Intravenous Chloramphenicol Research Articles

Isolated Articular Melioidosis

Melioidosis is an infection caused by a gram-negative bacilli, Pseudomonas pseudomallei. This organism can cause fatal infection in domestic animals and are probably transmitted to humans by soil contamination of skin abrasions, ingestion, and inhalation. Melioidosis is being increasingly diagnosed in Western countries in other than its endemic areas of tropical and subtropical zones. In the past, only a few single case reports of articular melioidosis were published in English journals, and almost all were secondary to melioidosis of another organ. Accurate diagnosis of this infection is important because a high mortality rate is usually associated with the septicemic form. Nine cases of isolated articular involvement were diagnosed between 1984 and 1988 in Northeast Thailand. Symptoms were subtle and diagnosis required a high degree of suspicion. Diagnosis depended on bacteriologic methods including Gram's stain, pus and blood cultures, and on an indirect hemagglutination titer of over 1:40. In addition to general measures for septic arthritis, antibiotic therapy using a combination of intravenous cotrimoxazole, doxycycline, and chloramphenicol was generally satisfactory. Second line drugs (i.e., more effective but also more expensive drugs that the authors administered when patients failed to respond to the first line drugs cotrimoxazole, doxycycline, and chloramphenicol) comprising intravenous ceftazidime and cotrimoxazole were administered in cases with an underlying disease. Comparison of the disease course before and during hospitalization as well as the total days of treatment between two small groups of patients with and without underlying disease revealed no statistically significant difference.

Chloramphenicol concentrations in sera of patients with typhoid fever being treated with oral or intravenous preparation

Serum chloramphenicol and chloramphenicol succinate concentrations in patients given equivalent doses of chloramphenicol base either intravenously or orally for typhoid fever were measured by high-performance liquid chromatography. The mean serum chloramphenicol concentrations were significantly lower in the 11 patients treated with intravenous chloramphenicol succinate than in the 15 patients treated with oral chloramphenicol capsules.

Inhibitory effects of intravenous chloramphenicol sodium succinate on the disposition of phenylbutazone in horses.

The effects of i.v. chloramphenicol sodium succinate on the pharmacokinetics of i.v. phenylbutazone in six healthy adult horses were investigated. Administration of chloramphenicol sodium succinate to mares reduced mean (+/- SD) phenylbutazone clearance from 0.600 +/- 0.222 to 0.339 +/- 0.123 ml/min per kg and increased mean (+/- SD) half life from 244 +/- 59.8 to 371 +/- 80.8 min and mean residence time from 333 +/- 86.2 to 533 +/- 124 min. The mean steady-state volume of distribution of phenylbutazone was unchanged, with mean (+/- SD) values of 187 +/- 28.9 ml/kg in control animals and 170 +/- 32.4 ml/kg after chloramphenicol sodium succinate.

Anaerobic meningitis in an infant associated with pilonidal cyst abscess

A 5-month-old infant whose infected pilonidal sinus was surgically removed, developed meningitis due to Bacteroides fragilis. A similar organism was also recovered from the infected pilonidal cyst along with anaerobic Gram positive cocci. The patient was treated with intravenous chloramphenicol for 4 weeks and recovered without sequella. Attention should be paid to the possibility of meningitis due to anaerobes in children with an infected pilonidal sinus.

Meningitis caused by flavobacterium meningosepticum after transsphenoidal hypophysectomy with recovery

Adult meningitis caused by Flavobacterium meningosepticum is rare. Five cases have been reported in the literature. The case reported herein developed in a woman after a transsphenoidal hypophysectomy. The isolate was resistant to erythromycin. Treatment with oral rifampicin combined with intravenous chloramphenicol and cefoperazone resulted in complete recovery.

Chloramphenicol dosage and pharmacokinetics in infants and children.

