REFERENCES
1. Brooke CGD: Problems of growth and development, in: O’Riordan JL (ed): Recent Advances in Endocrinology and
Metabolism New York, Churchill Livingstone, 1978, chap 7 2. Wise PH: Growth hormone deficiency: Choice of provocative
tests.Patient Management 2:57, 1978
3. Wise PH, Burnet RB, Geary TD, et al: Selective impairment
ofgrowth hormone release to physiological stimuli. Arch Dis Child 50:210, 1975
Reprint requests to (H.M.F.) Department of Family Medicine, University ofConnecticut Health Center, Farmington, CT 06032. PEDIATRICS (ISSN 0031 4005). Copyright © 1980 by the American Academy of Pediatrics.
puberty by February 1976 when height was 149.1 cm.
When last seen on Oct 29, 1976 at 15.2 years he was well. Total height gain of 38.1 cm had occurred with a mean
growth velocity of 9 cm/annum during treatment. The patient was admitted to Flinders Medical Centre
on March 11, 1976 having been found unconscious in his
bathroom. On admission he was responsive only to simple
commands, and a dense left hemiplegia and weakness of
the left seventh upper motor neuron was noted. There was mild neck stiffness. Brain stem compression super-vened some hours later with development of Cheyne-Stokes respiration, ventricular fibrillation, and cardiac arrest.
Autopsy confirmed the presence of massive intracra-nial hemorrhage secondary to extensive arteniovenous malformation. There was gross anatomical disruption with secondary hemorrhage into subarachnoid and yen-tricular systems. The vascular malformation was corn-pletely destroyed, and no abnormal vessels could be iden-tilled. There was no lesion in the cerebellum, and apart from pulmonary congestion, other systems were normal. The retinae were not examined.
DISCUSSION
Shortness of stature was investigated in this child
and attributed to isolated growth hormone
defi-ciency resulting from arteriovenous malformation
of the hypothalamus and pituitary. However, a
coincidence of idiopathic growth hormone
defi-ciency cannot be excluded, since the anatomical
lesion, as radiologically defined, appeared to be confined to one hemisphere. There was also a right-sided retinal angioma with cutaneous hemangioma
of the right upper side of the face. Although there
was no history of seizure or EEG abnormality, this
patient is considered to have had a variant of the
Sturge-Weber syndrome, with the lesion producing
interference with growth hormone release
mecha-nisms rather than paroxysmal convulsive
poten-tials.
It is unusual for a structural lesion to cause an
isolated deficiency of growth hormone as
demon-strated here: the minor pubertal delay demon-strated is common with growth hormone deficiency
of various etiologies. Had the patient lived longer, it is conceivable that other pituitary deficiencies may have developed.
A conservative approach was chosen as the
pa-tient was asymptomatic and the deep situation of
the malformation was felt to render hemorrhage
less likely. Whether the final event could have been
surgically prevented remains conjectural. It is also possible that growth hormone might have increased the vascularity of the malformation and hastened the outcome.
ACKNOWLEDGMENTS
We are grateful to the Hormone Pituitary Advisory Committee for making growth hormone available for treatment of this patient.
J. D. RUSSELL, MB, FRACP
P. H. WISE, PHD, FRCP, FRACP
Flinders Medical Centre
Bedford Park, South Australia
H. G. RISCHBIETH, MB, FRACP
Adelaide Children’s Hospital Adelaide, South Australia
Bacterial
Endocarditis
Caused
by Vitamin
B6-Dependent
Viridans
Group
Streptococcus
Bacterial endocarditis in children ‘ and adults4
is most commonly due to infection with viridans group Streptococcus. A variant of this organism,
which requires vitamin B6 or thiol compounds for
optimal growth has been recovered from adults with endocarditis.9 The purpose of this report is
to present the case histories of two children with bacterial endocarditis from whom a vitamin B
dependent viridans group Streptococcus was
re-covered and to emphasize the importance of this
both in diagnosis and therapy.
