Pediatric Infectious Diseases Revisited - part 3 doc

It was Carl Siegmund Franz Credé 1819–1892, a German obstetrician, who introduced the eye prophylaxis of eye drops containing 2% silver nitrate solution to every newborn child in his cli

the vaccine could be administered intramuscularly if, in the opinion of a physician familiar with the patient’s bleeding risk, the vaccine can be admin-istered with reasonable safety by this route A fine needle () 23 gauge) should be used for the immunization and firm pressure applied to the site, without rubbing, for * 2 min The patient or family should be instructed concerning the risk for hematoma from the injection Patients with platelet counts of less than 50 × 109/L should not receive intramuscular injections The subcutaneous or intracutaneous route should be considered as an alternative to the intramuscular route in patients with bleeding disorders Children with inherited coagulopathies should receive factor replacement prior to intramuscular injection [8, 17].

Immunization of recent recipients of human immunoglobulin

With the exception of yellow fever vaccine, the immune response to live viral vaccines may be inhibited by normal human immunoglobulin Therefore, live virus vaccines should be given 3 weeks before or 3 months after a dose of immunoglobulin If an individual is under medical treatment with high-dose or intravenous immunoglobulin, the physician who initiated this treatment should be consulted [8]

Immunization and breast-feeding

Breast-fed infants should be immunized according to routinely mended schedules Although live vaccines multiply within the mother’s body, the majority has not been demonstrated to be excreted in human milk Rubella vaccine virus might be excreted in human milk However, the virus usually does not infect the infant Where infection has occurred in an infant,

recom-it has been mild because the virus is attenuated Inactivated, recombinant, subunit, polysaccharide, conjugate vaccines and toxoids pose no risk for mothers who are breast-feeding or for their infants [8, 17]

Special recommendations for the immunization of hematopoietic stem cell transplant (HSCT) recipients and for solid organ recipients before transplantation exist [22–25]

Contraindications and false contraindications

Contraindications

Contraindications to immunization dictate circumstances when vaccines should not be given because the condition in an individual increases the risk for a serious adverse reaction following immunization The majority of con-

traindications are temporary, and the vaccine can be given later However,

in many cases immunization is delayed or denied because of conditions

falsely believed by the physician or the health worker to constitute a

con-traindication The World Health Organization and the majority of countries

have established and periodically updated lists of contraindications (and

often also false contraindications) to offer expert advice for physicians and

health workers involved in immunization for individual cases where doubt

occurs

Genuine contraindications are few and the numbers of individuals

to whom they apply are fewer still The various lists of contraindications

include mainly:

– acute illness

– altered immunity

– pregnancy

– severe adverse events after a previous dose

– children with neurological disorders

– anaphylaxis and allergy to vaccines and vaccine constituents

Depending on the individual vaccines, contraindications are provided

spe-cifically

False contraindications

Conditions that are NOT contraindications to immunization are called

‘false contraindications’ Examples are the following conditions:

– minor illness, such as upper respiratory infection or diarrhea, with

tempe-rature < 38.5 °C

– asthma or other atopic manifestations

– family history of convulsions

– treatment with antibiotics, low-dose or locally acting corticosteroids

– dermatoses, localized skin infection

– chronic diseases of heart, lung, kidney and liver

– stable neurological conditions, such as Down’s syndrome

– history of jaundice after birth

– prematurity

– malnutrition

– mother pregnant

– in incubation period of illness

Some of these conditions increase the risk from infectious diseases and such

individuals should be immunized as a matter of priority [17, 26]

1 Dittmann S (2006) Elimination der Poliomyelitis Polio-Nachrichten 2: 11–12

2 Dittmann S (2001) Vaccine safety: risk communication – a global perspective Vaccine 19: 2446–2456

3 Campbell H, Ramsay M, Gungabissoon U, Miller E, Andrews N, Mistry A,

Mallard R, Borrow R (2004) Impact of the meningococcal C conjugate tion programme in England Summary Surveillance Report from the Health

vaccina-Protection Agency, Centre for Infections Immunisation Department to end December 2004.

4 Centers for Disease Control and Prevention (2002) Epidemiology and tion of vaccine-preventable diseases In: Atkinson W, Hamborsky J, McIntyre L,

preven-Wolfe S (eds): The Pink Book, 9th edn, Appendix G: Reported cases and deaths

for vaccine-preventable diseases Public Health Foundation, Washington, D.C.

5 Six common misconceptions about vaccination and how to respond to them htpp://www.cdc/nip/publications/6mishome.htm (accessed August 14, 2006)

6 Offit PA, Quarles J, Gerber MA, Hackett CJ, Marcuse EK, Kollman TR, Gellin

BG, Landry S (2002) Addressing parents’ concerns: do multiple vaccines

over-whelm or weaken the infant’s immune system? Pediatrics 109:124–129

7 Public Health Agency of Canada (2002) Talking with patients about

immuniza-tion In : Canadian Immunization Guide 2002, Public Health Agency of Canada,

Ottawa, 42–54.

8 Responding to questions and concerns about immunization In: Australian Immunization Handbook, 8th edn 2003, online htpp://www9.health.gov.au/

immhandbook (accessed August 14, 2006)

9 Global Advisory Committee on Vaccine Safety (2003) MMR and autism Weekly Epidemiol Rec 78: 18

10 Global Advisory Committee on Vaccine Safety (2005) Thiomersal: havioural studies in animal models Wkly Epidemiol Rec 80: 3–4

neurobe-11 Institute of Medicine Immunization Safety Reviews: Measles-mumps-rubella vaccine and autism National Academy Press, Washington DC 2001 http://www cdc.gov/nip/news/iom-04–24.htm (accessed August 14, 2006)

12 US Centers for Disease Control Vaccines and autism – references http://

www.cdc.gov/nip/vacsafe/concerns/autism/autism-ref.htm (accessed August 14, 2006)

13 Davis RL, Kramarz P, Bohlke K, Benson P, Thompson RS, Mullooly J, Black S, Shinefield H, Lewis E, Ward J et al (2001) Measles-mumps-rubella and other measles-containing vaccines do not increase the risk for inflammatory bowel

disease Arch Pediatr Adolesc Med 155: 354–359

14 US Centers for Disease Control Measles vaccine and inflammatory bowel disease – references http://www.cdc.gov/nip/vacsafe/concerns/autism/ibd htm#references (accessed August 14, 2006)

15 (2002) Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders National Academy Press, Washington, D.C.

16 (2003) Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy National Academy Press, Washington, D.C.

17 (2002) Recommendations of the Advisory Committee on Immunization

Practices (ACIP) General recommendations on immunization Morb Mortal

Wkly Rep 51: No RR-2.

