of injection. After conditions of equilibrium with body fluids and tissues obtain, approximately 50 percent reduction in blood concentrations will occur in the ensuing 3 to 4 hour period.

Chloramphenicol sodium succinate requires conversion to free chloramphenicol before exhibiting marked antimicrobial activity. When given intravenously its distribution is approximately the same as that of chloramphenicol given intravenously; however, it requires some time before conversion to the effective free form. Intramuscular injection is followed by rapid conversion, and peak blood levels occur approximately 2 hours following injection.

Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid. Chloramphenicol enters cerebrospinal fluid even in the absence of meningeal inflammation, appearing in concentrations about half that found in the blood. This antibiotic has also been reported to occur in pleural and ascitic fluids, saliva, and in milk, and it diffuses readily into all parts of the eye. Transport across the placental barrier occurs, with somewhat lower concentration in cord blood of newborn infants than in maternal blood.

Seventy to ninety percent of a single oral dose of 50 mg. of chloramphenicol is secreted in 24 hours in the urine of human subjects, with 5 to 10 percent as free chloramphenicol and the remainder as microbiologically inactive metabolites, particularly the conjugate with glucuronic acid. Since the glucuronide is excreted rapidly, most nitro compounds in the blood are in the form of free chloramphenicol. Despite the small proportion of unchanged drug excreted in the urine, concentrations therein are relatively high, amounting to several hundred mg./ml./24 hours in patients receiving divided doses of 50 mg./kg./day. Small amounts of active drug are also found in bile and in feces. The disposition of the drug given by parenteral routes is similar.

INDICATIONS

Chloramphenicol, an antibiotic having therapeutic activity against a wide variety of organisms, must, in accordance with the concepts in the "warning box" above. be used only in certain severe infections.

The decision to choose chloramphenicol from among a group of antibiotics suggested by in vitro studies to be potentially effective against a specific pathogen (s) should be guided by severity of infection, relative susceptibility of the pathogen (s) to the various antibacterial drugs, relative efficacy of the various drugs in the infection, and the important additional concepts contained in the "warning box" above.

RICKETTSIAL DISEASES

The response of patients with rickettsial infections. including epidemic and murine typhus fevers, Brill's disease, scrub typhus fever, Rocky Mountain spotted fever, and rickettsial pox, has been dramatic with virtual elimination of mortality and marked shortening of the course of illness. Average length of the febrile period after administration of chloramphenicol is 2 days in patients with epidemic typhus fever and 3 days in those with other typhus fevers. Treatment should be given for a minimum of 6 days or 4 days after temperature returns to normal.

Relapse may occur when treatment is given only for 48 hours early in the disease. This can be prevented by giving additional doses on the fifth and sixth days after the initial course. Also, patients in relapse respond as readily to treatment as do those with primary infection.

In patients with Rocky Mountain spotted fever, defervescence occurs about the fourth day after therapy is started. Treatment should be continued for 24 hours after normal temperature is attained.

TYPHOID FEVER

Chloramphenicol has been established as the drug of choice for this disease. After therapy is started, fever subsidies in 3 or 4 days regardless of age, severity of illness, or stage of disease. To lessen possibility of relapse, it is important that therapy be continued for from 8 to 10 days after reaching the afebrile period. Close observation of the patient for complications of the disease, and for the aforementioned side effects of the drug, is essential.

OTHER SALMONELLOSES

While chloramphenicol has proved to be a useful therapeutic agent in ameliorating and shortening the clinical course of salmonella infections other than typhoid, results are not as uniform. Recommended duration of treatment is the same as for typhoid fever.

URINARY TRACT INFECTIONS

Treatment for infections of the urinary tract should be based upon sensitivity of bacteria and on anatomic factors contributing to the infection. The more common organisms encountered in the urinary tract infections are Escherichia coli, Aerobacter aerogenes, Pseudomonas aeruginosa, Proteus sp., Staphylococcus aureus and Streptococcus fecalis.

Chloramphenicol has been found effective in treatment for about 70 percent of urologic infections, particularly those caused by Echerichia coli, Streptococcus fecalis, and Proteus sp. Relief of symptoms and repeated bacteriological studies should be depended upon to indicate duration of treatment.

SURGICAL INFECTIONS

Surgical infections such as postoperative wound infections, cellulitis, infected sinus tract, and peritonitis or intra-abdominal abscess from ruptured intestine, diverticula, or appendix, usually are due to microorganisms sensitive to chloramphenicol. The antibiotic is given, adjunctively to surgical intervention, in the recommended dosage for an average of from 10 to 16 days.

