Abstract
Staphylococcus sp. is not only a commensal bacterium but also a major human pathogen that causes a wide range of clinical infections, such as skin and soft tissue infection, pleuropulmonary and osteoarticular infection, and endocarditis as well as life-threatening systemic infections. More evidence is currently emerging to show that Staphylococcus, particularly Staphylococcus aureus, can colonize the reproductive systems and affect their structure and function. Staphylococcal infection has become one of the most common causes of infertility in both males and females. This chapter focuses on the epidemiology, pathophysiology, clinical manifestations, and treatment of staphylococcal infection and infertility.
Keywords
- Staphylococcus
- infection
- infertility
1. Introduction
Bacterial infection in reproductive organs is one of the most common causes of infertility in both male and female patients. It is also associated with sexually transmitted infections and adverse pregnancy outcomes. Infection with different microorganisms, such as chlamydia, mycoplasma, and certain bacteria, may lead to various clinical manifestations of human reproductive function.
2. Overview of staphylococcal infection
2.1. The staphylococci
Bacteria in the genus
2.2. The pathogenesis of Staphylococcus aureus
2.3. The host defense against staphylococcal infection
Neutrophils represent the host’s first line of defense against invasion by
When innate immune mechanisms are not sufficient to clear the bacterial infection, an adaptive immunity against
2.4. Clinical manifestations of staphylococcal infection
Manifestations of staphylococcal infections usually depend on the type of infection, the site, the route, and the microbial dose. Common types of infections include skin infections (e.g. folliculitis, furuncles, impetigo, wound infections, and scalded skin syndrome), soft-tissue infections (e.g. pyomyositis, septic bursitis, and septic arthritis), toxic shock syndrome, purpura fulminans, endocarditis, osteomyelitis, pneumonia, food poisoning, and urinary tract infection [1, 9]. Despite associated with such a wide spectrum of clinical manifestations,
3. Epidemiology of genitourinary staphylococcal infection
Barring the role of a few bacteria such as
Parallel to the situation in females, abnormal presence of
In healthy women of child-bearing age, the protective mucosa in the vagina is populated with microflora typically dominated by lactobacilli, and their dominance over pathogenic anaerobes is positively associated with vaginal health. Thanks to the biological antagonism provided by a healthy vaginal microbiota, opportunistic microorganisms are in very low numbers in normal vagina. It is proven that lactobacilli provide a constant acidic pH value and maintain the appropriate concentration of hydrogen peroxide in the genital environment. While under the condition of BV, the concentration of lactobacilli reduces but of some pathogenic bacteria, especially anaerobes or microaerophiles, increase [18]. BV represents the most common vaginal syndrome that affects fertile, premenopausal, and pregnant women, with an incidence rate ranging from 20% to 50% [19, 20]. BV is not caused by one specific pathogenic microorganism but rather by an imbalance of vaginal microbiota.
Genitourinary MRSA carriage and infection are not rare. A retrospective study was previously conducted on 57 pregnant women positive for MRSA over a 4.5-year period. The data showed that skin and soft tissue infection accounted for 96% of cases and recurrent infection occurred in 58% of the women [21]. Vaginal colonization with
4. Staphylococcal infection and male infertility
Urogenital tract infections in males are one of the significant etiological factors in infertility. The infection of bacteria such as
Besides these prospective studies, several
In an effort to understand the mechanism whereby staphylococci modulate sperm activity, investigators currently identified some of the key molecules that have profound effect on sperm activity. Kaur and Prabha
In 2009, another protein with sperm regulatory effect, named sperm immobilization factor (SIF), was identified from
In addition to the effector molecules mentioned above, some novel mechanisms responsible for the staphylococcal regulation of sperm have now been discovered. A recent study on the semen of 589 infertile males indicated that other virulence genes in
5. Staphylococcal infection and female infertility
Bacterial infection in female reproductive system, such as staphylococcal infection, can profoundly affect all the phases of a woman’s life in relation to the period of pre-pregnancy, fertilization, pregnancy, and reproduction. It has been demonstrated that BV is the most common lower genital tract disorder among women of reproductive age. In particular, staphylococcal infection is presumed to be a contributing factor for the adverse pregnancy outcomes and female infertility. Staphylococcal infection causes malodorous vaginal discharge and is causally associated with sexually transmitted infections. Also, it has been implicated in the development of endometritis (endometriosis), another crucial factor to female infertility.
