Martha D. Yow

Ampicillin in the treatment of acute suppurative meningitis

During 1963 and 1964 in vitro sensitivity studies indicated that ampicillin waseffective against the three common etiologic agents of bacterial meningitis in children. Blood and cerebrospinal fluid studies revealed high blood levels and detectable cerebrospinal fluid levels of ampicillin in patients with and without meningeal disease but the mean cerebrospinal fluid/serum ratio was significantly higher in patients with bacterial meningitis. Twenty-eight children with acute bacterial meningitis were treated with ampicillin alone. No significant differences in mortality or complications were noted when the results of this therapy were compared with those in two groups of patients treated with conventional “triple therapy.”

THE PENETRATION OF BROAD‐SPECTRUM ANTIBIOTICS INTO THE CEREBROSPINAL FXUID*

Knowledge of the cerebrospinal fluid levels that can be achieved employing four main groups of broad-spectrum antibiotics (tetracyclines, chloramphenicol, cephalosporins, and the new broad-spectrum penicillins) is of major clinical significance. The purpose of this presentation is to mention the available information concerning the first three groups of antibiotics, to summarize the published data on ampicillin serum and spinal fluid levels, and to report the results of current studies designed to clarify the kinetics of ampicillin penetration into the cerebrospinal fluid. Knowledge regarding spinal fluid levels of the tetracyclines can be summarized by stating that all four major analogues of tetracycline have been shown to cross the blood-spinal fluid barrier in the presence and absence of inflammation of the rneninges.l4 In addition, the spinal fluid levels of the tetracyclines seem to reflect the height of the serum levels, the duration of therapy;14*7*eJ0 and it has been reported that higher spinal fluid levels may be achieved employing tetracycline than employing chlortetracycline or oxytetracycline.s Chloramphenicol has also been shown to enter the spinal fluid with relative ease in the presence of both inflamed and noninflamed m e n i n g e ~ . ~ J ~ ~ ~ Roy and his associatesll found that serum levels of 25-30 pg/ml were required to insure a spinal fluid level of 5 pg/ml in patients without meningeal disease and that the percentage relationship between the cerebrospinal fluid and the serum varied from 6% to 62% with a mean of 27%. Kelly and coworkerss found spinal fluid levels approximating 50% of the serum level in children with normal meninges. Other inve~t igators~~J~ have demonstrated spinal fluid levels to be % to M the serum level in patients with purulent meningitis. To date there is little published information regarding spinal fluid levels of the cephalosporins. Riley and his associates16 reported spinal fluid levels of cephalothin that varied from 0.4 to 1.6 pg/ml. These samples were obtained from a child with purulent meningitis. Klein and coworkers17 reported a spinal fluid level of 11.7 pg/ml of cephalothin with a simultaneous serum value of 15.9 pg/ml. In administering cephaloridine to a patient with Listerial meningitis, Cohen and coworkers18 found spinal fluid levels that varied from 6 to 50% of those in the serum. Murdockle reported spinal fluid levels of 0.03 to 0.25 pg/ml obtained in six young males who received 500 mg of cephaloridine intramuscularly during recovery from viral meningitis. During the last four years, considerable data regarding the penetration of ampicillin into the spinal fluid have been accumulated. In 1965, ThrupdO and his group reported information obtained in the process of treating 44 patients for meningitis due to Hemophilus influenzae, Neisseria meningitidis, or Diplococcus pneumoniae. These authors stated that the spinal fluid levels of ampicillin were variable within each group, ranging from 0.03 to 38 pg/ml. The spinal fluid/

The ototoxic effects of kanamycin sulfate in infants and children.

K A N A M Y C I N S U L F A T E has been available for clinical use for 3 years. During this time it has proved to be effective in the management of serious infections due to the staphylococcus and to many of the gramnegative bacilli. Since the antibiotic was isolated from a strain of streptomyces and its chemical structure closely resembles that of streptomycin and neomycin, its nephrotoxic and ototoxic potentials were recognized by both the manufacturer and the clinical investigators. Animal experiments with kanamycin suggested that nephrotoxicity was a more serious side effect than ototoxicity. However, clinical experience has proved the reverse to be true. Nephrotoxicity has not been a frequent serious problem whereas the

A localized outbreak of coccidioidomycosis in southern Texas

A localized outbreak of coccidioidomycosis in southern Texas involving 9 of 10 exposed persons is reported. Cultural confirmation was obtained from the lung biopsy specimen of one patient, from the sputum of a second patient, and from the soil of a rodent burrow in the exposure area. The ecologic characteristics of the geographic area and their relationship to the occurrence of this epidemic are discussed. The diagnosis and management of a severe but nonfatal case in a child is presented.