Twenty infants and children receiving intravenous chloramphenicol were studied to examine the pharmacokinetics of the parent compound and its precursor, the succinate ester (CAP-S). Plasma samples were obtained just prior to a 30-minute infusion of chloramphenicol succinate, immediately after or 30 minutes after infusion, and 90, 210, and 330 minutes after infusion. Complete 6-hour urine collections were obtained during 11 studies. Plasma and urine were assayed for chloramphenicol and its succinate ester by high-performance liquid chromatography. Peak plasma concentrations ranged from 11.0 to 51.1 micrograms/ml on doses of 50 to 100 mg/kg/day and were higher in the youngest age group. The elimination half-life of chloramphenicol averaged 4.0 hours. Multilinear regression analysis demonstrated an excellent relationship between body surface area, trough plasma chloramphenicol concentration, and total body chloramphenicol clearance. The hydrolysis of succinate ester to free chloramphenicol may delay the peak free concentration, and its renal elimination (average 21 per cent of the dose administered) significantly affects chloramphenicol pharmacokinetics. The clearance of chloramphenicol exhibited enzyme saturation kinetics in one patient studied at two different doses. Dosage adjustments of intravenous chloramphenicol in children must be made in relation to the trough chloramphenicol plasma concentration, renal elimination of CAP-S, and possible saturation of chloramphenicol metabolism.

Pharmacokinetics of intravenous chloramphenicol sodium succinate in adult patients with normal renal and hepatic function.

The pharmacokinetics of chloramphenicol (CAP) and total chloramphenicol succinate (CAPS) were studied in eight hospitalized adult patients with normal renal and hepatic function receiving intravenous chloramphenicol sodium succinate therapy. The steady-state peak concentrations of CAP (8.4-26.0 micrograms/ml) occurred at an average of 18.0 min (range 5.4-40.2) after cessation of the chloramphenicol sodium succinate infusion. Unhydrolyzed CAPS prodrug, representing 26.0 +/- 7.0% of the dose, was recovered unchanged in the urine indicating that the bioavailability of CAP from a dose of intravenous chloramphenicol succinate is not complete. A pharmacokinetic model was developed for simultaneous fitting of CAP and CAPS plasma concentration data. Pharmacokinetic parameters determined by simultaneous fitting were: V, 0.81 +/- 0.18 liters/kg; t1/2, 3.20 +/- 1.02 hr; CLB, 3.21 +/- 1.27 ml/min/kg for chloramphenicol; and V, 0.38 +/- 0.13 liters/kg; t1/2, 0.57 +/- 0.12 hr; CLB, 7.72 +/- 1.87 ml/min/kg for total chloramphenicol succinate.

Antibiotics and Colon Surgery-Reply

<i>In Reply</i>.—I confess that I fail to discern a substantive disagreement between Dr Menaker's practices and the position advocated in the editorial. Dr Menaker administers intravenous (IV) ampicillin, a cephalosporin, or chloramphenicol intraoperatively and postoperatively to his patients undergoing colorectal operations; in six of the 100 patients he described a wound infection developed.¹ Whether antibiotics should be administered parenterally or orally is one of the open, lively issues of current surgical discussion identified in the editorial. But the major editorial point was that the evidence from numerous controlled clinical studies was now sufficiently clear that all patients having a colorectal operation today should receive antibiotics by one route or another. The evidence in favor of antibiotics is so overwhelming that, in my view, this is no longer a moot issue.² While I share Dr Menaker's general concern about our current medicolegal climate, in my mind that climate

Pharmacologic interactions among chloramphenicol, phenytoin and phenobarbital

Bioactive chloramphenicol was measured in the sera of 34 infants and children receiving intravenous chloramphenicol succinate (25 mg/kg/dose) as therapy for meningitis, pneumonia, brain abscess or Rocky Mountain spotted fever. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations of chloramphenicol were 25.3 and 13.4 micrograms/ml, respectively. Concurrent administration of chloramphenicol succinate and phenobarbital in six patients resulted in reduced peak and trough concentrations of chloramphenicol of 16.6 and 7.5 micrograms/ml, respectively (P less than 0.05). Concurrent administration of chloramphenicol succinate and phenytoin in six patients resulted in an elevated mean peak serum concentration of chloramphenicol of 41.7 micrograms/ml (P less than 0.05). Five other patients treated with phenytoin had indeterminate serum chloramphenicol half-lives with chloramphenicol concentrations of 29 to 90 micrograms/ml. Potentially toxic chloramphenicol concentrations occurred in 9 of 17 controls, 0 of 6 patients who had received phenobarbital (P = 0.001) and 11 of 11 patients who had received phenytoin (P = 0.008). Patients receiving combined chloramphenicol succinate and anticonvulsant therapy require monitoring of serum concentrations of drug and adjustments in the dose of chloramphenicol succinate administered.

