Antibiotic Use in Chorioamnionitis November 2, 2015 Lindsay Waddington, - PowerPoint Presentation

Antibiotic Use in Chorioamnionitis November 2, 2015 Lindsay Waddington, PharmD PGY1 Pharmacy Resident

Objectives Define histological and clinical chorioamnionitis Identify risk factors for chorioamnionitis Explain the benefits of extended interval high dose gentamicin as compared to traditional dosing for pregnant patients Recognize when a neonate is at risk for gentamicin toxicity

Pharmacokinetics in Pregnancy Increased volume of distribution Plasma volume increases 50% Increased creatinine clearance and glomerular filtration rate Mean serum creatinine 0.5mcg/dL versus 0.7mcg/dL in non-pregnant patients Obstet Gynecol. 2005;105(7):473-479.; Obstet Gynecol 2010;115:344-349.; Clin Obstet Gynecol. 2008;51(3):498-506. Gentamicin Half-life 1.5 to 2 hours during pregnancy and labor 2 to 4 hours after delivery

Pharmacokinetics of Neonates Reduced clearance Increased volume of distribution Considerable inter-patient variability Gestational age (GA) is strongly related to glomerular filtration J Antimicrob Chemother . 2006;58:372-379.; Obstet Gynecol. 2005;105(7):473-479.

Let’s Pretend… CA is a 27yo female presents at 32 weeks gestation, complaining of increased uterine tenderness and pelvic pressure, feeling warm, and overall fatigue Vitals: Temp 102°F, HR 111, RR 18, BP 122/85

Someone on the team mentions… Chorioamnionitis

Chorioamnionitis Intra-amniotic infection Acute inflammation of the placental membranes Amnion (inner membrane) Chorion (outer membrane) Obstet Gynecol Clin N Am. 2005;32:287-296 .; J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol . 2010;37(2):339-354 .; Clin Perinatol . 2015;42:155-165 .

Significance Increasing incidence with lower gestational age Chorioamnionitis complicates 1-4% of all births 40-70 % of preterm births1-13% term births12% of cesarean deliveriesAssociated with increased neonatal mortality Obstet Gynecol 2010;115:344-349.; Clin Perinatol. 2010;37(2):339-354.

Classification Histological Chorioamnionitis Microscopic evidence of inflammation Culture positive amniotic fluid Clinical ChorioamnionitisLocal and systemic inflammationDiagnosis based on clinical criteria J Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2015;42:155-165.

Clinical Diagnostic Criteria Maternal fever (>101°F or >100.4°F for >1 hour) Plus one of the following Maternal leukocytosis >15K cells/mcLMaternal tachycardia >100/minFetal tachycardia >160/min Uterine tenderness Foul smelling or purulent amniotic fluidObstet Gynecol Clin N Am. 2005;32:287-296; Obstet Gynecol 2010;115:344-349 .; J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol . 2010;37(2):339-354.; Semin Fetal Neonatal Med. 2012;17:46-50.

Differential Diagnosis Labor (leukocytosis, tachycardia, “tenderness”, fever) Maternal systemic infection Urinary tract infection Upper respiratory infection BacteremiaFever related to drug administrationEpidural anesthesia

Common Pathogens Obstet Gynecol Clin N Am. 2005;32:287-296.; Clin Perinatol. 2010;37(2):339-354. PathogenIncidenceUreaplasma urealyticum 47% Mycoplasma hominis 30% Bacteroides 30% Gardnerella vaginalis 25% Group B streptococci 15% Escherichia coli 8%

Celebration of Knowledge A 27yo F 32 weeks gestation complaining of uterine tendernessWhat is your presumptive diagnosis as a pharmacist?A) No chorioamnionitisB) Histological chorioamnionitisC) Clinical chorioamnionitis Tmax 102°F BP 116/72 HR 109 (Fetal HR 145)

Mechanism of Infection Clin Perinatol . 2010;37(2):339-354.

Risk Factors Risk Factor Relative Risk Alcohol and tobacco use 7.9Prolonged Rupture of Membranes >18H6.9Epidural anesthesia 4.1 Prolonged Labor >12H 4.0 Multiple digital exams with rupture of membranes 2 to 5 GBS colonization 1.7 to 7.2 Internal monitoring 2.0 Meconium-stained amniotic fluid 1.4 to 2.3 Nulliparity 1.8 Bacterial vaginosis 1.7 J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol . 2010;37(2):339-354 .; Semin Fetal Neonatal Med. 2012;17:46-50 .

