Intraamniotic Infections: A major factor in preterm delivery

IIDNI

infectious Diseases Newsletter Volume 12, Number 10/11, October/November 1993

Editor

Associate Editors

Charles W. Stratton, IVlD

Charles E. Cherubin, MD

Richard E Jacobs, MD

I)epaament of Pathology Vandetbilt University Medical Center Nashville, Tennessee

Veterans Administration Medical Center Wilkes-Barre, Pennsylvania

Arkansas Children's Hospital Little Rock, Arkansas

Roger G. Finch, FRO', FRCI~, F F I ~

John T. Sinnott IV,

Nottingham City Hospital Nottingham, United Kingdom

University of South Florida Tampa, Florida

H. Bradford Hawley, MD

Philippe Van der Auwera, MD,PhD

Wright State School of Medicine Dayton, Ohio

Institut Jules Bordot Brussels, Belgium

)lilclll~

Intraamniotic Infections: A Major Factor in Preterm Delivery 73 John N. Greene David Rmkein Elizabeth A. Bradley Rebecca N. Stem John T. Sinnott The Differential Diagnosis of Ciostridial Soft Tissue Infections 76 Paul Valenstein Diarrhea Caused by an Unidentified Spirochete in a Patient with Acquired lmmunodeficiency Syndrome (AIDS) 79 Paul A. H¢llstern, Jr. John S. Czachor Streptococcus defectivus Endocarditis Robert D. Walsh

81

CraigVogel Burke A. Cunha Fatal Citrobocter freundii Bac~teremia Diane H. Johnson Burke A. Cunha

Elsevier 0278-2316/93/$0.00 + 6.00

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Intraamniotic Infections: A Major Factor in Preterm Delivery John N. Greene, MD, David Roskein, BS, Elizabeth A.

Bradley, BA,

R e b e c c a N . Stem, B A , J o h n T. S i n n o t t , M D Universityof SouthFlorida,Tampa.Florida

An intraamniotic infection causes serious complications for both the mother and the neonate. Methods for the early detection of the entity causing such an infection promise to reduce much morbidity and mortality. Evaluation of each test and outcome is necessary to determine appropriate Ireatment. Prematurity is the leading cause of perinatal morbidity and mortality. Intraamniotic infections initiate preterm labor and birth with resultant increases in maternal and perinatal morbidity as well as neonatal mortality. Though referred to by many names ineluding clinical chorioamnionitis, amnionitis, intrapartum infection, and amniotic fluid infection, intraamniotic infections must always be recognized for their potentially serious consequences. InWaamniotic infection is a clinically detectable infection of the gravid uterus and its contents; it develops

when bacteria seed the amniotic fluid. By definition, clinical symptoms of this infection must include fever and one or more of the following: maternal tachycardia (>100 beaWmin), fetal tachycardia (>160 beats/rain), maternal leukocytosis (>15,000/mm3), foul amniotic fluid odor, or uterine tenderness. Studies in 1980 revealed the incidence of intraamniotic infection to <1%. However, more recent prospective studies report higher incidences ranging from 4.2% to 10.5%. The management of this syndrome ranges from antibiotics to emergent delivery. Prior to labor and rupture of membranes, the amniotic cavity normally contains no bacteria. Growth of bacteria is thought to be prevented by inhibiting factors in the cervical mucus, and the mechanical barriers of placental membranes and amniotic fluid. Bacteria breach these natural barriers by several mechanisms. The most 0278-2316 IDINDN 12(10/1I)73-84, 1993

74 InfectiousDiseases Newsletter 12(10/11) October/November 1993 common mechanism is pressure change caused by uterine wall contractions and relaxations during labor, which allow entrance of bacteria into the amniotic cavity from the lower vagina and cervix. Coitus during late pregnancy has also been implicated as a mechanism of bacterial spread by introducing new organisms into the vagina. The movement of sperm and seminal fluid through the cervix may act to facilitate this spread. Fetal scalp electrodes, internal pressure catheters, and multiple vaginal exams have been implicated in the spread of microorganisms as well. Other risk factors include length of labor and duration of time since membrane rupture. Risk also increases with gestational age, possibly from additional exposure to the cervical bacteria. Invasive procedures such as diagnostic amniocentesis, intrauterine transfusions, and placement of a cervical cerclage have been shown to increase the incidence of infection by 0.1%, 5%, and 1% to 2%, respectivdy. Finally, maternal bacteremia is an important route for the spread of Listeria monocytogenes, Streptococcus pyogenes (GAS), and Campylobacter spp.. Pelvic infections are polymicrobial in nature, involving both aerobic and anaerobic flora. Intmamniotic infections are no exception. In one controlled study, an average of 2.2 bacterial species were isolated from the amniotic fluid of patients with inlraamniotic infection. There appear to be two groups of associated microorganisms isolated from amniotic fluid. That is, when one organism is present, it is significantly more likely that another in its group will also be present. The first group is bacterial vaginosisassociated organisms such as Gardnerella vaginalis, Mycoplasma hominis, and anaerobes. The second