Pharmacokinetic Comparison of Intravenous and Oral Chloramphenicol in Patients with Haemophilus in fluenzae Meningitis

The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 µ/g ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 µg ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 µg/ml) compared to intravenous administration (4.2 µ/ml) (P .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.

Periosteal Reaction of the Femur in an Infant With Fever

History A 5-month-old infant was admitted to the hospital for evaluation of a firm, tender, nonerythematous leftcheek swelling. Three weeks previously, she had been re-treated with antibiotics for a left buccal On the day of admission, her temperature was 38 °C rectally, WBC count was 23,000/cu mm, and ESR was 60 mm/hr. At this time, treatment with intravenous ampicillin sodium and chloramphenicol sodium succinate was started for recurrent buccal cellulitis. Swelling and tenderness of the right thigh developed on the second day. Initial roentgenograms of the right femur showed only soft-tissue swelling. A film of the right femur obtained on the eighth day (Fig 1) demonstrates considerable periosteal reaction with cortical hyperostosis limited to the diaphysis. A radionuclide scan using technetium Tc 99m medronate (anterior view of the pelvis and lower extremities) demonstrates considerable uptake in the right femur and adjacent soft tissues (arrow) (Fig 2). The area of

Persistent Pharyngeal Colonization with Haemophilus influenzae Type b After Intravenous Chloramphenicol Therapy

A recent prospective study has demonstrated that age-susceptible household contacts of children with Haemophilus influenzae type b (HIB) meningitis are at significantly increased risk of developing systemic HIB disease.1 Studies of meningococcal disease have suggested that chemoprophylaxis of close contacts of the index case may decrease this risk by reducing transmission from carriers to noncarriers.2 Chemoprophylaxis of household and day care contacts of children with HIB meningitis has been recommended.3 Three children treated with intravenous chloramphenicol for ampicillin-resistant HIB meningitis were found to harbor HIB in the pharynx prior to hospital discharge. These patients represent a potential source for the reintroduction of HIB into the household.

Pharmacokinetic study of chloramphenicol in patients with liver disease

The pharmacokinetics of intravenous chloramphenicol has been studied in 42 patients with liver disease and in 8 controls. The half-life of chloramphenicol (t 1/2) was increased in the various liver disorders, the metabolic clearance rate (MCR) and apparent volume of distribution (Vd) were decreased and the area under the time - concentrations curve (AUC) showed an increase. The t 1/2 of chloramphenicol showed a significant correlation with serum albumin and prothrombin time index.

Rapid estimation of chloramphenicol clearance in infants and children.

A method is presented by which chloramphenicol clearance (CL) can be estimated from a single serum sample obtained 6 hours after the initial intravenous dose. The method was evaluated prospectively in 20 infants and children who received intravenous chloramphenicol sodium succinate. Agreement between predicted and observed clearance was excellent (r = 0.914, p less than 0.001). The equation of the observed regression line was: observed 0.886x predicted + 0.019. The method appears to provide reasonably accurate estimates of clearance which can be used for rapid clinical adjustment of dose.