Celebration of Knowledge Which of the following is NOT a risk factor for chorioamnionitis ?A) Multiple digital examsB) History of previous term gestationsC) Prolonged laborD) Premature rupture of membranes E) History of smoking, drug, or alcohol abuse

So what does this mean for mom?

Maternal Complications Cesarean s ection Complications ( endomyometritis, pelvic abscess, wound infection, thromboembolism, bacteremia)Post partum hemorrhageAbnormal response to oxytocinLack of progression of laborPlacental abruptionSepsis J Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354.; Semin Fetal Neonatal Med. 2012;17:46-50.

Treatment Overview J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol. 2010;37(2):339-354.

Antibiotic Treatment for Mom Ampicillin 2g IV every 6 hours PLUS Gentamicin 1.5mg/kg IV every 8 hours OR Gentamicin 5mg/kg IV every 24 hoursJ Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354.

Which dose do you choose?

Closer Look at Aminoglycosides Gram negative bacteria (synergistic activity for some gram positive organisms) Concentration dependent Peak/MIC Post antibiotic effect (reduced adaptive resistance) 8th Cranial nerve toxicity Manifests as ototoxicity and/or vestibular imbalanceUsually permanent NephrotoxicityUsually reversibleObstet Gynecol. 2005;105(7):473-479.; Clin Obstet Gynecol. 2008;51(3):498-506.; Gentamicin. [package insert] Baxter 2012.

High Dose/Extended Interval Gentamicin Obstet Gynecol 2010;115:344-349. Lyell et al.DesignRandomized, double-blind, noninferiority trial Primary Outcome Maternal or neonatal morbidities Population 126 women with chorioamnionitis 32 to 42 weeks gestation Intervention 63 received gentamicin 5mg/kg IV Q24 hours 63 received gentamicin 1.5mg/kg IV Q8 hours *both arms also received ampicillin 2g every 6 hours and clindamycin 900mg IV every 8 hours if cesarean delivery Outcome No difference in maternal or neonatal morbidities (P=0.53)

High Dose/Extended Interval Gentamicin Traditional: 1.5mg/kg IV Q8 hours High dose/extended interval: 5mg/kg IV Q24 hours High dose/extended interval More effective (higher peaks from higher dose) More convenient (single daily dose)More cost-effective (fewer preparations and administrations)Less toxic (less drug accumulation) Obstet Gynecol. 2005;105(7):473-479.; Obstet Gynecol 2010;115:344-349.

Type 1 Penicillin Allergy Clindamycin 900mg IV every 8 hours PLUS Gentamicin 5mg/kg IV every 24 hours J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol. 2010;37(2):339-354.

Cesarean Section Add on coverage for anaerobes Non-penicillin allergic patient Clindamycin 900mg every 8 hours (Metronidazole 500mg every 8 hours) Penicillin allergic patientNo change if already on clindamycinJ Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354.

Celebration of Knowledge Why is high dose gentamicin utilized in practice? Less risk of toxicity Fewer administrations Reduced cost Similar efficacy as traditionalAll of the above

When to administer antibiotics?

Intrapartum Antibiotics Obstet Gynecol. 1988;72(6):823-828. Gibbs et al. Design Randomized trialPrimary Outcome Development of neonatal sepsis or pneumonia Population 45 women (>34 weeks gestation) with pregnancy complicated by chorioamnionitis Intervention 19 mothers received postpartum antibiotic 26 mothers received intrapartum antibiotics

Intrapartum Antibiotics Outcome Intrapartum dosing n=26 Postpartum dosing n=19P-valueDevelopment of neonatal sepsis04 0.03 Neonate l ength of stay 3.8 ± 1.1 5.7 ± 3.0 0.02 Number of febrile days 0.44 ± 0.7 1.5 ± 2.1 0.05 Administration of antibiotic for chorioamnionitis during labor results in improved outcomes Obstet Gynecol. 1988;72(6):823-828.

