What We Have Learned in the Last

Decade

HENRY M. FEDER, JR MD, Farmington, Conn

ABSTRACT: Chloramphenicol is a unique antibiotic. The kinetics and efficacy of the oraland intravenous preparations are comparable. Chloramphenicol is usually bacteriostaticbut is bactericidal against Haemophilus influenzae, Streptococcus pneumoniae, andNeisseria meningitidis, and chloramphenicol's clinical efficacy against these meningealpathogens is well established. Chloramphenicol can be used to treat serious pediatricinfections when Haemophilus influenzae is a likely pathogen, as well as typhoid fever ,anaerobic infections, bacterial meningitis in patients allergic to penicillin, brain abscesses,and rickettsial infections. The use of chloramphenicol is limited because of its toxicity.Aplastic anemia is very rare but can occur after either oral or intravenous administration.The gray syndrome can be eliminated and marrow suppression minimized by usingchloramphenicol at the recommended doses and monitoring levels. During the last decadethe increased use of chloramphenicol has not resulted in increased resistance or infrequent reports of toxicity. Thus, chloramphenicol remains an important inpatientantibiotic that can be invaluable for treating certain life-threatening infections.

1973 to 1977 susceptibilities of bacteria isolatedfrom hospitalized patients in the United States aridfound no increases in chloramphenicol resistance.Most nonenterococcal streptococci, Neissen'a,Haemophilus influenzae, and anaerobes are suscep-tible to chloramphenicol. Treponema pallidum, Bor-relia, Leptospira, Actinomyces, Pseudomonas pseudimlalïl£i,Legionella, Rickettsia, Chlamydia, and Mycoplasma arealso susceptible to chloramphenicol, It must benoted that in vitro susceptibility does not alwayscorrelate with in vivo efficacy ( eg, clinical efficacyof chloramphenicol has not been studied againstLegionella and Mycoplasma). Also, staphylococci areusually susceptible to chloramphenicol, but ~linicalstudies are lacking. Pseudomonas atruginosa,Acinetobacter, mycobacteria, fungi, and parasites areusually resistant to chloramphenicol.6.7 A Centersfor Disease Control (CDC) studyS showed that of5,474 Haernophilus influenzae cerebrospinal fluid andblood isolates done from 1977 to 1981, 21,2%were resistant to ampicillin, while no isolate wasresistant to chloramphenicol. It is important topoint out that HaemoPhilus influenzae organismsresistant to chloramphenicol have been repor:ted,9and thus susceptibilities must always be deter-mined. Moreover, meningitis due to H influenzaeresistant to both chloramphenicol and ampicillin

DURING THE LAST DECADE chloramphenicol has

enjoyed a resurgence of use and new data have

been generated. Chloramphenicol became avail-

able in 1949 and for the next ten years was a

popular outpatient and inpatient antibiotic. By

1960, after chloramphenicol's three important

toxicities-dose-related bone marrow suppression,l

aplastic anemia,2 and the gray syndrome3-hadbeen defined, its use declined. In the 1970s the useof chloramphenicol increased because ampicillin-

resistant Haemophilus influenzae and Bacteroides .fragilis

were susceptible to chloramphenicol and now in

the 1980s chloramphenicol is being replaced by

new cephalosporins and less toxic antibiotics for

anaerobes. The purpose of this report is to discuss

what has been learned about chloramphenicol dur-

ing the last decade of clinical use.

SPECTRUM

Although resistance has developed in countrieswhere chloramphenicol has been used indiscrim-

inantly ,4 bacterial susceptibilities to chloram-

phenicol in the United States have changed verylittle over the past decade. Lorians reviewed the

-From the Departments of Family Medicine and Pediatrics, University of

:::onnecticut Health Center, Farmington.

Reprint requests to Henry M. Feder, Jr., MD, Department of Family\1edicine, University of Connecticut HeaJth Center, Farmington, CT 06032.