5.1. Inflammatory response and hypothalamic endocrine
An immune/inflammatory challenge is considered as an important factor that impinges the reproduction process in animals and humans [38]. It can affect reproduction at the level of the hypothalamus, pituitary gland, or gonads. Nonetheless, the major impact is thought to occur within the brain or the pituitary gland [39]. Bacterial endotoxins can trigger the release of cytokines and other immune mediators in the hypothalamus, where the luteinizing hormone (LH)-releasing hormone and gonadotropin-releasing hormone (GnRH) neurons are located [40]. Numerous
As described above, staphylococcal infection either in peripheral or directly in vagina can arouse strong immune/inflammatory reaction systematically or locally. The released cytokines and chemokines then act on the pituitary gland and reproductive organs, which may finally lead to menoxenia, irregular ovulation, and infertility. Evidences have shown that staphylococcal infection generates a large quantity of cytokines in female reproductive system. These mediators have an important role in the control of reproductive neuroendocrine, ovarian physiology, fetal implantation and development, and placenta function. Previous study revealed a correlation between BV, elevated IL-1β and IL-8, and idiopathic infertility, suggesting that abnormal vaginal flora and the vaginal inflammatory response may be responsible for the idiopathic infertility in women undergoing
5.2. Premature ovarian failure
Female mammals are born with a finite number of oocytes that gradually decreases during prepubertal development and adult life [43]. Each oocyte is encircled by somatic granulosa cells (GCs) to form the basic functioning unit of the ovary—the follicle. The size of the oocytes at birth and the rate of endowment depletion dominate the ovarian functional lifespan. On the other hand, programmed cell death (apoptosis) has been considered one of the most prevalent mechanisms that contribute to the age-related exhaustion of oocytes. Therefore, a precise balance has to be achieved between prosurvival and proapoptotic molecules to maintain the final destiny of the follicle [44, 45].
It is well recognized that immune/inflammatory response participates in many aspects of reproductive physiology, such as ovulation, menstruation, and implantation. Recent studies suggest that the inflammatory stress caused by staphylococcal infection may also affect ovarian reserve and cyclicity in women. Proinflammatory reaction, such as its correspondent neurotransmitter secretion, inflammatory gene transcription, and signaling pathway activation, was thought to play essential roles in the process. Moreover, the production of neurotransmitter, such as sphingolipid ceramide, further acts as a second messenger to promote age-related apoptosis of oocytes. Evidence showed that lower ceramide levels observed in acid sphingomyelinase-deficient mice resulted in a larger postnatal pool of oocytes compared with their wild-type counterparts. Conversely, Bax-null female mice exhibited to extend the ovarian lifespan [46]. These data may provide novel perspectives on the regulation of oocyte dynamics by bacterial infection and link the critical biological processes such as infection, inflammation, cell survival, and female fertility.
5.3. Bacterial vaginosis and endometritis
BV is a polymicrobial syndrome mainly due to an imbalance of vaginal microbiota. Colonization and proliferation of staphylococci is supposed to be one of the reasons for the increase in pathogenic bacteria, anaerobic bacteria, or microaerophiles. During the pathogenesis of BV, the overgrowth of anaerobes promotes the production of noxious substances, such as polyamines and other compounds. These metabolic products may further trigger the release of proinflammatory cytokines IL-1β and IL-8 and thus cause tissue damage and physiological imbalance [47]. BV can directly affect congenital formation and female fertility as an ascending dissemination of the related bacteria species proved to cause tubal factor infertility.