Cellulitis: A prospective study

We prospectively studied 20 children, ages 2 to 12 years, seen with cellulitis. Each child had a complete blood count, a blood culture, and a culture of an aspirate from the lesion. The age of the child, the fever, and the extent of cellulitis determined whether the child was hospitalized. Outpatient antibiotic therapy was penicillin or dicloxacillin. Four children (20%) had an infection on the upper extremity: 14 (70%), the leg; 1 (5%), the forehead; and one (5%), the periorbital area. Three children (15%) had a white blood cell (WBC) count greater than or equal to 15,000 cu mm. Two were febrile. One child with a WBC count less than or equal to 15,000 cu mm was febrile. Two blood cultures (10%) were positive, both for Haemophilus influenzae. Twelve organisms were isolated from the aspirates: 8 Staphylococcus aureus (all penicillinase producing), 2 H influenzae, 1 Streptococcus pyogenes, and 1 Pseudomonas aeruginosa. Both children with H influenzae were febrile with WBC counts greater than or equal to 15,000 cu mm. Of the 17 children (85%) treated as outpatients, all but one responded. We recommend admission and cultures of the blood and an aspirate of the lesion for all facial cellulitis and treatment with oxacillin and chloramphenicol. In a truncal or extremity cellulitis, initial therapy should be directed against S aureus. If the child is febrile or the WBC count greater than or equal to 15,000 cu mm, H influenzae is a likely pathogen and thus intravenous chloramphenicol must be used after cultures are obtained.

Infection in a functioning ventriculoperitoneal shunt treated with intraventricular gentamicin

A case of successful treatment of a functioning ventriculoperitoneal (VP) shunt infection with high doses of intraventricular gentamicin sulfate is reported. The VP shunt reservoir of a four-month-old girl with hydrocephalus became infected. The scalp wound was debrided and intravenous methicillin sodium, 200 mg every six hours, was administered. When culture and sensitivity tests later showed Enterobacter cloacae, methicillin was discontinued. Intraventricular gentamicin, 2 mg/day, and intravenous carbenicillin, 400 mg/kg/day, were administered. Gentamicin dosage was increased twice over the next eight days to 6 mg/day. The trough cerebrospinal fluid (CSF) gentamicin level at 2 mg/day was 1.7 micrograms/ml, at 4 mg/day was 0.7 microgram/ml and at 6 mg/day was 19.6 micrograms/ml. Gentamicin was discontinued after 14 days; carbenicillin was continued for 7 more days. For a second shunt infection with Klebsiella pneumoniae, intraventricular gentamicin and intravenous chloramphenicol were given for 21 days. Previous reports of ventricular shunt infections are reviewed. The report indicates that it is possible to achieve therapeutic CSF levels of gentamicin in patients with patent VP shunts by administering 2--5 times (depending on ventricle size) the usual intraventricular dose.

INTRAVENOUS CEFOTAXIME IN CHILDREN WITH BACTERIAL MENINGITIS

Thirteen children with meningitis due to Hœmophilus influenzœ, β-hæmolytic streptococcus group B, Streptococcus pneumoniœ, Staphylococcus epidermidis, Neisseria meningitidis, Escherichia coli, or Pseudomonas œruginosa and who had been unsuccessfully treated with other antibiotics or had causative organisms which were resistant to available antibiotics were treated with intravenous cefotaxime. Nine children were cured; in one case infection (with a different organism) recurred but a further course of cefotaxime was successful; one child died, with sterile CSF; one child died from his underlying disease (astrocytoma); and one child was cured with sequels (hydrocephalus). A further child with meningitis caused by E. coli had been treated unsuccessfully by intravenous and intraventricular chloramphenicol and gentamicin; intravenous and intraventricular cefotaxime was successful. The agent was well tolerated. CSF levels were measured in seven children and ranged from 300 to 27 200 μg/l; published and unpublished in-vitro studies suggest that minimum inhibitory concentrations for cefotaxime against the organisms commonly causing bacterial mem- ingitis are usually well below 250 μg/l.