group consists of gut-associated organisms such as enterococci, E. coli, and miscellaneous aerobic Gram-negative bacilli. The species of bacteria most commonly found in the amniotic fluid are Bacteroides bivivus (25%), Streptococcus agalactaie (GBS)(12%), and E. coli (10%). GBS and E. coli are the leading causes of neonatal sepsis and meningitis. Though representing only 22% of the bacteria in amniotic fluid samples, they are responsible for 67% of maternal and neonatal bacteremia. Certain bacteria associated with chorioamnionitis, especially Ureaplasma urealyticum, GBS, E. coli, Fusobacterium spp., Bacteroides spp., and P eptostreptococcus spp., apparently trigger an inflammatory response that can lead to preterm labor and delivery. Two hypotheses have been proposed for the mechanism of this bacterial induction of labor. The first mechanism centers around bacterial production of phospholipase A2, which frees arachidonic acid. This product in turn activates the prostaglandin cascade, which culminates in uterine contraction. The second hypothesis suggests that bacterial endotoxin stimulates the decidual cells to release cytokines such as interleukin-I and tumor necrosis factor. These cytokines then initiate prostaglandin synthesis with subsequent uterine contraction. Tocolytic agents are ineffective in halting labor in this setting and preterm delivery usually ensues. Intraamniotic infections can lead to serious complications in both the neonate and the mother. These infections can cause placental villous edema, which results in decreased gas exchange. Consequential fetal hypoxia essentially doubles the risk for the development of respiratory distress syndrome in the neonate. Hypoxia can also disrupt regulation of cerebral cir-

culation, leading to intraventricular hemorrhage and periventricular leukomalacia. Other complications of intmamniotic infections such as pneumonia, enteritis, meningitis and even sepsis may develop in the fetus as a result of aspirating or of swallowing infected amniotic fluid. Perinatal mortality has been shown to be increased fourfold. Serious maternal complications can also occur. As the infection spreads outward from the amniotic cavity, the mother may develop endomyometritis, peritonitis, or sepsis. There is a fourfold increase in cesarean sections in patients with intraamniotic infections when compared to patients without intraamniotic infections. Intraamniotic infection is a clinical diagnosis based primarily on symptomatology. Of great concern is that only 12% of the patients with positive amniotic fluid cultures presenting with premature uterine contraction and intact membranes meet the clinical definition of intraamniotic infection. Asymptomatic patients with positive amniotic cultures are classified as having a subclinical intraamniotic infection and have a decidedly better prognosis for both mother and child. Since most patients present with only a few of the clinical signs, laboratory studies may provide a more accurate diagnosis. Biopsy of the amniotic membranes has been a technique previously advocated. However, it is risky, expensive, and labor intensive. Cultures of the amniotic fluid obtained through an intrauterine pressure catheter have also been used to identify patients at risk for intraamniotic infection. However, this lacks efficiency since culture results may take several days and prompt diagnosis is necessary for proper management. A third frequently used method

NOTE: No r©sponsibility ij ammmaed by the Pablinher for ~ny myery mid/or damage to per~as or ~ u a~ of ~ 1~, ~ ~ ~.. ~ , or ~ ~ ~ ~ ~ h,~.t of any i~Ta, products, instructions or ideas collaincd in the material herein. No suggested test or procedure s h o e d be carried out unless, in the reader's judgment, its risk is justified. Became of rapid advances in the medlcad sciences, we ~eccnm~-mi that the independent verificstion of diagnoses and drug dosages should be made. Discussions, views, and recommendations as to medicsl procedmes, choice of
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75