Another complication accompanied by vaginal staphylococcal infection is chronic endometritis (CE), a local inflammatory disease characterized by unusual plasmacytic infiltration in the endometrial stromal areas [48]. CE frequently happens in the later stage of the infection or under repeated infection. It tends to be neglected in gynecologic practice because of its less apparent symptom and the requirement of time-consuming histopathologic examinations. In most cases, the diagnosis is made based on gynecological indications, such as abnormal uterine bleeding (AUB) and infertility [49]. In a study on 64 CE patients and 28 healthy women, the biochemical analysis revealed that IL-6, IL-1β, and TNF-α levels were markedly higher in menstrual effluents of women with CE when compared with control subjects [50]. It is suggested that the infection and inflammation alter the endometrial cytokine profiles, which may further impair endometrial function and lead to menstrual abnormalities and reduced embryo receptivity [51]. Moreover, the proteomic analysis identified the key signaling pathways involved in inflammation and oxidative stress are closely related with carcinogenetic processes. These studies associate the onset of CE with female infertility, obstetric and neonatal abnormity, and complications. The altered endometrial gene expression may explain the impaired endometrial receptivity and endometrial hyperplastic lesions observed in women affected by CE [52].
5.4. Abnormal fetal implantation
In rodents and humans, implantation is the first coordinated encounter between mother and baby. The abnormal implantation and placentation may lead to various dysfunctions throughout the pregnancy. Pre-eclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria. It is estimated to affect about 8% of pregnancies and is thought to be unique to humans [53]. The etiology of PE still remains poorly understood, but abnormal placentation is proved to be a major reason for this disease. In addition, local infection and immune responses are critically involved in the process of implantation [54]. Increased placental secretion of proinflammatory cytokines as well as the angiogenic regulators has been implicated in the widespread maternal endothelial dysfunction and the development of PE. It has been shown that cytokines produced within the uterine microenvironment can alter trophoblast action [55], impair implantation, and placenta vascularization, which may account for the recurrent miscarriage in women [56]. Elevated circulating IL-15 levels, proportional to severity of diseases, have been detected in the serum of PE mothers when compared with healthy controls [57]. Also, IL-11 is also proved to be a contributing factor for the impaired trophoblast invasion, spiral artery remodeling, and altered placental labyrinth morphology. These functional abnormities further lead to the development of PE-like features, such as elevated systolic blood pressure (SBP), proteinuria, and kidney glomerular pathology. Another proinflammatory cytokine, interferon (IFN)-γ, was also elevated in plasma, circulating leukocytes, and decidua of patients with PE [58]. Besides this, decidual natural killer (dNK) cells, the predominant immune cell, coincide with the decidualization at the maternal-fetal interface in human and mice. All of these studies point to a critical role of immune/inflammatory response during the implanting and placental development. More importantly, vaginal
6. Therapy
Antibiotic strategy is considered the most potential therapeutic methods against staphylococcal infection and the resultant infertility. However, the emergence of antibiotic resistance has dramatically increased in the past two decades and becomes a serious threat to the worldwide public health. According to the National Healthcare Safety Network (NHSN) and Centers for Disease Control and Prevention,
6.1. Methicillin
The introduction of penicillin in the early 1940s significantly reduced fatal invasive staphylococcal infection. However, the resistant strains, mostly
6.2. Vancomycin
Vancomycin belongs to the glycopeptide antibiotic class and is effective in treatment of serious infections caused by
6.3. Linezolid
Linezolid has been used for treatment of serious infections caused by Gram-positive bacteria that are resistant to other antibiotics such as MRSA. Its spectrum of activity is similar to that of vancomycin, a well-established antibiotic for MRSA infections. Either linezolid or vancomycin has been recommended by the US guidelines as the first-line treatment for hospital-acquired (nosocomial) MRSA pneumonia [61]. Mechanistically, linezolid binds to the 50s subunit of the bacterial ribosome through interaction with the central loop of the 23S rRNA and thus impedes the growth of bacteria by disrupting their production of proteins. Point mutation of 23S rRNA is the most common mechanism of linezolid resistance [62]. The common side effects of linezolid include diarrhea, headache, nausea, vomiting, rash, constipation, altered taste perception, and discoloration of the tongue, although they happen relatively rarely.