18 American Academy of Pediatrics (2003) Immunocompromised children In:

LK Pickering (ed): 2003 Red Book: Report of the Committee on Infectious

Diseases 26th ed Elk Grove Village, IL, 69

19 Moss WJ, Clements CJ, Halsey NA (2003) Immunization of children at risk of

infection with human immunodeficiency virus Bull World Health Organ 81:

61–70

20 EPI Vaccines in HIV-infected Individuals

htpp://www.who.int/vaccines-dis-eases/diseases/HIV.shtml (accessed August 14, 2006)

21 Contraindications for childhood vaccinations

htpp://www.cdc.gov/nip/recs/con-traindications.htm (accessed August 14, 2006)

22 (2000) Guidelines for preventing opportunistic infections among

hematopoi-etic stem cell transplant recipients Recommendations of CDC, the Infectious

Disease Society of America, and the American Society of Blood and Marrow

Transplantation MMWR 49: RR-10

23 Avery RK, Ljungman P (2001) Prophylactic measures in the solid-organ

recipi-ent before transplantation Clin Infect Dis 33 (Suppl 1): 15–21

24 Stark K, Günther M, Schönfeld C, Tullius SG, Bienzle U (2002) Immunisations

in solid-organ transplant recipients Lancet 359: 957–965

25 Ljungman P (2004) Immunization in the immunocompromised host In: SA

Plotkin, WA Orenstein (eds): Vaccines, 4th edn Saunders, Philadelphia, 155–

168

26 (1998) Contraindications for vaccines used in EPI Wkly Epidemiol Rec 63:

279–281

Gonorrheal ophthalmia neonatorum: Historic impact

of Credé’s eye prophylaxis

coun-in their severity but often caused significant impairment of eyesight up to total blcoun-indness

in more than 5% This accounted for 25–40% of cases of blindness in Germany It was Carl Siegmund Franz Credé (1819–1892), a German obstetrician, who introduced the eye prophylaxis of eye drops containing 2% silver nitrate solution to every newborn child in his clinic in Leipzig on June 1st 1880 The incidence of gonorrheal ophthalmia neonato- rum immediately decreased from 10% to 0% Credé actively communicated these results and immediately published them in four publications within a time period of 3 years These publications, which are discussed here, are written in a very pragmatic and strictly clinical style, ignoring new basic scientific insights into the microbiology of gonorrhea

and the discovery of the corresponding pathogen, the “Micrococcus” by Albert Neisser,

which Credé considered unimportant for his purposes Against a high degree of tion by many physicians, Credé put all enthusiasm into the call for education of midwives

opposi-in this technique Credé knew that this was the central way to ensure that all newborns could obtain this prophylaxis, including outpatients and home deliveries Credé’s elo- quence led to the rapid spreading of “his” eye prophylaxis over the rest of the world The concentration of silver nitrate was often reduced from 2% to 1% thereafter and in most countries the performance of this prophylaxis was rapidly enforced by law By introduc- ing this method, Credé saved or improved the eyesight of millions of people – a signifi- cant contribution to obstetrics, neonatology and pediatrics, ophthalmology and mankind Still today, in the antibiotic era, other topical regimens for antiseptic prophylaxis against ophthalmia neonatorum are often referred to as “Credé’s prophylaxis”.

“However, the broad use of silver as a powerful clinical tool against tions is still in the future, because its full range of activity remains to be elucidated.”

infec-Q.L Feng et al., 2000 [1]

The endangered eyesight

In the pre-antibiotic era, i.e., until almost the middle of the 20th century, gonorrhea and ophthalmia neonatorum showed a high prevalence also in industrialized countries [2–7] In the middle of the 19th century more than 10% of all newborns in Germany developed gonorrheal ophthalmia neona-torum Clinical courses of gonorrheal ophthalmia neonatorum were quite different in their severity but often caused a huge and irreversible damage

to the eyes with a significant impairment of eyesight up to total blindness

as final outcome of the disease in more than 5% of the infections This accounted for 25–40% of cases of blindness in Germany [8–11] What about silver as a broadly acting antiseptic?

Carl Siegmund Franz Credé, introducer of the antiseptic eye

prophylaxis with silver nitrate

Carl Siegmund Franz Credé (23.12.1819–14.03.1892) (Fig 1) [8, 12–15] was born in Berlin where he went to school and studied medicine, with the exception of one semester at the university of Heidelberg (Germany)

The principle of “nihil nocere” – an attempt to keep necessary treatment

approaches as mild and gentle as possible – was his general philosophy

in medicine After several years of postgraduate study in Austria, France, Belgium and Italy, he returned to Berlin in 1847 and was appointed assistant

in obstetrics at Berlin’s clinic of obstetrics, where he remained until 1852 In

1850 he became a “Privatdozent” (university teacher) in obstetrics.

In 1852 he was appointed Director of the Berlin School of Midwives and Physician in Chief to the inpatient division of obstetrics and gynecology of the Berlin Royal Charité Hospital In 1856 Credé was appointed Professor of Obstetrics and Director of the inpatient hospital in Leipzig, Germany where

he retired in 1887 because of his poor health condition due to prostate cancer Within the time in Leipzig he became “Nestor of German midwifery” [8].During his time in Berlin he made a significant contribution to obstet-rics by introducing a new and safer method for the delivery of the placenta

(“Credé’scher Handgriff”/Credé’s method) [16, 17] Credé was a

consistent-ly modest person and did not claim priority for this method This method is still used today in emergencies such as hemorrhage after delivery

The affiliation with Leipzig gave him the chance of fully living his talents as a clinician, academic teacher and administrator, and his depart-ment became very prestigious He personally focused on obstetrics being convinced that improvements in obstetrics are a key parameter to reduc-ing the number of gynecological impairments The famous obstetrician and gynecologist Gerhard Leopold was Credé’s son-in-law [8]

Credé wrote several textbooks and original articles; he took over the editorship of gynecological journals of high reputation and was awarded the

“Senckenberg Preis/Senckenberg Award” due to his outstanding

achieve-ments in obstetrics and medicine [15] Further, he received the prestigious

post of a “Geheimer Medicinalrath/Aulic Counsellor”.

After 1860, Credé began to work on optimizing warming devices for

premature and feeble tiny children (“Erwärmungswanne”) [18], which he

established at his department thereafter – a significant contribution to obstetrics and a precursor of the incubators for newborns today

Whereas the “Credé’scher Handgriff” and the “Erwärmungswanne”

were mostly recognized by the public in the lifetime of Credé, he introduced

an eye prophylaxis for ophthalmia neonatorum (“Credé’sche Prophylaxe”),

which achieved highest recognition especially amongst physicians [15] The

prophylactic application of “Argentum nitricum/silver nitrate” 1:50 aqueous

solution was introduced in all newborns from June 1st 1880 onwards in the Leipzig obstetrics department

Figure 1 Carl Siegmund Franz Credé (1819–1892)

Credé wrote three consecutive publications with the same title on this

topic “Die Verhütung der Augenentzündung der Neugeborenen” [19–21]

(Prevention of inflammatory eye disease in the newborn) in the Journal

“Archiv für Gynäkologie” between 1881 and 1883 The first [19, 22] focused

on methodological aspects of the eye prophylaxis and will be the core issue

of this chapter His second publication presented more cases, and stressed the performance by midwives and by general practitioners The third sum-marized his results and comprehensively addressed new aspects of etiology and practicable everyday prevention of ophthalmia neonatorum by his method The second and third paper are discussed on the background of the

“revolutionary” first one later in this chapter In 1884, Credé summarized central aspects of his three publications in a booklet version in English [23]

An abbreviated English translation, translated by the WHO [22], of the first paper is given below For systematic purposes, the original of the first paper of Credé in German language [19] is attached to this chapter as an

“Addendum”

“Prevention of Inflammatory eye disease in the newborn

Information from the Maternity Clinic Leipzig by Credé” [22]

“I am (…) publishing the following information concerning the prevention

of inflammatory eye disease in the newborn (…) in this Archive because the disease is almost invariably caused by infection during delivery and

is therefore directly related to a diseased condition of the female genitals Responsibility for prevention of the disease must also lie solely with obste-tricians and midwives I shall confine my remarks exclusively to the practical question of prophylaxis