Infectious Diseases Newsletter 12(10/11) October/November 1993 is the measurement of leukocytes in the maternal serum. Unfortunately, leukocyte counts yield a sensitivity of only 67%. Ideally, tests should be easily performed, not training-intensive, and cost-effective. In the past decade more rapid, less expensive techniques have been developed toward these goals. Careful examination of currently used techniques such as Gram stains, leukocyte esterase, limulus amebocyte lysate, acridine orange, gas-liquid chromatography, and glucose levels reveals benefits and limitations of each test. Gram staining, the most commonly performed test for detecting intraamniotic infection, remains the standard against which all other tests are compared. Its poor sensitivity of 46.8% leads to many false-negative results. Furthermore, Gram stains require experienced laboratory personnel for their interpretation. Measurement of leukocyte esterase from the amniotic fluid, which is released by activated polymorphonuclear leukocytes, has been used for the detection of intraamniotic infection. Though this test has a sensitivity of 91% and specificity of 95%, its use is limited to the detection of more advanced infections. The limulus amebocyte lysate assay measures bacterial endotoxin with a sensitivity of 69%. However, when used in conjunction with the Gram stain, this sensitivity increases to 95%. Unfortunately, this test only del~cts endotoxin-producing organisms and, therefore, other microorganisms go undetected. Additionally, this study is both labor- and experience-intensive. Acridine orange is a fluorochrome dye with an affinity for the nucleic acid of bacteria. Bacteria are identified by their uptake of the orange fluorochrome stain. Human epithelial and inflammatory cell nuclei are distinguished by their green or yellow fluorescence. No significant difference between the sensitivity of the acridine orange test (43.8%) and a Gram stain (46.8%) has been found; acridine orange, therefore, has limited value as

a screening technique. The one advantage this test offers is that it is the only rapid method for detecting mycoplasm in amniotic fluid. Gas-liquid chromatography measures organic acids produced during bacterial metabolic processes. Although highly sensitive and specific, this test is costly, time-consuming, and requires sophisticated equipment and highly trained personnel. For these reasons, gas-liquid chromatographic analysis cannot be used routinely for diagnosis of intraamniotic infection. The last and most promising screening technique for intraamniotic infection measures the level of glucose in the amniotic fluid. Glucose levels are lowered in infected amniotic fluid presumably as a result of the metabolism and consumption of glucose by microorganisms and activated neutrophils. Measurement of glucose levels can exhibit a sensitivity as high as 86.9%; however, the false-positive rates are also high (8.3%). Treatment decisions based on tests with a high false-positive rate carry the risk of unnecessary delivery of preterm neonates. However, Gram stain evaluation in addition to sequential testing of glucose levels substantially reduces the high false-positive rate. Additional benefits of glucose testing include speed, minimal expense, and simplicity. Last, because of its high negative predictive value (97.8%), a high glucose concentration can be used to exclude infection in a patient with premature labor. In the future, polymerase chain reaction (PCR) will undoubtedly play a major role. PCR has the ability to detect infection in its initial stages by replication of a single bacterial gene present. However, the test is not yet efficient enough to ensure timely diagnosis and t~eatment. Two major factors, test synergy and patient condition, must be considered in deciding which tests are appropriate. Independently, the tests available are not ideal in detecting intraamniotic infection; therefore, a combination of tests should be used. Test synergy must be evaluated and ap© 1993 Elsevier Science Inc. 0278-2316/93/$0.00 + 6.00

plied to each patient's condition. For example, gestational age is an important determinant of treatment. At early gestational ages, antimicrobial therapy may be indicated for intraamniotic infection rather than delivery. Therefore, a clinician may require two positive tests to ensure proper detection, thereby lowering false-positive rates and, more importantly, lowering incidence of unnecessary premature deliveries. At late gestational ages, emphasis should lie on maximizing sensitivity. Failure to rapidly diagnose an intraamniotic infection at any gestational age postpones treatment and thus increases both maternal and fetal risk. Although no universal agreement exists for antibiotic treatment of intmamniotic infections, most studies use a penicillin (ampicillin) in combination with an aminoglycoside (gentamycin). These drugs readily cross the placenta and demonstrate efficacy against GBS and E. coli. Clindamycin is often added to this regimen to cover ~-lactamase producing Bacteroides spp.. Bacteroides are encountered more frequently in patients undergoing cesarean section because of the tissue injury involved. Newer broad-spectrum penicillins, cephalosporins, or ampicillin plus I~-lactamase inhibitors can be considered cost-effective alternatives to combination therapy. Antibiotic treatment is used to prevent neonatal complications such as pneumonia and bacteremia, as well as to protect the mother from complications such as septic shock, septic pelvic thrombophlebitis, or pelvic abscess. Antibiotic treatment should be continued until the patient is asymptomatic and afebrile for at least 24 hours and any septic area is drained. In the past, controversy existed as to the appropriate time to initiate treatment. The debate questioned whether intrapartum therapy was more successful than postpartum therapy in protecting the mother and infant from complications of intraamniotic infections. Since 1987, many studies have evaluated this issue. Intrapartum therapy was found to significantly de-