CASE REPORTS
Case I
310 PEDIATRICS Vol. 66 No. 2 August 1980 and the pulmonary artery banded. He remained in stable condition but with increasing cyanosis and was seen be-cause of a three-week history of “feeling feverish?’ A blood culture was obtained and it, as well as seven others
obtained subsequently, was positive for a vitamin B6-dependent viridans group Streptococcus. On admission to the hospital he did not appear acutely or chronically ifi. There was moderate cyanosis and clubbing. Vital signs
were normal. There were no petechiae, hemorrhages, or
other cutaneous signs of endocarditis. A thrill was
pal-pable in the third left intercostal space associated with a
grade 3/6 harsh systolic ejection murmur. A new diastolic murmur characteristic of aortic insufficiency was heard along the entire left sternal border. The hematocrit was
37.5%; the white blood cell count was 9,400/cu mm with
a normal differential; the erythrocyte sedimentation rate was 11 mm/hr; urinalysis was normal; and the
rheuma-toid factor was negative.
Echocardiogram showed fine fluttering of the tricuspid
valve and a vegetation was present on the aortic valve.
Dental examination showed erupting six-year molars but
no evidence of disease.
The minimum inhibitory concentration (MIC) of
pen-icilhin for the vitamin Be-dependent viridans group Strep-tococcus was 0.03 g/ml, which indicated penicillin sen-sitivity; however, the minimum bactericidal
concentra-tion (MBC) was 8 tg/ml indicating penicillin resistance
(Table). The combination of penicillin plus gentamicin
showed an in vitro additive effect. A one log,0 decrease in the number of organisms was observed in the presence of
both penicillin and gentamicin (both at one half of the
MBC) as compared to the number remaining after incu-bation with either antibiotic alone. The patient was treated with aqueous penicillin 200,000 units/kg/day and
with gentamicin 5 mg/kg/day. Both drugs were given
intravenously and therapy was continued for four weeks.
The patient’s serum bactericidal titer (Schlicter test) was
>1:128 one hour after the penicillin infusion.
At the end of the fourth week of therapy, the patient
suddenly sustained a cerebrovascular accident with the development of hemiparesis on the right side. There was no evidence of a central nervous system hemorrhage nor of infection and it was, therefore, concluded that this was
due to an aseptic embolus.
TABLE. Minimum Inhibitory Concentrations (MIC) and Minimum Bactericidal Concentrations (MBC)*
MIC MBC MBC/MIC
Case 1
Penicillin 0.03 8 266
Gentamicin 8 8 1
Streptomycin 16 32 2
Vancomycin 0.05 >32 >32
Case 2
Vancomycin 1 >32 >32
Penicillin 0.125 0.125 1
Streptomycin 2 16 8
Gentarnicin 8 16 2
* Minimum inhibitory concentrations (MIC) and
mini-mum bactericidal concentrations (MBC) expressed in
micrograms per milliliter determined using an initial
in-oculuin of 10 bacteria/nil ofB-dependent viridans group
Streptococcus.
Case 2
J.H., a 16-year-old girl was admitted to the hospital
because of a four-week history of fever and a two-week history of calf and hip pain. She had been in good health,
although a heart murmur of undetermined origin had
been heard for some time.
On admission she had a temperature of 38 C (100.5 F). She appeared in good health and positive findings on physical examination included a grade 4/6 pansystolic apical murmur with radiation to the axilla. No diastolic murmurs were heard. The sacroiliac area was tender but not swollen or warm. No petechiae or hemorrhages were seen and fundoscopic examination was normal. The he-matocrit was 34.9%; white blood cell count was 8,400/cu mm with a normal differential; the erythrocyte sedimen-tation rate was 103 mm/lu; and urinalysis was normal. The echocardiogram showed posterior mitral valve pro-lapse, but no vegetations were seen. Three blood cultures
were positive for vitamin B6-dependent viridans group
Streptococcus.
Because of a history of penicillin allergy, therapy was
started with intravenous gentamicin (180 mg/day) and vancomycin (2 gm/day). The gentamicin was discontin-ued on the tenth day of therapy since no synergy with vancomycin was demonstrated by the isobologram method.’#{176}Vancomycin, to which the bacteria were
sen-sitive by disc diffusion method, was continued for an additional 14 days.