The use of kanamycin sulfate as a therapeutic agent for infants and children: An analysis of 140 cases treated during a two-year period

Summary 1. Two years of experience with the use of kanamycin sulfate in the management of serious infections in 140 infants and children is reported. The major clinical diagnoses were gastroenteritis, septicemia, pneumonia, pyoderma, subcutaneous abscess, deep abscess, osteomyelitis, omphalitis, thrombophlebitis, and a group of miscellaneous infections. Seventy-eight of the infections were due to Staphylococcus aureus , 28 to Escherichia coli , 5 to Klebsiella pneumoniae , 5 to Proteus species, and 1 to β streptococcus. In 23 cases an etiological diagnosis could not be established. The dosage of kanamycin used during the latter part of the study and presently employed is 12.5 to 50 mg. per kilogram per day. The drug was administered intramuscularly and locally. The duration of the therapy depended upon the nature of the infection. 2. Kanamycin was found to be a valuable drug in the treatment of serious infections in infants and children. Its advantages are that it is bactericidal, it is rapidly absorbed following intramuscular injection obviating intravenous therapy, it is active in vitro against the majority of strains of staphylococci, including hospital strains, and against many gram-negative bacilli ordinarily resistant to other antibiotics. 3. The experience gained in this study suggests that the following situations are important indications for the use of kanamycin: initial use in patients with extremely severe infections due to organisms that can be expected to respond to kanamycin; initial use for the treatment of less severe infections due to kanamycin-susceptible bacteria occurring in patients, such as premature infants, in whom a rapid progression of the disease process is anticipated; later use in patients with infections due to organisms found to be resistant to other antibiotics and sensitive to kanamycin. 4. The potential hazards in the use of kanamycin are nephrotoxicity and ototoxicity as have been reported in adults. There was no evidence that either was a problem in the group of children presented here, although large doses of kanamycin were used and in some instances the drug was administered for long periods. It should be kept in mind that there is increased risk of toxicity in patients who have diminished excretion of the drug due to pre-existing renal disease with decreased glomerular filtration rates.

THE USE OF KANAMYCIN IN A STAPHYLOCOCCAL EPIDEMIC IN INFANTS AND CHILDREN

The existence of a staphylococcal outbreak in the maternity service at Jefferson Davis Hospital afforded an opportunity to use kanamycin in a large number of newborn infants. Since kanamycin can be administered by the intramuscular route and is highly bactericidal against the S/aphylococrus it seemed to be especially suitable for use in these patients. Indeed, the severity of the illnesses in this outbreak and the high mortality rate, using established methods of treatment, made the trial of this new antibiotic advisable. During a four-month period fifty chi!dren were treated with kanamycin. Fourteen of these patients proved to have infections due to other organisms or staphylococcal disease that was not hospital acquired. The remaining thirty-six patients represented nosocomial infections and are presented here.

PANEL DISCUSSION: KANAMYCIN IN PEDIATRIC PRACTICE WITH SPECIAL REFERENCE TO OBSERVATIONS ON OTOTOXICITY

D R . YOW: Papers presented here this afternoon have emphasized the efficacy of kanamycin in the treatment of Gram-negative bacillary infections. The purpose of this panel discussion is to define the problem of ototoxicity secondary to the use of this drug in infants and children. I will ask Dr. High to start the discussion by presenting his experiences in this area. ROBERT HIGH (Temple University School of Medicine, Philadelphia, P a . ) : Since 1958, over 1200 infants and children have received kanamycin by intramuscular administration a t our hospital. Their ages ranged from less than 1 day to 15 years. The daily doses range from 10 to 100 mg/kg, although relatively few patients received the larger doses and usually such doses were not continued for periods in excess of three weeks. Most daily doses ranged from 15 to 20 mg/ kg. Some of these patients have been reported previously. * Detailed observations of toxicity cannot be presented since we are concerned solely with ototoxicity. I t is our impression that most infants and children tolerate the intramuscular administration of kanamycin without incurring ototoxic reactions with any appreciable frequency. These impressions are based chiefly on clinical observations because of the difficulty in testing small babies and young infants with precise hearing measurements. First, the gross estimates of the patient’s hearing ability measured by response to the spoken word in conversational tones have not shown recognizable hearing losses, except as I will subsequently describe. Second, the continuing ability of infants and young children to acquire a new vocabulary has been recognized. In infants and children the acquisition of new words is a good indication of normal hearing in ranges up to 4000 cycles per second. Third, a review of our audiometric studies, which number over 500 a year, show no cases of nerve deafness presumedly induced by the administration of kanamycin except those to be described subsequently. This observation obviously does not preclude the possibility tha t some such cases were not recognized. The recognized cases of drug-induced deafness observed in our institution since 1958 have usually followed the parenteral administration of streptomycin but in one instance apparently followed the long term oral administration of neomycin.