(…) My request for further testing of the prophylaxis I am ing is therefore addressed to those of my colleagues who work in maternity hospitals or obstetric clinics and (…) are frequently confronted with this condition

recommend-Most obstetricians would probably share my view that the case of vaginal catarrh and infections that are so frequently encountered are attributable to gonorrheal infection and that the discharge remain infectious long after the specific symptoms of gonorrhea have disappeared; moreover, in some cases where there is virtually no further trace of discharge, the infection may still

be considered to have occurred in the mother’s vagina when an tory eye condition develops in the first few days after birth

inflamma-Transmission of the infectious substance from another child with eye disease is inconceivable (…) inasmuch as every child who is suffering from inflammatory eye disease is moved with its mother to a ward that is entirely separate in all respects from the maternity ward The possibility of mothers infecting their children, for example through fingers soiled by lochial dis-

charge, is also remote because the child’s cot is always placed beyond reach

of the mother, who only comes into contact with the child when the nurse places it on her breast

I am therefore convinced (…) that all affected children in (…) hospital (…) were infected solely by direct transmission of vaginal discharge to the eye during delivery The infected eye usually begins to show symptoms of disease 2 or 3 days after birth, but also sooner or later – the sooner, the more serious the condition

(…) I have set myself the doubtless worthwhile task of finding effective ways and means of preventing this disease (…) and of detecting the infec-tious discharge

I initially focused on ensuring extensive and effective treatment and cleansing of the diseased vaginas of pregnant and delivering women But the results were poor and unsatisfactory; although there were fewer cases of eye disease (…) I then began to disinfect the children’s eyes themselves and from then on the success recorded was surprisingly encouraging

My experiments proceeded as follows: first, the vaginas of all pregnant and delivering women admitted to the hospital with gonorrhea or chronic vaginal catarrh were cleaned out with lukewarm water or a light solution (2:100) of carbolic or salicylic acid as frequently as possible – every half hour in the case of delivering women The incidence of eye disease declined but the problem persisted (…)

In October 1879, I carried out my first test involving the introduction

of prophylactic eye drops into the newborn babies immediately after birth, using a borax solution (1:60) because it seemed to be the mildest and least caustic substance This was only done, however, in the case of children whose mothers were ill and whose vaginas had been cleansed during the whole delivery process in a manner described above From December 1879,

I replaced the borax by solutions of Argentum nitricum (1:40), which were injected into the eyes shortly after birth The eyes were carefully washed beforehand with a solution of salicylic acid (2:100) The children of sick mothers who were treated in this way remained healthy, while other chil-dren who had not been given preventive treatment (…) still fell ill, in two cases quite seriously

From 1 June 1880, all eyes without exception were disinfected diately after birth by means of a weaker solution of Argentum nitricum (1:50) (…) a glass stick was used to introduce a single drop of liquid into each eye, which was gently opened by an assistant and which had been cleaned beforehand with ordinary water Then the eyes were cooled for

imme-24 h with a canvas cloth soaked in salicylic water (2:100) The numerous vaginal douches, on the other hand, were abandoned (…) All children treated in this way remained free from even mild attacks of inflammatory eye disease, although many mothers showed advanced symptoms of vaginal blenorrhea (…) Only one child (…) fell ill on the 6th day with a moder-ate inflammation of the conjunctiva of the left eye, without swelling of the

eyelid, which healed within 3 days It emerged that, quite by chance, owing

to pressure of work, the prophylactic eye drops had not been administered

to this child

To date, no adverse effect on the treated eyes has been observed Not infrequently the administration of the eye drops is followed by a slight hyperemia and in some cases by slight increased secretion from the conjunc-tiva in the first 24 h Then these symptoms disappear They could perhaps

be avoided if further tests indicate that a weaker solution of Argentum nitricum is sufficient

As has been shown, the procedure is simple, (…) completely without risk and seemingly reliable in terms of its effect

(…) my set of observations is (…) still sufficiently extensive and striking

to warrant further urgent application of the procedure I wish to lay special emphasis on the finding that the desired effects are achieved through dis-infection of the eyes themselves rather than the vagina It is to be hoped that the future will tell whether the eye procedure that I have been using is the best and most reliable one (…) For the time being, I have no reason to deviate from my own method

Needless to say, the successful banishment of inflammatory eye eases at least from maternity hospitals and clinics would constitute a major achievement in many respects

Lastly, I wish to present some figures for cases of inflammatory eye ease observed in this maternity hospital in recent years (…)

births

Number of cases of inflammatory eye disease

*This is the case in which the eyes were not disinfected; the figure should therefore read 0.0%

In the first paper (1881; [19]) Credé strictly focused on practical aspects of prophylaxis of ophthalmia neonatorum It was recognized that the way of transmission was by direct contact with vaginal excretions He described hygienic procedures of cleaning the vagina, described several interim stages

of eye drops applied to the newborn, and ended up with the abandonment

of vaginal douches/extensive cleaning of the vagina and introduction of

the consequent direct eye prophylaxis in every delivered newborn with a single drop of 2% silver nitrate solution per eye applied to the middle of the cornea by a glass rod from June 1st 1880 onwards This prophylactic method was declared as highly efficacious, easy to handle and without adverse effects apart from a slight hyperemia and some increased secre-tion from the conjunctiva within the first 24 h in some cases Already in this paper Credé recommended that this procedure of eye prophylaxis should also be put into the hands of midwives Etiologically, Credé only mentioned

an “Infektionsstoff” (contagious agent) as reason for the disease; further microbiological aspects – including Neisser’s new discovery of 1878/1879 – are not addressed

The second paper (1881; [20]) verified the effectiveness of this dure by reports of an additional 400 new cases (first paper [19]: 200 cases) including 300 newborns treated with a simplified regimen In contrast to the method described first, in the simplified regimen, the cord was cut and the newborn was washed Thereafter the eyes were wiped clean with water, and a 2% silver nitrate solution was applied by the same way as mentioned before In contrast, no consecutive treatment/manipulations at the eyes were performed None of the 400 newborns developed ophthalmia neonatorum

proce-In this paper, Credé highlighted that the application of 2% silver nitrate solution directly into the newborn’s eye has to be performed immediately after the first manipulations, as mentioned above, after delivery Further, for the first time, Credé addressed the aspect of introducing this method of eye prophylaxis to general practitioners active in obstetrics for prophylaxis

of corresponding newborn outpatients In particular, the need for putting the prophylaxis into the hands of midwives was stressed again In addition, the aspect of treatment for ophthalmia neonatorum by stronger solutions

of silver nitrate was addressed for the first time The most critical/political aspect coming up in this paper was the suggestion – as mentioned before – of giving the prophylaxis into the hands of midwives, which meant break-ing with a prestigious medical privilege in obstetrics by apparently by-pass-ing the outstanding authority of the physician/obstetrician Credé suggests that every midwife should obtain a bottle of 2% silver nitrate solution and

a corresponding glass rod His interest was that hereby ophthalmia torum could be eradicated Microbiologically, the disease was attributed to

neona-a “Contneona-agium” neona-as the cneona-ausneona-ative neona-agent without more detneona-ailed discussions neona-and without presentation of Neisser’s actual new insights

The third paper (1883; [21]) gave a synopsis of Credé’s overall ences on ophthalmia neonatorum and was divided into two parts The first part focused on the aspect of prevention and the second part on the aspect

experi-of etiology experi-of ophthalmia neonatorum

In the relatively short first part of this paper, Credé stated that he sidered the issue of prophylaxis for ophthalmia neonatorum as solved The method suggested by him appeared easy to handle, safe and effective He gave the advice not to deviate from this proposed method, as in some insti-

con-tutions, where modified procedures were performed, poorer results were achieved.