All symptoms disappeared on the second day of ther-apy and the patient was discharged after a four-week hospitalization. She was seen two weeks after discharge
and had no complaints, but two blood cultures obtained
on this visit were positive for vitamin B6-dependent viii-dana group Streptococcus. She was rehospitalized; on admission her vital signs were normal and results of her physical examination remained the same as at previous discharge. Laboratory studies were normal including an erythrocyte sedimentation rate of 12 mm/hr. A search for a source ofinfection could not be found, but four impacted
wisdom teeth were extracted as a precaution.
Skin tests to the major and minor penicillin determi-nants were negative, and the patient was given increasing doses of penicillin without reaction. She was treated for four weeks with intravenous aqueous penicillin (10 million
units/day) and intramuscular streptomycin (1 gm/day).
The pencithn MIC
and
MBC for the organism were 0.125tg/ml. The MIC to vancomycin was 1 tg/ml and the MBC was 32 mg/mt (Table). Synergy was demonstrated by a two log,o decrease of the number of viable organisms
when the isolate was grown in the presence of both penicillin and streptomycin as compared to the number remaining after incubation with either antibiotic alone.
The serum bactericidal titer was 1:128 one hour after the penicillin infusion. The patient has been followed for one
year following this second course of therapy and has done well.
DISCUSSION
Viridans group Streptococcus grows well in
cul-ture, incubated aerobically or anaerobically, and is
thus easily recovered from the blood of patients with bacterial endocarditis. In the two patients
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described above, the disease was caused by viridans group Streptococcus whose growth is dependent on the presence of the culture medium of vitamin B6
or thiol compounds.
The anaerobic (type 7B) Bactec blood culture
medium (Johnston Laboratories, Cockeysville,
MD) used in our laboratory contains the thiol
com-pound, L-cysteine HC1 (0.05% w/v) and the aerobic
(type 8B) medium contains pyridoxal HC1 (0.001%
w/v). Both bottles support the growth of vitamin
Be-dependent Streptococcus. When streptococci are seen in the Gram stain of a blood culture, the broth is subcultured onto blood agar media containing L-cysteine HC1 (0.05% w/v) or onto a blood agar plate with a staphylococcal streak which provides the
necessary nutrients. Using this system, we have isolated vitamin Be-dependent Streptococcus from five patients in addition to those reported here.
Cayeux et al5 drew attention to thiol requiring streptococcal strains recovered from three patients
with bacterial endocarditis. These were probably
mutant forms, for in two of the patients, the
strep-tococci initially recovered did not require thiol
sup-plementation for growth, but after 20 days of un-successful therapy with penicillin and an aminogly-coside, thiol requiring streptococci were recovered from the involved valves. In the third case, a thiol
requiring Streptococcus was recovered from blood
cultures after nine months of nonspecific antibiotic
therapy. Most cases of endocarditis caused by B6-dependent viridans group Streptococcus have oc-curred in patients without previous antibiotic ther-apy.9 Similarly, the two patients reported here had no recent antibiotic exposure.
When treating bacterial endocarditis, it is
impor-tant to achieve cidal antibiotic levels in the patient’s
serum. Adequate levels are considered to have been
achieved when the serum bactericidal activity is present in dilutions of eightfold or greater.” Viii-dans group Streptococcus which causes
endocardi-tis usually demonstrates penicillin MICs of 0.1 tg/
mi7.’2 however, the vitamin B5-dependent viridans
group Streptococcus has often been found to be
penicillin resistant.5’7 A characteristic of the
peni-cilhins is that their MBC for an organism is usually not much higher then their MIC.13 Sabath et al’4
reported eight strains of Staphylococcus aureus
(three recovered from patients with endocarditis)
with low MICs for nafcilhin, cephalothin, or vanco-mycin but whose MBCs for the same antibiotics
were extremely high. This MBC/MIC divergence
(termed tolerance when the MBC/MIC is 32)’
could explain a poor clinical response to therapy
when a single antibiotic is used to treat endocarditis. The serum antibiotic levels will inhibit the causa-tive organism but not kill it. Both of our isolates exhibited tolerance (Table).