Lymphosarcoma with Virus-Like Particles in a Neonatal Foal

Lymphosarcoma is a common neoplasm affecting all species of domestic animals. The first report of lymphosarcoma in a domestic animal was in a horse in 1853 [9]. A recent review of lymphosarcoma in the horse cited 9 1 cases [9]. At least seven other cases have been reported 11-3, 6, 10, 141. In cases in which age was reported, only three of 30 horses were less than 4 years old; two were in foals 2 and 4 months old [9]. A 10-year-old Quarter Horse mare, which had previously delivered three normal live foals, gave birth to a weak and ataxic foal. It was examined when about 3 hours old; Actinobacillus equi septicemia was suspected. The foal was treated symptomatically with intravenous chloramphenicol and fluids containing glucose and electrolytes. Colostrum was milked from the mare and force-fed to the foal. The foal died about I hour after being treated and was necropsied within 2 hours of death. The abdominal lymph nodes were enlarged. Tissues fixed in formalin were lung, spleen, abdominal lymph node, kidney, liver and several sections of small intestine. Thymus was not submitted. The normal architecture of the lymph node was replaced by a uniform population of discrete cells (fig. I) . These cells had large, round to oval nuclei with vesicular chromatin and a thin rim of cytoplasm. Nucleoli were prominent and mitotic figures were numerous. The nuclei of a few of these cells were pyknotic. Similar cells were in the lymph node capsule and perinodal fat. The germinal centers in the spleen were composed of uniform cells similar to those in the lymph node. These areas contained many more cells with pyknotic nuclei than were in the lymph node. The interstitium of the renal cortex (fig. 2) and medulla, as well as the lamina propria and muscularis of the small intestine (fig. 3), were infiltrated by cells resembling those in the lymph node. These cells were interpreted to be neoplastic lymphoblasts. Centrolobular hepatocytes were vacuolated, but neoplastic cells were not seen in the liver. Based on findings of light microscopy, lymphoblastic lymphosarcoma was diagnosed. Sections of formalin-fixed lymph node were cut into I-millimeter cubes and processed for electron microscopy. Ultrathin sections showed virus-like particles budding into the smooth endoplasmic reticulum (fig. 4) and free in the cytosol near the nucleus of neoplastic lymphoblasts (fig. 5). These particles contained a core, shell and nucleoid-features that are compatible with those of C-type oncornavirus 141. A blood sample from the mare was heparinized and lymphocytes isolated by the Ficoll-Hypaque density gradient centrifugation were washed and suspended ( 106/ml) in RPMI-1640 medium with 10% inactivated fetal calf serum. Phytohemagglutinin was added to a final concentration of 5 pg/ml and the cells incubated at 37' C in an atmosphere with 5% COn for 48 hours [7]. The cells were then harvested and processed for examination in an electron microscope. Virus particles could not be demonstrated in the cultured lymphocytes. The classification and characteristics of lymphosarcoma in various species of domestic animals have been reviewed [8]. Although the number of reported cases of lymphosarcoma in horses was insufficient to make accurate observations on its epidemiology, presenting signs vary, depending on the organ system or systems affected. Gastrointestinal signs of recurrent colic or diarrhea may occur [ 13, 141. Emaciation, chronic cough and peripheral lymphadenop-

Human Tear pH-Reply

In Reply .—Dr Gutman has made an important point. Because of the possible complications of untreated or inadequately treated orbital cellulitis (including cavernous sinus thrombosis, meningitis, and brain abscess), it is important that appropriate antibiotics be chosen and used promptly in high dosages. Since the time of submission of our manuscipt, strains of ampicillin-resistant H influenzae type b have appeared in Pittsburgh and in many other areas. A new recommendation from the Committee on Infectious Diseases of the American Academy of Pediatrics has been published ( Pediatrics 57:417, 1976), which again emphasizes the importance of initial treatment with a parenteral penicillin and intravenous chloramphenicol for suspected or proved severe disease due to H influenzae type b, but, perhaps inadvertently, it does not mention cellulitis, not even orbital cellulitis. Orbital cellulitis should be included in this recommendation if the patient is less than 5 years old, and particularly if the patient is

Bacteroides pericardial effusion and cardiac tamponade in a patient with chronic renal failure

A 31-year-old woman with chronic renal insufficiency and recurrent pericarditis developed and enlarging cardiac silhouette and physical signs of cardiac tamponade. Cardiac catheterization demonstrated pericardial effusion with hemodynamic evidence of cardiac compression. At pericardial exploration, 1.5 L. of foul-smelling purulent material was removed from a distended pericardial sac. Cultures of both the exudate and pericardium revealed pure growth of Bacteroides fragiles. The patient was subsequently treated with intravenous chloramphenicol and has had an uncomplicated clinical course since that time. This represents the first reported case of cardiac tamponade secondary to culturally proved Bacteroides pericarditis in the setting of chronic renal insufficiency.