%, P<0.001), endometritis (3.8% vs. 6.1%, P=0.02) wound infection (2.4% vs. 6.6%, P<0.001).
5.	Rescue cervical encerclage	Vaginal flora	Inj Ampicillin 2 gm single dose		To prevent ascending infection from vaginal flora to exposed membranes
6.	Puerperal sepsis / Septic abortion / chorioamnionitis	Gram positive: Streptococci (A,B,D), Staph. aureus Gram negative: E.coli, Enterobacteria ceae including Klebsiella, Enterobacter, Citrobacter, Pseudomonas aeruginosa, Proteus mirabilis, Gardnerella vaginalis, Bacteroides Clostridium perfringes, Anaerobes	Inj. Piperacillin + Tazobactem 4.5 gm IV 8 hrly X 7-14 days	Clindamycin 600-900 mg IV 8 hourly+ Gentamicin 60 mg IV 8 hourly+ metronidazole 500 mg IV 8 hourly Or Ampicillin-Sulbactam 3 g IV Q6H	Usually antimicrobial
7.	Hysterectomy (AH, VH, Laparoscopic) and surgeries for pelvic organ prolapse and/or stress urinary incontinence	Polymicrobial: Gram positive: Staphylococci, Gram Negative: enterococci, aerobic gram negative, Anaerobes Bacteroides spp,	Cefazolin 2 gm IV single dose Dose is 3 gm if patient is >100kg	Cefuroxime 1.5 g IV single dose OR If allergic to cephalosporin, Clindamycin 600 -900 mg IV + gentamicin 1.5mg/kg IV	In AH & LH, vagina is opened at end of procedure & exposure to vaginal flora is brief. In VH, there is greater colonisation of surgical site. In AH for cancer with resection of upper vagina, there may be colonization with anaerobes. In such cases, metronidazole 500 mg IV may be added. If BV is suspected, oral metronidazole 500 mg BD for 7 days is given, beginning at least 4 days pre-op
8.	Laparoscopy (uterus and/or vagina not entered) / Hysteroscopy / Ectopic pregnancy	Skin commensals: Staph. aureus	Cefazolin 1 gm IV single dose.	Cefuroxime 1.5 g IV sinlge dose If allergic, use IV clindamycin 600 mg
9.	Abortions (medical and surgical)	Chlamydia, Neisseria gonorrhoeae	Azithromycin 1 g orally plus metronidazole 800 mg orally at time of abortion	Doxycycline 100 mg orally twice daily for 7 days, starting on day of abortion, plus metronidazole 800 mg orally at time of abortion	No prophylaxis for missed / incomplete abortion
10.	HSG	Chlamydia, Neisseria gonorrhoeae	Doxycycline 100 mg orally before procedure		Doxycycline continued twice daily for 5 days if there is history of PID or fallopian tubes are dilated at procedure
11.	Pelvic Inflammatory disease (mild to moderate)	N. gonorrhoeae, C. trachomatis and anaerobes E. coli, Bacteroides GBS, GAS, S. aureus, respiratory pathogens (eg, H. influenzae, S. pneumoniae,	NACO: Tab. Cefixime 400 mg orally STAT PLUS Tab. Metronidazole 400 mg BD X 14D PLUS Cap. Doxycyline, 100 mg bd X 14 D	CDC: Levofloxacin 500 mg OD X 14 days OR Ofloxacin 400 mg OD X 14 days With or without Metronidazole 500 mg BD X 14 days OR Ceftriaxone 250 mg IM single dose plus Doxycycline orally 100 mg BD X 14 days with or without Metronidazole 500 mg BD X 14 days
12	Pelvic Inflammatory disease (severe) eg tubo-ovarian abscess, pelvic abscess		Cefotetan 2 g IV BD PLUS doxycycline 10 0 mg orally or IV BD	Cefoxitin 2 g IV every 6 hours PLUS Doxycycline 100 mg orally or IV every 12 hours OR Clindamycin 900 mg IV every 8 hours PLUS gentamicin loading dose IV or IM (2 mg/kg), followed by maintenance dose (1.5 mg/kg) every 8 hours. Single daily dosing (3– 5 mg/kg) can be substituted	An attempt should be made to obtain cultures and deescalate based on that. Duration is two weeks, but can be extended depending upon clinical situation. Antibiotics may be altered after obtaining culture reports of pus/or blood
13.	Vaginal candidiasis	C. albicans, C. glabrata, C. tropicalis	Tab Fluconazole 150 mg orally single dose OR local Clotrimazole 500 mg vaginal tablet once only	Miconazole, nystatin vaginal tablets/creams	Treat for 7 days in pregnancy, diabetes Recurrent infections: 150 mg Fluconazole on day 1,4,7 then weekly for 6 months
14.	Vaginal trichomoniasis	T. vaginalis	Tab.Secnidazo le 2 gm oral, single dose OR Tab. Tinidazole 500 mg orally, twice daily for 5 days OR Tab. Metronidazole 400 mg, twice daily for 7 days		Alcohol avoided during treatment and 24 hours after metronidazole or 72 hours after completion of tinidazole to reduce possibility of disulfiram-like reaction. Partner treatment essential
15.	Bacterial vaginosis	Overgrowth of anaerobes (Gardnerella vaginalis)	Metronidazol e 400 mg orally BD X 7 days OR Metronidazol e gel 0.75%, one applicator (5 g) intravaginal x 5 days OR clindamycin Cream 2%, one applicator (5 g) intravaginal x 7 days	Secnidazole 2 g orally OD X one day OR Tinidazole 2 g orally OD X 2 days OR Tinidazole 1 g orally OD X 5 days OR clindamycin orally 300 mg BD X 7 days OR clindamycin ovules 100 mg intravaginally OD HS for 3 days*	Refrain from sexual activity or use condoms during the treatment. Clindamycin cream is oil-based and might weaken latex condoms

Guidelines by Indian Council of Medical Research :

Dr Soumya Swaminathan, Director General, Indian Council of Medical Research Secretary, Department of Health Research