The second part of this paper was announced to focus on etiological aspects of ophthalmia neonatorum Indeed, this was only partly the issue, and this part of the paper was in many perspectives highly political

The transmission of ophthalmia neonatorum via direct vaginal contact

was reaffirmed and aspects such as duration of the delivery period, gender

of the newborn, etc., were discussed from the etiological perspective Credé

stated that he considered the “Diplococcus Neisser” the most probable

caus-ative pathogen (“specifisch gonorrhoeisches Virus Diplococcus Neisser”) This one sentence of his series of publications was Credé’s only hint at Neisser’s tremendous achievements concerning the etiology of gonorrhea (Neisser’s second comprehensive publication on the etiology of gonorrhea had been published 1 year before in 1882)

In the following part, Credé stated that it was his achievement, having obtained the insight that vaginal douches were almost ineffective and that the contagious agent had to be destroyed sufficiently, that the prophylactic efforts, which had not been performed before, were put into place As a method for the sufficient destruction of the contagious agent he stated again the administration of 2% silver nitrate solution directly into the eyes of every newborn child, including consecutive hygienic precautions to prevent

a later inoculation of the child’s eye by vaginal discharge from the mother

As dose justification for the 2% silver nitrate solution he cites a study from Hecker [24], who performed the eye prophylaxis with a 1% silver nitrate solution Of 133 children, 4 developed ophthalmia neonatorum in this study, although even Hecker pointed out that compliance was poor within this study, and it still remained unclear to the reader if the eyes were washed with NaCl solution afterwards, as described in the paper in case of treatment for ophthalmia neonatorum with aqueous silver nitrate solution Credé ignored all of this argumentation and insisted that the 1% silver nitrate solution was ineffective for the prophylaxis of gonorrheal ophthal-mia neonatorum, which he considered as an undisputable justification for his 2% regimen

Afterwards, a long, enthusiastic plea for giving the prophylaxis into the hands of midwives was given again It was discussed that even potential misuse by midwives could not cause significant disadvantages in contrast to the tremendous advantages of a broad application of this prophylaxis A lot

of concerns against giving the prophylaxis into the hands of midwives, which were brought forward by physicians, were cited, discussed and declared invalid

At the end of this manuscript, Credé highlighted that on January 31st

1883 his prophylactic eye regimen was enforced by law for cases of hospital deliveries in Austria The procedure should – by law – be performed only by physicians; indeed, Credé did not oppose in this special case Nevertheless,

he encouraged every country to release such a law

The complementary booklet on this issue (fourth publication), written

in English language (1884; [23]), gave a comparable synopsis on gonorrheal ophthalmia neonatorum and its prophylaxis such as given in the third paper.Fascinating is, how extremely precise and concerned Credé was with issues he was dealing with In the English publication, for example, he gave

a very detailed description of the solution, its storage and the glass rod being applied It was described that the solution of silver nitrate should be kept

in a dark bottle made of glass with a glass stopper The glass rod to be used should be 15 cm in length, 3 mm thick and rounded at both ends The little bottle and glass rod had to be stored in a small drawer in the swaddling table The solution had to be renewed every 6 weeks, but it was pointed out that it was not critical, concerning safety and efficacy, if the solution was accidentally used for a longer period of time No room for personal freedom was left open concerning this issue This description was an excellent reflec-tion of Credé’s personality With him, nothing was left open to accident and/or to spontaneous occurrence

Ludwig Sigesmund Albert Neisser and insights into etiology and pathophysiology of gonorrhea at Credé’s time

Ludwig Sigesmund Albert Neisser (1855–1916) was a German physician and bacteriologist [25–32] He was a school classmate of Paul Ehrlich (1854–1915) in Breslau – former Germany – and studied medicine mainly

in Breslau thereafter Consecutively, he started specializing in ogy, although he primarily intended to specialize in internal medicine but could not get an appointment as assistant in Breslau Apart from working

dermatol-on echinococcosis (PhD thesis), leprosy and syphilis, he was the persdermatol-on who

discovered the “Micrococcus” as the causative pathogen of gonorrhea.

As a basis for this discovery, the botanist Ferdinand Cohn (1828–1898) taught Neisser Robert Koch’s (1843–1910) smear test for the microscopic examination of bacteria Julius Friedrich Conheim (1839–1884) and Carl Weigert (1845–1904) taught him bacterial staining techniques, including the methylene blue staining technique Further, Neisser had access to an excellent innovative Zeiss microscope that was equipped with Ernst Abbe’s (1840–1905) innovative condenser system and an oil-immersion object lens system This equipment allowed him detailed microscopic examinations, which were not the usual “state of the art” in 1879, the year when Neisser

discovered the “Micrococcus” microscopically.

Finally, in 1879 Neisser published a paper “Über eine der Gonorrhoe

eigenthümliche Micrococcenform” (“A form of Micrococcus typical for

gon-orrhea”) [33] In this paper he was the first person to describe that a very cal form of a somewhat peach-like (semmelartig) “Micrococcus/Diplococcus”

typi-(“Micrococcus” [33, 34], “Micrococcenhaufen” [33], “Semmelform” [33, 34],

“Diplococcus” [34]) was always found as sole bacteria in a large quantity

in genital smears of patients suffering from symptomatic gonorrhea He

mostly observed this “Micrococcus” topologically associated with

inflam-matory cells and/or epithelia Further, he stated that the best diagnostic results were obtained using the methylene blue staining technique, and that the microscopic picture was extremely typical for the disease and for him

to be certain of the association Beside a few doubts and the tion for a scientific proof, based on something like the later-discussed, com-municated and published Koch-Henle postulates (1875–1885; ideas arising and postulated by Robert Koch in the late 1870s, “Wollsteiner Zeit”) [35],

recommenda-Neisser was at that time rather convinced that the “Micrococcus” was the

causative agent of gonorrhea This statement was the milestone of Neisser’s

discovery of the “Micrococcus” as causative pathogen of gonorrhea He further stated that he found this “Micrococcus” in eye smears of gonorrheal

eye infections in adults and children He already started with cultivation approaches in 1879, which were at that time not successful, probably due

to the fact that Neisser’s poor health condition restricted the time he could spend on his scientific activities beside his clinical duties

In 1882 he published a second paper “Die Micrococcen der Gonorrhoe” (“Micrococci and gonorrhea”) [34] This paper was a very comprehensive, but from the author’s view, somewhat unconventionally structured review paper in which Neisser – in the beginning – points out in a disappointed manner that it took over a year after his first publication for other scien-

tists to pick up the topic of the “Micrococcus” and gonorrhea, and publish

new insights on this issue In this paper Neisser (a) extensively repeated his observations as stated in [33], and additionally (b) gave a drawn picture

of the “Micrococcus” and its different division stages, (c) pointed out that

other colleagues had also verified his observations (e.g., Aufrecht, Bókai, Brieger, Ehrlich, Gaffky, Haab, Hirschberger, Leber, Sattler, and Weiss), (d) reported that he successfully treated a case of gonorrheal eye infection with silver nitrate solution, (e) reported that he – beside other colleagues