RESPIRATORY TRACT INFECTIONS

Because of its wide antibacterial spectrum and its ability to diffuse into infective foci, chloramphenicol may be of value in the treatment of selected severe respiratory tract infections due to susceptible microorganisms. However, as with any antibacterial agent, the administration of chloramphenicol must be adjunctive to the overall therapeutic approach to this family of diseases. Appropriately treated, good results can be expected in bacterial pneumonia and empyema; in bacterial complications of bronchiectasis and bronchitis; all of which are severe disorders often chronic and difficult to eradicate. Patients on recommended doses usually become afebrile in from 18 to 72 hours, however, roentgenographic clearing may be slower.

The use of broad spectrum antibiotics, including chloramphenicol, in the treatment of respiratory tract infections, particularly when significant necrotic debris is present, may result in overgrowth of nonsusceptible organisms in respiratory tissue, including Pseudomonas aeruginosa and fungi.

Neoplastic, fungal, and mycobacterial disease as a cause of persisting respiratory disease should be ruled out by appropriate means.

MENINGEAL INFECTIONS

Many microorganisms causing meningitis are susceptible to chloramphenicol. The drug's high diffusibility results in effective concentrations in the cerebrospinal fluid. Institution of therapy cannot be delayed until results of laboratory tests are known. Many clinicians consider chloramphenicol the drug of choice for meningitis caused by H. influenzae as almost all strains are sensitive to this antibiotic. Parenteral dosage is recommended until the patient is afebrile, after which oral medication may be used. Medication should be continued for a minimum of 7 days to avoid relapse.

MISCELLANEOUS INFECTIONS

Chloramphenical has proved to be useful and frequently effective in treatment for many diverse infections, including brucellosis, bartonellosis, relapsing fever, granuloma inguinale, plague, and ornithosis. Other effective therapeutic agents should receive consideration as the treatment of choice. Whenever definite contraindications are known, such as hypersensitivity to these agents, or clinical response is poor, the judicious use of chloramphenicol is warranted, keeping in mind aforementioned warnings, precautions, and side effects.

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CONTRAINDICATIONS

Chloramphenicol is contraindicated in individuals with a history of previous sensitivity reaction to it.

It must not be used in the treatment of trivial infections such as colds, influenza, or infections of the throat; or as a prophylactic agent to prevent bacterial infections.

PRECAUTIONS AND SIDE EFFECTS

While untoward reactions in man are infrequent with chloramphenicol, they have nevertheless been reported with both short term and prolonged administration of the drug. Reactions attributed to chloramphenicol may be considered under the following headings:

BLOOD DYSCRASIAS

Aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia have been associated with the administration of chloramphenicol.

When, during the course of therapy blood counts show unusual deviations which may be attributable to the drug such as reticulocytopenia, leukopenia or thrombocytopenia, therapy with chloramphenicol should be discontinued.

GASTROINTESTINAL REACTIONS

After several days of therapy, glossitis may occur. Stomatitis, when it occurs is generally mild and usually consists of congestion and tenderness of the buccal mucosa. This is an indication to stop the drug. On rare occasions, superimposed infection by Candida albicans may produce widespread oral lesions of the thrush type. Diarrhea and irritation of perianal tissues have been reported after administration of chloramphenicol. These conditions are usually mild and disappear when chloramphenicol therapy is stopped, although occasionally they are protracted.

The pathogenesis of pseudomembranous enterocolitis of the intestines is not clear, but commonly staphylococci have been implicated. This severe reaction occurs in patients already ill with pneumonia or peritonitis, or it may follow surgical operation. Pseudomembranous enterocolitis has been reported.

NEUROTOXIC REACTIONS

Headache, mild depression, "dazed feelings," internal ophthalmoplegia, mental confusion, and delirium have been described in patients receiving chloramphenicol for a variety of infectious diseases. Optic and peripheral neuritides have been reported as effects of chloramphenicol therapy. If symptoms of decreased visual acuity or peripheral neuritis occur during therapy, prompt withdrawal of the drug is indicated and large doses of oral or parenteral vitamin B complex should be considered.

Newborn Infants-Premature and Full-Term. See discussion under Dosage Recommendations.

OTHER REACTIONS

Angioneurotic edema and vesicular and maculopapular types of dermatitis have been reported in patients sensitive to chloramphenicol. Urticaria and vesicular lesions also have been observed. Dermal lesions, usually mild, ordinarily subside promptly when the drug is stopped.

Febrile reactions have been reported.

The Jarisch-Herxheimer reaction has been reported after chloramphenicol therapy in patients with syphilis, brucellosis, and typhoid fever. In patients with typhoid fever treated with chloramphenicol, several investigators have recorded a "shock-type reaction" characterized by circulatory collapse, attributed to sudden release of typhoidal endotoxin in an already weakened patient. Unlike the Herxheimer reaction, temperature is usually depressed, but exacerbation of fever has been reported. Recrudescence usually appears within 24 hours of the start of chloramphenicol therapy and persists from 24 to 48 hours.

PRECAUTIONS

See "warning box" for precautions.