Feder .CHLORAMPHENICOL 1129

liver, lungs, and kidneys after intravenous admin-istration. In infants and children, 6% to 80% ofthe drug is not hydrolyzed and is excreted un-changed in the urine. 18 Chloramphenicol succinateshould not be given by the intramuscular route.This recommendation is based on clinical relapseof typhoid fever in four of four patients treatedwith intramuscular chloramphenicol succinateversus relapse in one of four patients treated withoral chloramphenicol.19 In a 1985 study, Shannet al20 demonstrated reliable absorption of in-tramuscular chloramphenicol succinate, butclinical studies are needed before the intra-muScular route can be recommended.

The therapeutic range for chloramphenicolserum levels is 10 to 20 JLg/ml. The half-Iife ofchloramphenicol can vary from patient to patientand can vary with time in a single patient. Thehalf-Iife of chloramphenicol is usually prolongedin premature and term neonates, in patients withliver dise:ase, in patients with portal hypertension,and, in my experience, in patients with septicshock.6.21

Chloramphenicol has excellent tissue penetra-tion and excellent penetration into body fluids, in-cluding synovial fluid, pleural fluid, ascites fluid,aqueous humor, sputum, breast milk, and cere-brospinal fluid with either inflamed or uninflarrie:dmeninges. About 5% to 10% of active chloram-phenicol is excreted unchanged in the, urineresulting in urine levels of 150 to 200 JLg/m1; inrenal failure, however, urine levels ,are greatlydecreased. 6.22

Simultaneous administration of chlorampheni-col and phenobarbital can decrease the half-Iife ofchloramphenicol.23 Simultaneous administrationof chloramphenicol and phenytoin can increase23or decrease24 the half-Iife of chloramphenicol andcan also increase the half-Iife of phenytoin. 6 Thus,use of chloramphenicol with phenobarbital orphenytoin or both necessitates moJiitoring thelevels of these drugs.

The current dosage recommendations forchloramphenicol are 25 mg/kg/day for prematureinfants and neonates less than 2 weeks of age, 50mg/kg/day for neonates 2 to 4 weeks of age, 50to 100 fig/kg/day for older infants and children,and 50 mg/kg/ day for adults given in four divideddoses. In infants and children, I initiate therapywith 50 to 75 mg/kg/day because 100 mg/kg/dayfrequendyresults in high levels. Ideally, chloram-phenicol peak (one hour after infusion) and trough(just before next dose) levels should be obtained24 to 48 hours after starting therapy, then repeatedevery three to five days. It is important thatchloramphenicol levels are monitored more closely

has been reported. 10 In the United States Salmonella

and Shigella are usually susceptible to chloram~

phenicol. Infrequently, during therapy, Salmonella

can develop R -factor-mediated chloramphenicolresistance. 4

Standard susceptibility determinations are

usually done by inhibitory tests. To determine

whether an antibiotic is bactericidal, specific cidal

testing ( eg, minimal bactericidal concentration

[MBC]) must be requested. In the last decade

studies have emphasized that chloramphenicol can

be either bacteriostatic or bactericidal. Chloram-

phenicol is usually bactericidal against Haemophilusinfluenzae, Streptococcus pneumoniae, and Neisseria men-

ingitidis, and bacteriostatic against staphylococci,

Enterobacteriaceae, and anaerobes.6.11.12

ANT AGONISM/SVNERGISM

There are conflicting reports regarding an-

tagonism and synergism between chloramphenicoland other antibiotics. In vitro synergism, an-

tagonism, and indifference have been demon-

strated between chloramphenicol and ampicillin

for HaemoPhilus inflUenzae.6.13 In vitro antagonism

has been demonstrated between chloramphenicol

and penicillin or ampicillin for StreptococcuS

pneumoniae, Neisseria meningitidis, or group B strep-

tococci.6.14 Also, antagonism has been shown

between chloramphenicol and gentamicin.15 In a

study of 21 enteric qrganisms, chloramphenicoland ampicillin wer~ usually synergistic when

chloramphenicol was bactericidal, and antagonisticwhen chloramphenicol was bacteriostatic.16 The

clinical significance of the antagonism or synergism

between chloramphenicol and penicillins or

aminoglycosides is unknown.