– had been successful in cultivating the “Micrococcus” in 1881/1882, (f) gave

information on Bókai’s successful inoculation experiments with cultured

“Micrococcus” material in volunteer male students achieving an acute and typical genital gonorrhea, (g) gave information that the “Micrococcus” was

apathogenic on inoculating the conjunctiva of dogs and rabbits, and (h) gave information on current treatment options and the pathophysiology of gonorrhea, highlighting genital and ocular gonorrheal infections Indeed, the name of Carl Credé was never mentioned

As Bókai’s insights appeared not to have convinced Neisser, he

repeat-edly stated in this paper [34] that the strict proof for the “Micrococcus” as

causative agent of gonorrhea still had to be produced This seems an gerated skeptic statement considering this broad data basis and the aspect

exag-that Neisser repeatedly stated in this paper exag-that the “Micrococcus” could

always, and only, be found in case of symptomatic gonorrhea In contrast, the Koch-Henle postulates became overemphasized within the scientific

community at that time, which also put Neisser under an extreme pressure

concerning the validity of his insight that the “Micrococcus” was the

caus-ative agent of gonorrhea, due to the categorical force of demonstrating that

a pathogen unambiguously fulfilled these postulates

Finally, it was Neisser’s friend and school classmate Paul Ehrlich who

named Neisser’s “Micrococcus” the “Gonococcus” Therefore, a lot of Neisser’s students named Neisser the “Father of Gonococcus” [30].

Discussion of Credé’s activities and his “four publications with the same title”

In Credé’s case there was an urgent medical need for an effective laxis against gonorrheal ophthalmia neonatorum Credé realized that vaginal douches were almost ineffective in preventing ophthalmia neonatorum, and that a strong antiseptic agent for prophylactic application at the ocular infec-tion site – the newborn’s eye – was needed Potential irritative side effects had to be tolerable at this sensitive organ Further, he recognized the threat

prophy-of re-contamination prophy-of the eye by vaginal discharge especially in the first weeks after delivery so that strict hygienic requirements as well as teaching and education on this aspect became necessary and were introduced

Credé reduced the concentration of the 2.5% silver nitrate solution (eye drops) that he used initially to 2.0% and immediately recognized that he was “on the safe side” with this regimen, reducing the incidence of ophthal-mia neonatorum from approximately 10% to 0% Adverse effects of chemi-cal eye irritations were considered insignificant or even almost ignored most probably due to the high medical benefit obtained by this technique

In contrast, Hecker’s tests and results with 1% silver nitrate solution were not properly analyzed, although, to our knowledge today, a 1% solu-tion of silver nitrate would also have been appropriate with comparable effectivity but less irritative adverse effects at the eye Credé was convinced

of the urgent need of enforcing such an eye prophylaxis as soon as possible and there was obviously no time left for him for a proper dose finding study, e.g., verifying or falsifying Hecker’s observations

Further, Credé solely acted as a clinician and did not join the scientific

activities around the Micrococcus/Diplococcus and gonorrhea discussion,

which were driven by Neisser and were highly contemporary, within just

years 1879 (first paper of Neisser describing the Micrococcus cally [33]) to 1882 (Neisser’s second, review publication on the Micrococcus

microscopi-with positive cultivation and inoculation results [34]) To the present author,

it still remains an open historic miracle, as to why these two outstanding persons, Credé and Neisser, did not recognize each other appropriately Credé could have obtained a lot of additional scientific merits by joining these discussions and activities, but despite this he strictly focused on the clinical aspects of prophylaxis of ophthalmia neonatorum, most probably to

speed up and to enhance the pressure for an establishment of his lactic regimen as soon as possible Credé, therefore, focused strictly on the obstetrician’s/neonatological aspect, ignoring all recent new microbiological discoveries concerning gonorrhea within his papers published in 1881 [19,

prophy-20], 1883 (here the “Micrococcus Neisser” is only mentioned in one short

sentence as most probable pathogenic agent for gonorrheal ophthalmia neonatorum [21]) and 1884 (in English [23]) The author has never seen such a focused, condensed and straightforward approach without any scien-tific detour from the streamlined intentions as that performed by Credé.Credé additionally recognized that the midwives were the central persons/institution for rapidly spreading this prophylactic regimen to hos-pitalized patients/deliveries and outpatients This led to a high degree of controversies with his colleagues as many of them realized this as a form

of undermining the authority of the physician and obstetrician Credé wrote two outstanding books for midwives, where the aspect of ophthalmia neonatorum was also included [36, 37] Further, demonstrating his positive attitude towards the responsibilities of midwives, Credé became appointed

“Nestor of German midwifery” [8] This reflects that Credé had no concerns regarding a potential conflict of interests and/or competence between physi-cians/obstetricians and midwives

By this pragmatic, clinical, non-academic, and consequent way, by 2 years after Credé’s first publication on prophylaxis of ophthalmia neonatorum ([19]; 1881), his prophylaxis became enforced by law for clinical deliveries

in Austria in 1883, which is highlighted in his 1883 publication [21] Here Credé claimed that all countries should introduce his method and should enforce it by law [21]

His four publications on ophthalmia neonatorum all have the same title, are easy to read, clearly structured, and in most parts highly repetitive, and

do not allow alterations of the suggested prophylactic regimen For today’s understanding they appear almost like a guideline or kind of a directive.Even the famous ophthalmologist Lucien Howe (1848–1928) [38] was

so impressed by this approach that he established it in the “New World” Nevertheless, he used a weaker concentration of 1% silver nitrate as did many other physicians and countries by law In addition, silver acetate was used alternatively instead of silver nitrate in many places [39]

In summary, Credé made a great contribution to mankind, broadly

“enforcing” the eye prophylaxis against gonorrheal ophthalmia rum within 2 years without spending any unnecessary time for the final

neonato-“i-dot” of optimization of this technique

Credé’s prophylaxis today

In recent times, especially after the discovery and development of potent antibiotics, the etiology of ophthalmia neonatorum has changed signifi-

cantly Despite cases of ophthalmia neonatorum due to Neisseria

gonor-rhoeae infections, chlamydial eye infections in the newborn became more

the primary focus compared to gonorrheal eye infections [40–45] Silver nitrate and acetate show no sufficient activity in prophylaxis of chlamydial eye infections and exhibit irritative adverse effects of chemical conjunc-tivitis including consecutive psychological adverse effects (impairment in eye-to-eye contact in early maternal-infant attachment), which are currently under discussion [46–50] Many antibiotic and other aseptic kinds of eye prophylaxis have therefore been considered and evaluated for prophylaxis

of ophthalmia neonatorum [51–55] At present, aseptic eye prophylaxis with povidone-iodine at different concentrations (preferably 1–2.5%) is often recommended [56–63]

Nevertheless, one aspect did not change: the name for the procedure itself Independent of which compound the prophylactic eye drops contain, the procedure of eye prophylaxis against ophthalmia neonatorum is often still today declared as “Credé’s prophylaxis” [64–67]

Further, with the program “VISION 2020”, the WHO states that thalmia neonatorum is still an important health issue today [68, 69], which reflects its persistent actuality

oph-Some confusion about Carl Credé?