76 Infectious Diseases Newsletter 12(10/11)

October/November 1993 crease the duration and degree of maternal postpartum pyrexia, as well as to shorten hospital stay. Intrapartum therapy was also found to decrease neonatal sepsis and death, thereby improving neonatal outcomes as compared to those cases treated with postpartum antibiotics. The high incidence of unfavorable outcomes associated with intraamniotic infection emphasizes the need for early diagnosis and treatment. When managed appropriately, these infections respond well with good out-

come for both mother and infant. The key to appropriate treatment lies in the early detection of infection. While many promising tests are currently being developed, additional research, especially in the area of PCR, is needed to improve techniques for the rapid diagnosis of intraamniotic infections.

Bibliography Charles D: Obstetric and PafinatalInfections. St. Louis,Mosby YearBook, 1993. Coultrip LL, Grossman JH: Evaluation of

rapid diagnostic tests in the detection of microbial invasion of the amniotic cavity. Am J Obstet Gynecol 167:12311242, 1992. Gibbs RS, Castillo MS, Rodgers PJ: Management of acute chorioamnionitis. Am J Obstet Gynecol 136:709--715, 1980. Gibbs RS, Duff P" Progress in pathogenesis and management of clinical intraamniotic infection. Arn J Obstet Gynecol 164:1317-1325, 1991. Hillier SL, Krohn MA, Kiviat NB, et al.: Microbiologic causes and neonatal outcomes associated with chorioanmion infection. Am J Obstet Gynecol 165:955-960, 1991.

The Differential Diagnosis of Ciostridial Soft Tissue Infections Paul Valenstein, MD Catherine McAuley Health Center, Ann Arbor, Michigan

The isolation of Clostridia spp. from soft tissue specimens or from blood will often bring to mind the diagnosis of clostridial myonecrosis, also called "gas gangrene." This diagnosis creates anxiety in the laboratorian and clinician alike, as gas gangrene is well known for its rapid progression, need for heroic measures such as massive tissue debridement or amputation in order to control the infection, and the high mortality associated with this infection despite the best efforts for therapy. However, Ciostridia spp. may be involved in a variety of soft tissue infections other than gas gangrene. These clostridial infections are often confused with clostridial myonecrosis. This review will compare and contrast clostridial myonecrosis with six other soft tissue infections that may involve Clostridia spp.; these are vascular gangrene, suppurative myositis, crepitant cellulitis, necrotizing faseiitis, synergistic necrotizing cellulitis, and wound colonization. In addition, clostridial bacteremia will be reviewed, because its presence often leads to a

consideration of soft tissue clostridial infection.

Microbiology

Clostridia spp. are spore-forming Gram-positive bacilli that are widely distributed throughout the environment. They are found in soil, marine sediment, and the intestinal tract of most vertebrates. These organisms are considered anaerobes as they only sporulate in an anaerobic environment. However, their tolerance to oxygen varies greatly. C. haemolyticum, for example, is a strict anaerobe and cannot be isolated from clinical specimens unless exquisite attention is paid to collection and transportation of the specimen so as to ensure the absence of oxygen. In contrast, C. histolyticum will grow under aerobic conditions and often is confused with Bacillus spp. Differentiation in the clinical microbiology laboratory can be done by growing the isolate under anaerobic conditions because Bacillus will not sporulate and C. histolyticum will. A catalase test is also useful as Bacillus © 1993 Elsevier Science Inc. 0278-2316/93/$0.00 + 6.00

spp. are catalase-positive and C. histolyticum is not. Clostridia spp. can vary in Gramstains, with Gram-positive, Gram-variable, or Gram-negative staining reactions being seen. The morphology also varies; some species such as C. perfringens exhibit large, squared-off "box car" bacilli with blunted ends and no spores while other species are thinner, more pleomorphic, and have spore visible in clinical materials. There are more than 50 recognized species of Clostridia, but most clinical infections are caused by C. perfringens and C. ramosum. C. perfringens can be readily identified by its production of lecithinase and lipase and by the presence of a double zone of hemolysis around colonies incubated anaerobically on sheep blood agar. Other Clostridia slap. may be identified by their biochemical reactivity as well as by gas-liquid chromatographic analysis of fermentation products using reaction tables found in standard microbiology laboratory manuals. There is, however, some debate about the clinical usefulness of identifying