6.4. Daptomycin
Daptomycin is the first cyclic lipopeptide approved for clinical use in 2003. It is a calcium-dependent antibiotic comprising a lipid molecule conjugated with anionic peptide. Daptomycin interacts with the cytoplasmic membrane in a calcium-dependent, leading to the cell membrane depolarization, ion loss, and cell death [63]. Many antibiotic-resistant strains, such as MRSA and VRSA, were found to be effectively inhibited by daptomycin. Till 2008, the first case of daptomycin resistance was reported, and the underlying mechanism is currently still not very clear [64]. However, the mutation of the mprF gene, which encodes lysyl-phosphatidyl glycerol (LPG) synthetase, might be related to the occurrence of resistant strains. LPG can catalyze the coupling of lysine to PG and transfer the lysyl-PG to the outer leaflet of the membrane. In this way, LPG increases the positive charge and thus reduces the binding of Ca2+-bound daptomycin to bacterial membranes [65].
Besides the routinely used antibiotics mentioned above, numerous new antibiotics are developed to serve as the alternatives in treating staphylococcal infection and the associated infertility. For example, teicoplanin or quinupristin/dalfopristin has been widely used with daptomycin to treat Gram-positive bacterial infection. Some of the potential antibiotics, such as oritavancin and iclaprim, are currently in the early stages of clinical development, and other promising candidates, such as ceftobiprole, dalbavancin, and telavancin, are still being developed [66].
References
- 1.
Lowy FD. Staphylococcus aureus infections. N Engl J Med. 1998;339:520–532. - 2.
Guinan ME, Dan BB, Guidotti RJ, Reingold AL, Schmid GP, Bettoli EJ, Lossick JG, Shands KN, Kramer MA, Hargrett NT, Anderson RL, Broome CV. Vaginal colonization with Staphylococcus aureus in healthy women: a review of four studies. Ann Intern Med. 1982;96:944–947. DOI:10.7326/0003-4819-96-6-944 - 3.
Pauli NT, Kim HK, Falugi F, Huang M, Dulac J, Henry Dunand C, Zheng NY, Kaur K, Andrews SF, Huang Y, DeDent A, Frank KM, Charnot-Katsikas A, Schneewind O, Wilson PC. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J Exp Med. 2014;211:2331–2339. DOI:10.1084/jem.20141404 - 4.
Thammavongsa V, Missiakas DM, Schneewind O. Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science 2013;342:863–866. DOI:10.1126/science.1242255 - 5.
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805–820. DOI:10.1016/j.cell.2010.01.022 - 6.
Figdor CG, van Kooyk Y, Adema GJ. C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol. 2002;2:77–84. DOI:10.1038/nri723 - 7.
Miller LS, Cho JS. Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol. 2011;11:505–518. DOI:10.1038/nri3010 - 8.
McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: an update. Annu Rev Microbiol. 2001;55:77–104. - 9.
Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015;28:603–661. DOI:10.1128/CMR.00134-14 - 10.
Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, Nouwen JL. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005;5:751–762. - 11.
Peacock SJ, Paterson GK. Mechanisms of methicillin resistance in Staphylococcus aureus . Annu Rev Biochem. 2015;84:577–601. DOI:10.1146/annurev-biochem-060614-034516 - 12.
Hillier SL. Diagnostic microbiology of bacterial vaginosis. Am J Obstet Gynecol. 1993;169:455–459. - 13.
Momoh ARM, Orhue PO, Okolo PO, Odaro D, Momoh AA. The antibiogram types of auto-agglutinating Staphylococcus aureus strains isolated from the semen samples of males with infertility problems in Edo state, Nigeria. E3 J Med Res. 2012;1:17–24. - 14.
Ghiasi M, Fazaeli H, Kalhor N, Sheykh-Hasan M, Tabatabaei-Qomi R. Assessing the prevalence of bacterial vaginosis among infertile women of Qom city. Iran J Microbiol. 2014;6:404–408. - 15.
Isaiah IN, Nche BT, Nwagu IG, Nnanna II. Current studies on bacterospermia the leading cause of male infertility: a protégé and potential threat towards mans extinction. N Am J Med Sci. 2011;3:562–564. DOI:10.4297/najms.2011.3559 - 16.