In the
first case a
cure was achieved by the use of gentamicin in addition to penicillin (to which theorganism exhibited tolerance). In the second case
the organism was tolerant to vancomycin and the patient relapsed when vancomycin alone was used. A combination of penicillin and streptomycin
re-sulted in a cure. This case demonstrates the impor-tance of obtaining an MBC as well as an MIC against clinical isolates from patients with endocar-ditis. Acceptance of the susceptibility of
this
orga-nism based on the Kirby-Bauer test alone misdi-rected our therapy.
When determining the MBC and MIC of serum
against vitamin B,-dependent viridans group
Strep-tococcus it is important that vitamin B6- or
thiol-supplemented media be used. Carey et al7 reported
a spuriously low MIC of 0.012 tg/mi for penicillin
when a B-depondent viridans group Streptococcus
was tested in unsupplemented media. When the
organism was later retested in thiol-supplemented
media, the MIC was 0.78 ,g/ml. This was clinically
important as the patient relapsed after treatment
with penicillin alone but was cured with the com-bination of penicillin and streptomycin.
Based on our experience with these two patients,
we recommend that blood cultures obtained from
patients suspected of having bacterial endocarditis
be inoculated into a medium which can support the
growth of vitamin B6-dependent viridans group
Streptococcus. If
this
organism is recovered, it isimportant that the MIC and the MBC be
deter-mined in vitamin B6- or thiol-enriched media and
that therapy be initiated with a combination of
penicillin and an aminoglycoside until sensitivity
testing has eliminated the possibility of resistance
or tolerance.
SUMMARY
Two cases of bacterial endocarditis in children,
caused by viridans group Streptococcus which re-quires vitamin B6 or thiol compounds for growth
are reported. It is important to recognize these
organisms as a possible cause of endocarditis
be-cause supplemented media are needed for their
isolation and sensitivity testing. These organisms
may
be
penicillin-sensitive, -resistant, or -tolerant. An organism is considered tolerant to an antibiotic when the minimum bactericidal concentration ofthat antibiotic is 32 times the minimum inhibitory concentration. One of our patients relapsed when treated with a single antibiotic to which the B6-dependent viridans group Streptococcus was toler-ant. if a Be-dependent viridans group Streptococcus is isolated from a patient with endocarditis, therapy should be initiated with penicillin and an aminogly-coside until sensitivities are available. Sensitity
Reprint requests to (E.S.L.) Department of Pediatrics, Univer-sity of Arizona, Health Sciences Center, Tucson, AZ 85724. PEDIATRICS (ISSN 0031 4005). Copyright © 1980 by the American Academy of Pediatrics.
312 PEDIATRICS Vol. 66 No. 2 August 1980
adequate therapy can be confirmed by determining the serum bactericidal activity.
ACKNOWLEDGMENTS
We are indebted to Linda LaChance and Kathy Sorbo for secretarial assistance, and Leslie Goodale, the Pedi-atnic Clinical Librarian, for all her help.