Antibiotic Agents Summary Most studied regimen Ampicillin 2g IV Q6 hours plus gentamicin 1.5mg/kg IV Q8 hours Most utilized regimen Ampicillin 2g IV Q6 hours plus high dose gentamicin 5mg/kg IV Q24 hours Cesarean section (add anaerobic coverage)Clindamycin 900mg IV Q8 hours or metronidazole 500mg Q8 hoursPenicillin allergyClindamycin 900mg IV Q8 plus gentamicin J Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354.; Semin Fetal Neonatal Med. 2012;17:46-50.

Supportive Care Pain management Antipyretic therapy (acetaminophen) Reduce hyperthermic stress on the fetusReduce tachycardiaMinimize risk for cesarean section due to fetal distressFluids Clin Perinatol. 2010;37(2):339-354.

Induction or Augmentation of Labor Induction of vaginal birth Cesarean section if complications arise Labor not progressing, non reassuring fetal statusAverage time from diagnosis to delivery is 3-5 hoursImproved outcome as long as mom receives at least 1 dose prior to deliverySingle dose after delivery (<5%) failure rateContinuation of antibiotics for mom post delivery not recommended Obstet Gynecol. 1988;72(6):823-828.; Clin Perinatol. 2010;37(2):339-354.

Treatment Overview J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol. 2010;37(2):339-354. Questions?

Bugs vs. Drugs Mismatch? Gentamicin plus ampicillin No genital mycoplasma coverage Pathogen Incidence Ureaplasma urealyticum47%Mycoplasma hominis 30% Bacteroides 30% Gardnerella vaginalis 25% Group B streptococci 15% Escherichia coli 8%

What does chorioamnionitis mean for baby?

Preterm Birth Clinical chorioamnionitis Membrane injury Induction of labor J Matern Fetal Neonatal Med. 2012;25(S4): 29-31.; Clin Perinatol . 2010;37(2):339-354 .; Semin Fetal Neonatal Med. 2012;17:46-50 . Presence of infection Maternal Inflammatory Response Release of cytokines and chemokines

Neonatal Complications Funisitis Preterm birth Chronic lung disease Intraventricular hemorrhage Cerebral white matter injuryNeonatal sepsisAdministration of appropriate antibiotics can reduce risk up to 80%Pneumonia Perinatal deathJ Pregnancy. 2013;2013:412831.; J Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354 .; Clin Perinatol . 2015;42:155-165 .; Semin Fetal Neonatal Med. 2012;17:46-50 .

Neonatal Sepsis Common pathogens Group B Streptococcus Escherichia coli Listeria monocytogenesClinical SignsRespiratory distress, irritability, hypothermia, acidosis, apnea, cyanotic spells, poor feeding, fever, tachycardia, and lethargyDiagnosisBlood cultures, WBC with differential, CRP J Pregnancy. 2013;2013:412831.; J Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354.; Clin Perinatol . 2015;42:155-165 .; Semin Fetal Neonatal Med. 2012;17:46-50 .

Bugs vs. Drugs Mismatch? Ampicillin and gentamicin cover neonatal sepsis pathogens Drugs do not concentrate well in the amniotic fluid Drugs CAN enter fetal circulationToo late to treat for chorioamnionitis bugsTry to prevent neonatal sepsis

Treatment of Neonatal Sepsis Within 1 to 2 hours of birth Ampicillin 50mg/kg frequency based on gestational age Gentamicin 4mg/kg Q24 hoursDuration for confirmed sepsis: minimum of 10 days J Pregnancy. 2013;2013:412831.; J Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354.; Clin Perinatol . 2015;42:155-165 .; Semin Fetal Neonatal Med. 2012;17:46-50 .

Gentamicin Toxicity Gentamicin crosses the placental barrier Measurable amounts in neonatal serum Estimate f etal levels to be 34% to 42% of maternal levelsTarget troughs <2mcg/mLNephrotoxicity due to sustained trough levels rather than transient peaksOtotoxicity associated with persistently elevated peaksExcreted via glomerular filtration J Antimicrob Chemother. 2006;58:372-379.; Obstet Gynecol. 2005;105(7):473-479.; Clin Obstet Gynecol. 2008;51(3):498-506 .; Gentamicin .[ package insert] Baxter 2012.