Some confusion might arise as two other Carl Credé are described within medical history Some brief information is given here to avoid confusion:

Benno Carl Credé

Benno Carl Credé (also: Carl Benno Credé; 1847–1929) was Carl Siegmund Franz Credé’s son [70–72] Despite his christian name Benno, he also appears under the name Carl Credé in the literature Credé studied medi-cine and specialized as a surgeon in Dresden, Germany, thereafter

Scientifically, Credé followed the steps of his father in so far as ing research activities on silver in colloidal form, which he introduced into medical practice in 1897 This was possible by collaboration with the com-pany “Chemische Fabrik von Heyden”, and led to the development of the

perform-“Collargolum Credé” (“Collargol”) [73, 74] for systemic, parenteral

thera-py Thus, it should be highlighted that the “Collargolum Credé” goes back

to Benno Carl Credé and not to his father, Carl Siegmund Franz Credé.Wrong information concerning Credé is deriving from the internet, which is found in the biography of Otto Spiegelberg [75]: “After the closing

of the Monatsschrift für Geburtshilfe und Frauenkrankheiten (appeared 1853–1869) Spiegelberg and Carl Benno Credé (1847–1929) in 1870 found-

ed the Archiv für Gynäkologie, of which almost every volume contained a

contribution of his” Actually, the editors of the “Archiv für Gynäkologie” were “(Otto) Spiegelberg” and “Credé”, in this case Carl Siegmund Franz Credé and not his son, Benno Carl Credé.

Carl Credé

Carl Credé (Carl Credé-Hoerder; 1878–1952) [76, 77], a physician, had an uncle – who was also a physician – with the name Dr Hoerder Later on Carl Credé incidentially took over the name Carl Credé-Hoerder He fur-ther used his synonym “Credo” He was politically extremely active and a co-founder of the “Verein sozialistischer Ärzte” (Association of physicians following socialists’ ideology) In his position as physician he specialized in gynecology and obstetrics Due to his political activities, Credé spent several years in prison, following the (unjustified?) accusation of violation of the German law concerning abortion (§218 StGB; Germany)

In 1913, he published a scientifically less significant paper on “Die

Augeneiterung der Neugeborenen, Pathologie, Therapie und Prophylaxe”

[77] (Ophthalmia neonatorum, etiology, pathology, therapy and laxis) In the present author’s estimation, the motivation for this publication was to be brought together with the ideas of Carl Sigmund Franz Credé, possibly to cause confusion If or how Credé was related to Carl Siegmund Franz Credé remains historically unclear

prophy-Acknowledgement

I would like to express my thanks for assistance especially to the staff of the “ZB MED/Deutsche Zentralbibliothek für Medizin” (The German National Library of Medicine) in Cologne, Germany

Im Allgemeinen kommen die Augenentzündungen der Neugeborenen seltener in den höheren Ständen vor, häufig schon im Proletariate, aber in den Entbindungsanstalten gehören sie zu einer fortlaufenden, höchst lästi- gen Plage und Sorge Deshalb wende ich zunächst meine Aufforderung, die von mir empfohlene Prophylaxis weiter zu erproben, an diejenigen Herren Collegen, welche in Entbindungsanstalten oder in geburtshülfli- chen Polikliniken thätig sind, und, gleich mir, häufige Erkrankungen zu beobachten haben.

Wohl von den meisten Geburtshelfern wird meine Ansicht eilt werden, dass die so überaus häufig vorkommenden Katarrhe und Entzündungen der Vagina auf gonorrhoischer Infection beruhen und dass die Ansteckungsfähigkeit des Secretes noch fortbesteht, nachdem lange die specifisch gonorrhoischen Erscheinungen verschwunden sind, ja dass

geth-in Fällen, wo fast kegeth-in Secret mehr gefunden wird, doch noch die erfolgte Ansteckung in der Mutterscheide stattgefunden hat, wenn in den ersten Tagen nach der Geburt eine Augenentzündung sich entwickelt.

Eine Übertragung des Infectionsstoffes von einem anderen augenkranken Kinde ist für die Leipziger Entbindungsanstalt völlig auszuschließen, da jedes inficirte augenkranke Kind mit seiner Mutter auf die Krankenstation verlegt wird, welche von der Station der Wöchnerinnen nach allen Richtungen hin vollständig getrennt ist Auch können die Wöchnerinnen die Kinder mit- tels ihrer Finger, welche etwa durch Lochialsekret verunreinigt wären, kaum inficiren, weil die Kinder stets von den Müttern so weit entfernt in ihren Bettchen liegen, dass die Mütter sie nicht erreichen können und nur dann mit den Kindern in Berührung kommen, wenn diese ihnen von den Wärterinnen

an die Brust gelegt werden.

Somit bin ich nach meinen Beobachtungen und Einrichtungen der Ueberzeugung, dass fast ohne Ausnahme die in der hiesigen Anstalt erkrank- ten Kinder nur durch eine directe Uebertragung des Vaginalsecretes in das Auge während des Geburtsactes inficirt werden Die Erkrankung des inficirten Auges beginnt in der Regel etwa zwei bis drei Tage nach der Geburt, aber auch früher und später, je früher, desto intensiver.

Ich habe mir nun schon seit längerer Zeit die gewiss lohnende Aufgabe gestellt, die Mittel und Wege zu finden, wie man die für so viele Augen verderbliche Krankheit verhüten, wie am besten dem ansteckenden Secrete beikommen könne.

Meine ersten Bemühungen erstreckten sich auf eine möglichst dehnte zweckmässige Behandlung und Reinigung der kranken Vagina der Schwangeren und Gebärenden Die Resultate waren jedoch gering, nicht befriedigend; die Zahl der Erkrankungen der Augen nahm zwar ab, aber sie verschwanden nicht Darauf begann ich die Desinfection der Kinderaugen selbst und fortan wurden die Erfolge überraschend günstig.

ausge-Der Gang meiner Versuche war folgender: Zuerst wurden bei allen MIT

G ONORRHOE ODER CHRONISCHEM V AGINALKATARRH in die Anstalt menden Schwangeren und Gebärenden reinigende Ausspülungen der Vagina

kom-mittels lauwarmen Wassers oder leichter Carbol- oder Salicylsäurelösungen (2:100) möglichst häufig, bei Gebärenden jede halbe Stunde gemacht Die Erkrankungen der Augen wurden seltener, hörten aber nicht auf, ja verliefen

in einigen Fällen noch hartnäckig und bösartig.

Im October 1879 machte ich den ersten Versuch mit prophylaktischen Einträufelungen in die Augen der Neugeborenen gleich nach der Geburt und bediente mich einer Lösung von Borax (1:60), weil ich dieses Mittel für das mildeste, wenigst ätzende hielt Es geschah dies aber zunächst nur bei Kindern von kranken Müttern, bei denen gleichzeitig die oben angeführten Ausspülungen der Scheide während der ganzen Geburt gemacht worden waren Auch diese Methode führte nicht zum gewünschten Ziele, und ich nahm vom December 1879 statt des Borax Lösungen von Argentum nitri- cum (1:40), welche bald nach der Geburt in die Augen eingespritzt wurden Vor der Einspritzung wurden die Augen mit einer Lösung von Salicylsäure (2:100) sorgfältig gewaschen Die so behandelten Kinder kranker Mütter bli- eben gesund, indess andere Kinder, welche selbst und ebenso ihre Mütter, weil wir letztere für nicht erkrankt hielten, nicht prophylaktisch behandelt worden waren, erkrankten immer noch, zwei ziemlich heftig.