REFERENCES
HENRY M. FEDER, JR, MD
University of Connecticut Health Center
Farmington, Connecticut and Hartford Hospital
Hartford, Connecticut
NEIL OLSEN, MD
JAMES C. MCLAUGHLIN, PHD RAYMOND C. BARTLETF, MD LEON CHAMEIDES, MD Hartford Hospital
Hartford, Connecticut
1. Blumenthal 5, Griffiths SP, Morgan BC: Bacterial endocar-ditis in children with heart disease. Pediatrics 26:993, 1960 2. Caldwell RL, Hurwitz RA, Girod DA: Subacute bacterial
endocarditis in children. Am J Dir Child 122:312, 1971 3. Johnson DH, Rosenthal A, Nadas AS: A forty-year review
of bacterial endocarditis in infancy and childhood. Circula-tion 51:581, 1975
4. Garvey GJ, Neu HC: Infective endocarditis-an evolving disease. Medicine 57:105, 1978
5. Cayeux P, Aces JF, Chabbert YA: Bacterial persistence in streptococcal endocarditis due to thiol-requiring mutants. J
Infect Di.s 124:247, 1971
6. Carey RB, Gross KC, Roberts RB: Vitamin B6-dependent
Streptococcus mitior (mitis) isolated from patients with sys-temic infections. J Infect Dis 131:722, 1975
7. Carey RB, Barry BD, Roberts RB: Antimicrobial therapy of vitamin Bdependent streptococcal endocarditis. Ann In-tern Med 87:150, 1977
8. Frenkel A, Hirsch W: Spontaneous development of L forms of streptococci requiring secretions of other bacteria or sal-phydryl compounds for normal growth. Nature 191:728, 1961 9. McCarthy LR, Bottone EJ: Bacteremia and endocarclitis
caused by satelliting streptococci. Am J Clin Pathol 61:585, 1974
10. Eickoff, TC: In vitro effects of carbemcillin in combination with gentamicin or polymyxin B against Pseudomonas aeruginosa. Appl Microbiol 18:496, 1969
11. Klastersky J, Dancan D, Swings G, et al: Antibacterial activity in serum and urine as a therapeutic guide in bacterial infections. J Infect Dis 129:187, 1974
12. Zakrzewski T, Keith JD: Bacterial endocarditis in infants and children. J Pediatr 67:1179, 1965
13. Fleming A: On the antibacterial action of cultures of a penicillin with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol 10:226, 1929
14. Sabath LD, Laveridiere M, Wheeler N, et al: A new type of penicillin resistance of Staphylococcus aureus. Lancet 1:443, 1977
Congenital
Adrenal
Hyperplasia
Presenting
with
Posterior
Labial
Fusion
Without
Clitoromegaly
In females with congenital adrenal hyperplasia,
21-hydroxylase deficiency without salt loss is
usu-ally recognized in the neonate because of ambiguous
genitalia (ie, citoromegaly with or without labial
fusion), or at a later age because of progressive
virilization and/or accelerated linear growth. We
are reporting the second case of posterior labial
fusion without citoromegaly as the presenting sign
of congenital adrenal hyperplasia due to
21-hydrox-ylase deficiency. Here, as in the prior case of Wolff
et al,’ the absence of clitoromegaly postponed
rec-ognition of the patient’s problem.
CASE REPORT
C.V. was born at term to a 25-year old, gravida 2, para 1, Mexican-American woman after a normal pregnancy; only vitamins were taken during the pregnancy. At birth the infant weighed 4.4 kg; length measurement was un-available. Labial fusion was noted by her pediatrician at age 3 weeks. The infant was otherwise well.
On referral to our endocrine clinic at age 5 weeks, physical examination revealed a weight of 5.3 kg (95%), height of 60 cm (>98th percentile), and systolic blood
pressure of 82 mm Hg. There was complete labial fusion
except for a small opening anteriorly and no citorome-galy; labial rugation was present (Fig 1). The nipples and genitalia were not excessively pigmented. The urethral opening was seen; the vaginal opening could not be seen. Findings from the rest of the physical examination were normal.
Laboratory examinations confirmed a mild 21-hydrox-ylase deficiency (Table). Her chromosomal karyotype was 46 XX; serum electrolytes were normal. A
vagino-gram performed at 21 months of age showed a normal
vagina and cervix (Fig 2). Treatment with hydrocortisone (8 mg/day) was begun at 10 weeks of age. Her bone age at 6 months of chronologic age was 10 to 14 months. At age 21 months, the patient continues on hydrocortisone (10 mg/day), growth velocity has decreased (height ap-proaching 95%-previously far above 95%), and
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1980;66;309
Pediatrics
Chameides
Henry M. Feder, Jr, Neil Olsen, James C. Mclaughlin, Raymond C. Bartlett and Leon
Streptococcus
-Dependent Viridans Group
6
Bacterial Endocarditis Caused by Vitamin B
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1980;66;309
Pediatrics
Chameides
Henry M. Feder, Jr, Neil Olsen, James C. Mclaughlin, Raymond C. Bartlett and Leon
Streptococcus
-Dependent Viridans Group
6
Bacterial Endocarditis Caused by Vitamin B
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