Uneke CJ, Ugwuoru CD. Antibiotic susceptibility of urogenital microbial profile of infertile men in South-eastern Nigeria. Andrologia 2010;42:268–273. DOI:10.1111/j.1439-0272.2009.00988.x - 17.
Huerta M, Cervera Aguilar R, Hernández I, Ayala AR. Frequency and etiology of seminal infections in the study of infertile couples. Ginecol Obstet Mex. 2002;70:90–94. - 18.
Mastromarino P, Vitali B, Mosca L. Bacterial vaginosis: a review on clinical trials with probiotics. New Microbiol. 2013;36:229–238. - 19.
Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001–2004 National Health and Nutrition Examination Survey data. Obstet Gynecol. 2007;109:114–120. DOI:10.1016/S0920-5861(96)00164-2 - 20.
Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, Markowitz LE. The prevalence of bacterial vaginosis in the United States, 2001–2004; associations with symptoms, sexual behaviors, and reproductive. Sex Transm Dis. 2007;34:864–869. - 21.
Laibl VR, Sheffield JS, Roberts S, McIntire DD, Trevino S, Wendel GD Jr. Clinical presentation of community-acquired methicillin-resistant Staphylococcus aureus in pregnancy. Obstet Gynecol. 2005;106:461–465. - 22.
Chen KT, Huard RC, Della-Latta P, Saiman L. Prevalence of methicillin-sensitive and methicillin-resistant Staphylococcus aureus in pregnant women. Obstet Gynecol. 2006;108:482–487. DOI:10.1097/01.AOG.0000227964.22439.e3 - 23.
Donders GG, Vereecken A, Bosmans E, Dekeersmaecker A, Salembier G, Spitz B. Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis. BJOG 2002;109:34–43. DOI:10.1111/j.1471-0528.2002.00432.x - 24.
Koumans EH, Markowitz LE, Hogan V. Indications for therapy and treatment recommendations for bacterial vaginosis in nonpregnant and pregnant women: a synthesis of data. Clin Infect Dis. 2002;35:S152–S172. - 25.
Harmanli OH, Cheng GY, Nyirjesy P, Chatwani A, Gaughan JP. Urinary tract infections in women with bacterial vaginosis. Obstet Gynecol. 2000;95:710–712. - 26.
Marconi M, Pilatz A, Wagenlehner F, Diemer T, Weidner W. Impact of infection on the secretory capacity of the male accessory glands. Int Braz J Urol. 2009;35:299–308. - 27.
Onemu SO, Ibeh IN. Studies on the significance of positive bacterial semen cultures in male fertility in Nigeria. Int J Fertil Womens Med. 2001;46:210–214. - 28.
Filipiak E, Marchlewska K, Oszukowska E, Walczak-Jedrzejowska R, Swierczynska-Cieplucha A, Kula K, Slowikowska-Hilczer J. Presence of aerobic micro-organisms and their influence on basic semen parameters in infertile men. Andrologia 2015;47:826–831. DOI:10.1111/and.12338 - 29.
Fraczek M, Piasecka M, Gaczarzewicz D, Szumala-Kakol A, Kazienko A, Lenart S, Laszczynska M, Kurpisz M. Membrane stability and mitochondrial activity of human-ejaculated spermatozoa during in vitro experimental infection with Escherichia coli ,Staphylococcus haemolyticus andBacteroides ureolyticus . Andrologia 2012;44:315–329. DOI:10.1111/j.1439-0272.2012.01283.x - 30.
Fraczek M, Hryhorowicz M, Gaczarzewicz D, Szumala-Kakol A, Kolanowski TJ, Beutin L, Kurpisz M. Can apoptosis and necrosis coexist in ejaculated human spermatozoa during in vitro semen bacterial infection? J Assist Reprod Genet 2015;32:771–779. DOI:10.1007/s10815-015-0462-x - 31.
Rodin DM, Larone D, Goldstein M. Relationship between semen cultures, leukospermia, and semen analysis in men undergoing fertility evaluation. Fertil Steril 2003;79(Suppl. 3):1555–1558. - 32.