Vom 1 Juni 1880 an wurden nun alle Augen ohne Ausnahme gleich nach der Geburt desinficirt und zwar in der Weise, dass eine schwächere Lösung von Argentum nitricum (1:50) gewählt, auch die Flüssigkeit nicht mehr eingespritzt, sondern nur mittels eines Glasstäbchens in jedes durch einen Gehülfen sanft geöffnete, vorher mit gewöhnlichem Wasser gereinigte Auge ein einziger Tropfen Flüssigkeit eingeträufelt wurde Dann wurden die Augen

24 Stunden lang mit in Salicylwasser (2:100) getränkten Leinwandläppchen gekühlt DIE ZAHLREICHEN V AGINALDOUCHEN WURDEN DAGEGEN GÄNZLICH AUFGEGEBEN und kamen nur aus anderen Gründen, die ganz unabhängig von den Vaginalkatharren waren, zur Anwendung SÄMMTLICHE SO BEHAN -

DELTE K INDER SIND VON A UGENENTZÜNDUNGEN , SELBST LEICHTESTEN

G RADES , VERSCHONT GEBLIEBEN , obwohl manche der Mütter hochgradige Scheidenblenorrhöen und trachomatöse Wucherungen zeigten Nur ein Kind (Jahresnummer 339) erkrankte am SECHSTEN Tage an einer mässi- gen Entzündung der Conjunctiva des linken Auges, ohne Schwellung des Augenlides, welche nach drei Tagen wieder geheilt war, und stellte sich heraus, dass bei diesem Kinde im Drange der Geschäfte zufällig die prophylaktische Einträufelung nicht gemacht worden war.

Irgend ein Nachtheil für die so behandelten Augen haben wir bis jetzt nicht beobachtet Nicht selten folgt der Einträufelung eine geringe Hyperämie, ab und zu auch eine etwas verstärkte Secretion der Conjunctiva in den ersten 24 Stunden Dann verschwinden auch diese Erscheinungen Vielleicht sind sie zu vermeiden, wenn die weiteren Versuche ergeben sollten, dass eine schwächere Lösung des Argentum nitricum genügt.

Das Verfahren ist demnach sehr einfach, überall von einigermaassen geschickten Händen leicht auszuführen, ganz gefahrlos und, wie es scheint, zuverlässig in der Wirkung.

Meine Beobachtungsreihe ist freilich noch zu klein, um ganz sichere Schlüsse zuzulassen, immerhin aber gross und namentlich frappant genug,

um zu weiterer Anwendung dringend aufzufordern DEN H AUPTWERTH MÖCHTE ICH IN DIE E RFAHRUNG LEGEN , DASS NICHT DIE D ESINFECTION DER

V AGINA , SONDERN NUR DIE DER A UGEN SELBST ZUM GEWÜNSCHTEN Z IELE FÜHRT Ob nun gerade das von mir geübte Verfahren an den Augen das beste und sicherste sei, oder ob noch bessere gefunden werden können, wird hof- fentlich die Zukunft lehren Zunächst habe ich keinen Grund, von meiner Methode abzuweichen.

Sollte es gelingen, die Augenentzündungen auch nur aus den Entbindungsanstalten und den Polikliniken zu verdrängen, so wäre schon dadurch ein Gewinn von grosser Tragweite nach verschiedenen Richtungen hin erreicht, was ich hier wohl nicht näher auseinanderzusetzen brauche Schließlich theile ich ganz kurz eine Zahlenreihe über die in den letzten Jahren in der hiesigen Entbindungsanstalt beobachteten Augenentzündungen mit Vielleicht sind anderswo die Erkrankungen der Vagina und demnach die der Kindesaugen weniger häufig, als gerade in Leipzig, dessen eigenthümli- che, von vielen, auch grösseren Städten abweichende Verhältnisse besonders

in Betracht gezogen werden müssen.

Geburten Augenerkrankungen Zahl der Procentsatz

1 Feng QL, Wu J, Chen GQ, Cui FZ, Kim TN, Kim JO (2000) A mechanistic study

of the antibacterial effect of silver ions on Escherichia coli and Staphylococcus aureus J Biomed Mater Res 52: 662–668

2 Quelmaltz ST (1740) De caecitate infantum floris albi materni ejusque virulanti pedisseque dissertatione PhD Thesis, Leipzig

3 Gibson B (1807) On the common cause of puriform ophthalmia of new-born

children Edinburgh Med Surg J 3: 159–161

4 Ammon FA v (1825) Pathology of the eye bulbus and its adnexes during the ness entitled ophthalmitis of the new-born child (“Das pathologische Verhalten des Augapfels und seiner Häute während des Verlaufs der sogenannten

ill-Augenentzündung neugeborener Kinder”) In: Hecker’s Annalen, Vol 1, TCF

Enslin, Berlin, 129–142

5 Bednar A (1848) Treatment of ophthalmia neonatorum (“Über die Behandlung

der Augenentzündung der Neugeborenen”) Zschr k k Ges Ärzte 5: 139–145

6 Mackenzie W (1854) Practical Treatise on the Diseases of the Eye Longmann,

11 Schaller UC, Klauss V (2001) Is Credé’s prophylaxis for ophthalmia

neonato-rum still valid? Bull WHO 79: 262–263

12 Dunn PM (2000) Dr Carl Credé (1819–1892) and the prevention of ophthalmia

neonatorum Arch Dis Child Fetal Neonatal Ed 83: 158–159

13 Rosenberg J (1892) In memoriam, Carl Siegmund Franz Credé Am J Obstet Gynecol 25: 780–783

14 Leopold G (1891) Talk in remembrance of Carl Siegmund Franz Credé (“Carl

Siegmund Franz Credé Gedächtnisrede”) Arch Gynäkol 42: 193–212

15 Author unknown (Dr L) (1892) Karl Credé Illustrierte Zeitung, press release,

no 2543

16 Credé CSF (1854) Manual expression of the placenta (“Handgriff zur Entfernung der Plazenta”) Klinische Vorträge über Geburtshilfe, Hirschwald, Berlin, 599–

600

17 Speer H (1957) Carl Siegmund Credé, placental expression, and the prevention

of ophthalmia neonatorum Obstet Gynecol 10: 335–339

18 Credé CSF (1884) Incubation systems for early for date and weak small dren (“Ueber Erwärmungsgeräthe für frühgeborene und schwächliche kleine

chil-Kinder”) Arch Gynäkol 24: 128–147

19 Credé CSF (1881) Die Verhütung der Augenentzündung der Neugeborenen

(“Prevention of inflammatory eye disease in the newborn”) Arch Gynäkol 17:

50–53

20 Credé CSF (1881) Die Verhütung der Augenentzündung der Neugeborenen

(“Prevention of inflammatory eye disease in the newborn”) Arch Gynäkol 18:

367–370

21 Credé CSF (1883) Die Verhütung der Augenentzündung der Neugeborenen

(“Prevention of inflammatory eye disease in the newborn”) Arch Gynäkol 21:

179–195

22 Credé CSF (2001) Prevention of inflammatory eye disease in the new-born (“Die Verhütung der Augenentzündung der Neugeborenen”) Translation of

[19] by WHO Bull WHO 79: 265–266

23 Credé CSF (1884) Die Verhütung der Augenentzündung der Neugeborenen (“Prevention of Inflammatory Eye Disease in the Newborn”) Hirschwald,