The use of this antibiotic, as with other antibiotics, may result in an overgrowth of nonsusceptible organisms, including fungi. Constant observation of the patient is essential. If new infections caused by nonsusceptible organisms appear during therapy, the drug should be discontinued and appropriate measures should be taken. Monitoring of liver and kidney function should be accomplished during therapy in patients with existing liver or kidney disease.

PREPARATION, ADMINISTRATION, AND DOSAGE RECOMMENDATIONS

The majority of micro-organisms susceptible to chloramphenicol will respond to a concentration between 5 and 20 mcg./ml. The desired concentration of active drug in blood should fall within this range over a major portion of the treatment period. Dosage of 50 mg./kg./day in divided doses will achieve levels of this magnitude. Except in certain circumstances-for example, premature and newborn infants-lower doses may not achieve these concentrations. Chloramphenicol, like other potent drugs, must be prescribed at recommended doses known to have therapeutic activity. Close observation of the patient should be maintained and in the event of any side effects dosage should be reduced or discontinued. Sterile chloramphenicol sodium succinate is suitable for intramuscular, intravenous, or subcutaneous use.

ADMINISTRATION

The following methods of administration are recommended on the basis of tolerance, ease of handling, and safety.

1. Intramuscularly, as a 25- to 40-percent solution injected deep into the muscle as one of the common sites of intramuscular injection.

2. Intravenously, as a 10-percent solution to be injected over a 1-minute interval. If desired, the solution can be added to a larger volume of parenteral fluid for intravenous infusion.

3. Subcutaneously, as a 10-percent solution injected through a short, smallgage needle. As with the intravenous route, the concentrated solution can be added to fluids for subcutaneous clysis.

The powder in the vial is prepared for injection by the addition of an aqueous diluent such as water for injection or 5-percent dextrose injection. Although chloramphenical sodium succinate is highly soluble, the rate of solution is somewhat slower in the more highly concentrated solutions. Gentle shaking of the vial hastens solution. The following dilution table may be used as a guide for preparing solutions for injection.

For most infections due to susceptible organisms, adults should receive 50 mg./kg./day. Patients with infections due to less susceptible organisms may require up to 100 mg./kg./day. In either case, this should be divided into four doses at 6-hour intervals. Note carefully the dosage table below.

Adults with impairment of hepatic or renal function or both may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted accordingly. Precise control of concen

tration of the drug in the blood may be carefully followed by the available microtechniques (see discussion under Newborn Infants-Premature and

Dosage of 59 mg./kg./day is adequate for infections caused by most susceptible organisms. Severe infections, that is, septicemia or meningitis, especially when adequate cerebrospinal fluid concentrations are desired may require dosage up to 100 mg./kg./day. However, dosage should be reduced to 50 mg./kg./day as soon as clinical response occurs. The daily dose should be divided into 4 doses, and given at 6-hour intervals.

Children with impaired liver or kidney functions or both may retain excessive amounts of the drug; see following discussion.

NEWBORN INFANTS-PREMATURE AND FULL TERM

Sterile chloramphenicol sodium succinate may be used in an initial dose of 25 mg./kg. followed by 25 mg./kg./day in 3 equal doses at 8-hour intervals which produces and maintains concentrations in blood and tissues adequate to control most infections. Increased dosage in these individuals, demanded by severe infections, should be given only to maintain the blood concentration within a therapeutically effective range, as best determined by available microtechniques. Full term newborn infants ordinarily may receive from 25 to 50 mg./kg./day equally divided into 3 doses at 8-hour intervals. The same routes of administration as noted above may be employed; generally intramuscular administration is preferred.

These dosage recommendations are extremely important because blood concentration in all premature infants and full-term infants under 2 weeks of age differs from that of infants over that age. The difference is due to variations in the metabolic disposition of this and other drugs in this age group which in turn depends upon the maturity of the metabolic function and status of the liver and the kidneys. When these functions are immature (or seriously impaired in adults) high concentrations of the drug are found which tend to increase with succeeding doses.

Toxic reactions and some fatalities have occurred in the premature and newborn age group; the signs and symptoms associated with these reactions have been referred to as the "gray syndrome." One case of "gray syndrome" has been reported in an infant born to a mother having received chloramphenicol during labor. The following summarizes the clinical and laboratory studies that have been made on these patients:

1. In most cases therapy with chloramphenicol had been instituted within the first 48 hours of life.

2. Symptoms first appeared after 3 to 4 days of continued treatment with high doses of chloramphenicol.

3. The symptoms appeared in the following order: (a) abdominal distention with or without emesis; (b) progressive pallid cyanosis; (c) vasomotor collapse, frequently accompanied by irregular respiration; and (d) death within a few hours of onset of these symptoms.

4. The progression of symptoms from onset to exitus was accelerated with higher dose schedules.

5. Preliminary blood serum level studies revealed unusually high concentrations of chloramphenicol after repeated doses.

6. Termination of therapy upon early evidence of the associated symptomatology frequently reversed the process with complete recovery.