Kaur K, Prabha V. Impairment by sperm agglutinating factor isolated from Escherichia coli : receptor specific interactions. Biomed Res Int. 2013;2013:548497. DOI:10.1155/2013/548497 - 33.
Kaur S, Prabha V. Receptor mediated amelioration of the detrimental effects of sperm agglutinating factor on sperm parameters. Andrology 2013;1:624–631. DOI:10.1111/j.2047-2927.2013.00088.x - 34.
Prabha V, Gupta T, Kaur S, Kaur N, Kala S, Singh A. Isolation of a spermatozoal immobilization factor from Staphylococcus aureus filtrates. Can J Microbiol. 2009;55:874–878. DOI:10.1139/w09-032 - 35.
Prabha V, Chaudhary N, Kaur S. Molecular mimicry between spermatozoa and bacteria. J Urol. 2011;186:2442–2447. DOI:10.1016/j.juro.2011.07.084 - 36.
Li B, Yang X, Ye JZ, Chen HL, Hou YB, Du J, Zhou TL. Spermatozoal immobilization ability and virulence genes of Staphylococcus aureus isolated from the semen of infertile men. Zhonghua Nan Ke Xue. 2015;21:881–886. - 37.
Berktas M, Aydin S, Yilmaz Y, Cecen K, Bozkurt H. Sperm motility changes after coincubation with various uropathogenic microorganisms: an in vitro experimental study. Int Urol Nephrol. 2008;40:383–389. DOI:10.1007/s11255-007-9289-4 - 38.
Herman AP, Krawczynska A, Bochenek J, Dobek E, Herman A, Tomaszewska-Zaremba D. LPS-induced inflammation potentiates the IL-1beta-mediated reduction of LH secretion from the anterior pituitary explants. Clin Dev Immunol. 2013;2013:926937. DOI:10.1155/2013/926937 - 39.
Herman AP, Tomaszewska-Zaremba D. Effect of endotoxin on the expression of GnRH and GnRHR genes in the hypothalamus and anterior pituitary gland of anestrous ewes. Anim Reprod Sci. 2010;120:105–111. DOI:10.1016/j.anireprosci.2010.03.011 - 40.
Igaz P, Salvi R, Rey JP, Glauser M, Pralong FP, Gaillard RC. Effects of cytokines on gonadotropin-releasing hormone (GnRH) gene expression in primary hypothalamic neurons and in GnRH neurons immortalized conditionally. Endocrinology 2006;147:1037–1043. - 41.
Refojo D, Arias P, Moguilevsky JA, Feleder C. Effect of bacterial endotoxin on in vivo pulsatile gonadotropin secretion in adult male rats. Neuroendocrinology 1998;67:275–281. - 42.
Spandorfer SD, Neuer A, Giraldo PC, Rosenwaks Z, Witkin SS. Relationship of abnormal vaginal flora, proinflammatory cytokines and idiopathic infertility in women undergoing IVF. J Reprod Med. 2001;46:806–810. - 43.
Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev. 2009;30:465–493. DOI:10.1210/er.2009-0006 - 44.
Tilly JL. Apoptosis and ovarian function. Rev Reprod. 1996;1:162–172. - 45.
Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod. 2005;11:162–177. - 46.
Uri-Belapolsky S, Shaish A, Eliyahu E, Grossman H, Levi M, Chuderland D, Ninio-Many L, Hasky N, Shashar D, Almog T, Kandel-Kfir M, Harats D, Shalgi R, Kamari Y. Interleukin-1 deficiency prolongs ovarian lifespan in mice. Proc Natl Acad Sci USA. 2014;111:12492–12497. DOI:10.1073/pnas.1323955111 - 47.
Romero R, Chaiworapongsa T, Kuivaniemi H, Tromp G. Bacterial vaginosis, the inflammatory response and the risk of preterm birth: a role for genetic epidemiology in the prevention of preterm birth. Am J Obstet Gynecol. 2004;190:1509–1519. - 48.