Gentamicin Crossing the Placental Barrier Locksmith et al. 2005 Design Prospective, randomized Primary Outcome Umbilical cord gentamicin concentration at delivery Population 38 women at least 34 weeks gestation Intervention 20 women received gentamicin 120mg then 80mg Q8 hours 18 women received gentamicin 5.1mg/kg Q 24 hours (high dose) Obstet Gynecol. 2005;105(7):473-479.

Obstet Gynecol. 2005;105(7):473-479. High dose/extended interval gentamicin produced adequate concentrations in both mom and baby Outcome Traditional dosing n=20High dose n=18 Median maternal peak 7.1mcg/mL 18.2 mcg/mL Time to <2mcg/mL 5 hours 10 hours Extrapolated fetal peak * 2.9mcg/mL 6.9mcg/mL Gentamicin Crossing the Placental Barrier *( based on umbilical level at delivery)

Alternative to Gentamicin Cefotaxime 50mg/kg/day divided every 4 to 6 hours if at risk for gentamicin toxicity Pediatrics.  2006 Jan;117(1):67-74. Clark et al. DesignRetrospective database review Primary Outcome Evaluate outcomes for 2 different antibiotic regimens within the first 3 days of life Population 128,914 neonates Findings Adjust odds ratio for death comparing neonates who were empirically treated with ampicillin/cefotaxime to ampicillin/gentamicin 1.5 (95% CI 1.4-1.7)

Alternative to Gentamicin Pediatrics.  2006 Jan;117(1):67-74. Ampicillin and Cefotaxime N=24,111 Ampicillin and GentamicinN=104,803Relative RiskLiver dysfunction 96 (0.398%) 158 (0.151%) 2.6 Renal failure 237 (0.983%) 394 (0.376%) 2.6 Cardiac arrest 154 (0.639%) 287 (0.247%) 2.3 Coagulopathy 310 (1.286%) 609 (0.581%) 2.2 Disseminated intravascular coagulation 131 (0.543%) 269 (0.257%) 2.1 Renal dysfunction 189 (0.784%) 39 (0.381%) 2.1

Celebration of Knowledge Upon delivery complicated by chorioamnionitis a gentamicin level drawn from baby is 2.4mcg/ mL. MD would like to start empiric antibiotics to cover for neonatal sepsis. You recommend ampicillin 50mg/kg Q12H and:A) C efotaxime 50mg/kg/day divided Q4 to 6 hours because gentamicin trough is high and baby is at risk for toxicityB) Gentamicin 5mg/kg Q24 because trough is below toxicity level C) Gentamicin 1.5mg/kg Q8 because trough is high

Other considerations

Prevention Prolonged premature rupture of membranes without signs and symptoms of chorioamnionitis 7-10 days of antibiotics (1-2 days of IV followed by oral therapy) Ampicillin Macrolide (erythromicin or azithromycin)Goals of therapyReduced incidence of chorioamnionitisProlong time to deliveryImprove neonatal outcomesDecrease use of surfactant and oxygen therapyJ Matern Fetal Neonatal Med. 2012;25(S4):29-31.; Clin Perinatol. 2010;37(2):339-354 .

Other considerations Upon delivery we have to draw a level from baby Limited blood supply Early trauma Waiting for levels delays administration of antibiotics

Remaining questions?

What if… …there was a predictive model to determine if baby’s gentamicin level is >2mcg or <2mcg Predictable kinetics in adults (Hartford nomogram) Rumack -Matthew diagram for acetaminophen toxicity Consider time from administration to delivery, gestational age, total time since administration, mom’s SCr, baby’s birth weight, mom’s weight/total dose given

Rumack-Matthew Nomogram Gentamicin Administration Gentamicin Nephrotoxicity Nephrotoxicity

Key Points Chorioamnionitis can lead to preterm birth and neonatal sepsis Numerous risk factors for chorioamnionitisAdministration of antibiotics can improve both maternal and neonatal outcomesTreat with ampicillin and high dose gentamicinGentamicin has a risk of 8th cranial nerve toxicity and nephrotoxicity

Thank you

Antibiotic Use in Chorioamnionitis November 2, 2015 Lindsay Waddington, PharmD PGY1 Pharmacy Practice Resident