Berlin

24 Hecker C v (1882) On blephanorrhoea neonatorum (“Über Blephanorrhoea

neonatorum”) Arch Gynäkol 20: 386–398

25 Oriel JD (1989) Eminent venerologists 1 Albert Neisser Genitourin Med 65:

30 http://www.whonamedit.com/doctor.cfm/2441.html

31 Kampmeier RH (1978) Identification of the gonococcus by Albert Neisser

1879 Sex Trans Dis 5: 71–72

32 Haneveld GT (1979) The centenary of the gonococcus: the importance of its discovery and the acknowledgement of this in The Netherlands (Ludwig

Sigesmund Albert Neisser) Ned Tijdschr Geneeskd 123: 1875–1878

33 Neisser A (1879) A form of micrococcus typical for gonorrhea (“Über eine der

Gonorrhoe eigenthümliche Micrococcenform”) Zentralbl Med Wissenschaften

17: 497–500

34 Neisser A (1882) Micrococci and gonorrhea (“Die Mikrokokken der

Gonorrhoe”) Dtsch Med Wochenschr 8: 279–283

35 Köhler W (1994) Historical development of medical microbiology (“Historische Entwicklung der Medizinischen Mikrobiologie”) In: H Brandis, HJ Eggers, W

Köhler, G Pulverer (eds): Handbook of Medical Microbiology (“Lehrbuch der Medizinischen Mikrobiologie”) Fischer, Stuttgart, 3–17

36 Credé C, Winckel F (1875) Handbook for Midwives (“Lehrbuch der Hebammenkunst”) S Hirzel, Leipzig, 117–118 / 237–243 (§§167, 358–366)

37 Credé C, Leopold G (1892) Handbook of Obstetrics for Midwives (“Lehrbuch der Geburtshülfe für Hebammen”) S Hirzel, Leipzig, 254–258 (§§ 358–365)

38 Vail D (1963) Lucien Howe: the laboratory and experimental ophthalmology

Am J Ophthalmol 55: 261–279

39 Sullivan MF (1952) Silver acetate as a prophylactic for ophthalmia

neonato-rum J Indian Med Assoc 21: 528–529

40 Cordell JPM (1936) Ophthalmia neonatorum Trans Ophthalmol Soc UK 56:

3–7

41 Holmes KK, Counts GW, Beatty HN (1971) Disseminated gonococcal

infec-tion Ann Intern Med 74: 979–993

42 Wilcox RR (1972) A world look at the venereal disease: recrudescence of the

venereal diseases Med Clin North Am 56: 1057–1071

43 Armstrong JH, Zacarias F, Rein MF (1976) Ophthalmia neonatorum: a chart

review Pediatrics 57: 884–892

44 Handsfield HH, Hodson KK (1973) Neonatal gonococcal infection: orogastric

contamination with Neisseria gonorrhoeae J Am Med Assoc 225: 697–701

45 Huber-Spitzy V, Arocker W, Schmidt C (1987) Ophthalmia neonatorum Klin Mbl Augenheilk 191: 341–343

46 Lehrfeld L (1935) Limitations of use of silver nitrate in prevention of

ophthal-mia neonatorum J Am Med Assoc 104: 1468–1469

47 Robson KS (1967) The role of the eye-to-eye contact in maternal-infant

attach-ment J Child Psychol Psychiatry 8: 13–25

48 Nishida H, Risemberg HM (1975) Silver nitrate ophthalmic solution and

chemical conjunctivitis Pediatrics 56: 368–373

49 Butterfield PM, Emde RN, Svejda MJ (1981) Does the early application of

silver nitrate impair maternal attachment? Pediatrics 67: 737–738

50 Graf H, Retzke U, Schilling C, Schmidt M (1994) Reaction of the mic front region to the Credé-prophylaxis (“Die Reaktion des vorderen

ophthal-Augenabschnittes auf die Credé-Prophylaxe”) Zentralbl Gynäkol 116: 639–

642

51 Greenberg M, Vandow JE (1961) Ophthalmia neonatorum: evaluation of

different methods of prophylaxis in New York City Am J Public Health 51:

836–845

52 CDC (Centers for Disease Control) (1989) Sexually transmitted diseases

treat-ment guidelines MMWR 38: 8

53 Chen JY (1992) Prophylaxis of ophthalmia neonatorum: comparison of silver

nitrate, tetracycline, erythromycin and no prophylaxis Pediatr Infect Dis J 11:

1026–1030

54 Seiga K, Shoji T (1993) Chemoprophylaxis of ophthalmia neonatorum through vertical infection Evaluation of Crede’s method using norfloxacin and genta-

mycin Jpn J Antibiot 46: 331–336

55 Kramer A, Behrens-Baumann W (1997) Prophylactic use of topical

anti-infec-tives in ophthalmology Ophthalmologica 211 (S1): 68–76

56 Benevento WJ, Murray P, Reed CA, Pepose JS (1990) The sensitivity of

Neisseria gonorrhoeae, Chlamydia trachomatis, and herpes simplex type II to disinfection with povidone-iodine Am J Ophthalmol 109: 329–333

57 Isenberg SJ, Apt L, Yoshimori R, Leake RD, Rich R (1994) Povidone-iodine for

ophthalmia neonatorum prophylaxis Am J Ophthalmol 118: 701–706

58 Isenberg SJ, Apt L, Wood M (1995) A controlled trial of povidone-iodine as

prophylaxis against ophthalmia neonatorum N Engl J Med 332: 562–566

59 Reimer K, Fleischer W, Brogmann B, Schreier H, Burkhard P, Lanzendorfer

A, Gumbel H, Hoekstra H, Behrens-Baumann W (1997) Povidone-iodine

lipo-somes – an overview Dermatology 195 (S2): 93–99

60 Kramer A, Below H, Behrens-Baumann W, Muller G, Rudolph P, Reimer K

(2002) New aspects of the tolerance of povidone-iodine in different ex vivo models Dermatology 204 (S1): 86–91

61 Isenberg SJ, Apt L, Campeas D (2002) Ocular applications of povidone-iodine

Dermatology 204 (S1): 92–95

62 Simon JW (2003) Povidone-iodine prophylaxis of ophthalmia neonatorum Br

J Ophthalmol 87: 1437

63 Isenberg SJ, Apt L, Del Signore M, Gichuhi S, Bermann NG (2003) A double

application approach to ophthalmia neonatorum prophylaxis Br J Ophthalmol

66 Watten RG (1994) Reinvention of visual fatigue: accumulation of scientific

knowledge or neglect of scientific history? Ophthalmic Physiol Opt 14: 428–

432

67 Editorial Board (2002) New aspects in prophylaxis of ophthalmia neonatorum

(Credé prophylaxis) Wien Klin Wochenschr 114: 171–172

68 Laga M, Meheus A, Piot P (1989) Epidemiology and control of gonococcal

ophthalmia neonatorum Bull WHO 67:471–477 [Erratum: Bull WHO (1990)

68: 690]

69 Gilbert C, Foster A (2001) Childhood blindness in the context of VISION 2020

– The Right to Sight Bull WHO 79: 227–232; http://www.scielosp.org/scielo.

Leipzig, 1–9

74 Beyer JL (1904) Use of Kolloidal Metalls in Medicine: Silver and Mercury (“Über die Verwendung kolloider Metalle – Silber und Quecksilber – in der Medizin”) L Simion, Berlin, Germany

77 Albrecht B, Albrecht G (1989) Carl Credé In: Albrecht B, Albrecht G (eds):

Diagnoses Remembrances on physician of the 20th century (“Diagnosen Ärzteerinnerungen aus dem 20 Jahrhundert”) Der Morgen, Berlin, 416–417