Kitaya K, Matsubayashi H, Yamaguchi K, Nishiyama R, Takaya Y, Ishikawa T, Yasuo T, Yamada H. Chronic endometritis: potential cause of infertility and obstetric and neonatal complications. Am J Reprod Immunol. 2016;75:13–22. DOI:10.1111/aji.12438 - 49.
Gilmore H, Fleischhacker D, Hecht JL. Diagnosis of chronic endometritis in biopsies with stromal breakdown. Hum Pathol. 2007;38:581–584. DOI:10.1016/j.humpath.2006.09.002 - 50.
Tortorella C, Piazzolla G, Matteo M, Pinto V, Tinelli R, Sabba C, Fanelli M, Cicinelli E. Interleukin-6, interleukin-1beta, and tumor necrosis factor alpha in menstrual effluents as biomarkers of chronic endometritis. Proc Natl Acad Sci USA. 2014;112:15928–15933. DOI:10.1073/pnas.1515076112 - 51.
Maybin JA, Critchley HO, Jabbour HN. Inflammatory pathways in endometrial disorders. Mol Cell Endocrinol. 2011;335:42–51. DOI:10.1016/j.mce.2010.08.006 - 52.
Di Pietro C, Cicinelli E, Guglielmino MR, Ragusa M, Farina M, Palumbo MA, Cianci A. Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol. 2013;69:509–517. DOI:10.1111/aji.12076 - 53.
Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–799. - 54.
Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol. 2013;31:387–411. DOI:10.1146/annurev-immunol-032712-100003 - 55.
Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod. 2005;11:613–630. DOI:10.1093/humupd/dmi023 - 56.
Toth B, Haufe T, Scholz C, Kuhn C, Friese K, Karamouti M, Makrigiannakis A, Jeschke U. Placental interleukin-15 expression in recurrent miscarriage. Am J Reprod Immunol. 2010;64:402–410. DOI:10.1111/j.1600-0897.2010.00879.x - 57.
Sones JL, Lob HE, Isroff CE, Davisson RL. Role of decidual natural killer cells, interleukin-15, and interferon-gamma in placental development and preeclampsia. Am J Physiol Regul Integr Comp Physiol. 2014;307:R490–R492. DOI:10.1152/ajpregu.00176.2014 - 58.
Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon gamma in successful pregnancies. Biol Reprod. 2009;80:848–859. DOI:10.1095/biolreprod.108.073353 - 59.
Seybold U, Kourbatova EV, Johnson JG, Halvosa SJ, Wang YF, King MD, Ray SM, Blumberg HM. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis. 2006;42:647–656. - 60.
Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42(Suppl. 1):S5–S12. - 61.
American Thoracic Society & Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and health care-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388–416. DOI:10.1164/rccm.200405-644ST - 62.
Mendes RE, Deshpande LM, Jones RN. Linezolid update: stable in vitro activity following more than a decade of clinical use and summary of associated resistance mechanisms. Drug Resist. 2014;17:1–12. DOI:10.1016/j.drup.2014.04.002 - 63.
Patel D, Husain M, Vidaillac C, Steed ME, Rybak MJ, Seo SM, Kaatz GW. Mechanisms of in-vitro-selected daptomycin-non-susceptibility in Staphylococcus aureus . Int J Antimicrob Agents. 2011;38:442–446. DOI:10.1016/j.ijantimicag.2011.06.010 - 64.
Hobbs JK, Miller K, O’Neill AJ, Chopra I. Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus. J Antimicrob Chemother. 2008;62:1003–1008. DOI:10.1093/jac/dkn321 - 65.
Jones T, Yeaman MR, Sakoulas G, Yang SJ, Proctor RA, Sahl HG, Schrenzel J, Xiong YQ, Bayer AS. Failures in clinical treatment of Staphylococcus aureus infection with daptomycin are associated with alterations in surface charge, membrane phospholipid asymmetry, and drug binding. Antimicrob Agents Chemother. 2008;52:269–278. - 66.
Vuong C, Yeh AJ, Cheung GY, Otto M. Investigational drugs to treat methicillin-resistant Staphylococcus aureus . Expert Opin Investig Drugs. 2016;25:73–93. DOI:10.1517/13543784.2016.1109077