PHARMACOKINETICS

During the last decade, the pharmacokinetics

of chloramphenicol have been reexamined using

precise assays. The chloramphenicol package in-sert and the 1985 Physicians ' Desk Reference state in

pold print:As soon as feasible, an oral dosage form of chloramphenicolshould be substituted for the intravenous form because ade-quate blood levels are achieved with chloramphenicol bymouth.Oral forms are completely absorbed and give levels

comparable to those of intravenous chloram-

phenicol succinate. The oral forms include

chloramp~enicol palmitate, a tasteless ester

available as a suspension, and chloramphenicol

base, available in capsules. .Chloramphenicolpalmitate, which has no antimicrobial activity, is

hydrolyzed in the duodenum to active chloram..

phenicol and is then completely absorbed.17

Chloramphenicol succinate, a soluble ester

without antimicrobial activity, is hydrolyzed in the

September 1986 .SOUTHERN MEDICAL JOURNAL. Vol. 79. No.91130

in premature infants and neonates, in patientswith liver disease, and in patients receivingphenobarbital or phenytoin. Ideally, in these pa-tients, levels should be measured 18 to 24 hoursafter starting therapy, then repeated every two tothree days. Dosage should be adjusted to keeplevels between 10 and 20 p.g/ml.

TOXICITY

Chloramphenicol has three well established

toxicities-aplastic anemia,2 the gray syndrome,3

and bone marrow suppression.1 Although in the

last decade the gray syndrome and bone marrow

suppression have been better defmed, the risk fac-

tors for aplastic anemia remain controversial.

The incidence of fatal aplastic anemia associated

with oral chloramphenicol has been estimated to

be one case for every 24,500 to 40,800 courses.25

There are more than 700 case reports of aplastic

anemia following oral chloramphenicol. The

incidence of aplastic anemia after intravenous

chloramphenicol is not known6; however, there are

now ten case reports of aplastic anemia associated

with intravenous chloramphenicol.6.26-29

The association of aplastic anemia with oral

chloramphenicol may be misleading because

chloramphenicol toxicity studies were done at a

time when most patients received oral chloram-

phenicol. Two recent hospital audits of chloram-

phenicol revealed that 97% of chloramphenicol-

treated patients received only intravenous

therapy .30 According to incideIllce figures for

meningitis31 and the pediatric use of chloram-

phenicol for other infections, approximately

500,000 pediatric patients have received initial

therapy with intravenous chloramphenicol during

the last decade. Yet the only case26 of aplastic

anemia reported in the pediatric age group is thatof a 17 -year-old patient whose bone marrow

aplasia may not have been from the chloram-

phenicol.32 The low number of case reports

associating intravenous chloramphenicol with

aplastic anemia has led US6 and others33 to

speculate that intravenous chloramphenicol causesless aplastic anemia than oral chloramphenicol,

but this speculation is not supported by all ex-

perts.34 It is doubtful that this controversy will be

resolved because a prospective study comparingthe use of oral and intravenous chloramphenicol

would require many thousands of patients. If a

patient has an intravenous line for fluids or other

medication, I use intravenous chloramphenicol;if a patient does not need an intravenous line, I

use oral chloramphenicol. The inherent morbidity

and mortality of an intravenous line negates the

potentially decreased toxicity of intravenous

chloramphenicol.

There are four case reports of aplastic anemicafter ocul~r chloramphenicol preparations. 6.35After passmg through the nasolacrimal ducts,ocular chloramphenicol can be absorbed in the

gastrointestinal tract. Ocular chloramphenicolshould be used only for infections caused byorganisms resistant to all other ocular antibiotics.

The gray syndrome, which is characterized byabdominal distention, pallid cyanosis, and circula-tory collapse, was first reported in neonates whoreceived more than 100 mg/kg/day of chloram-phenicol for at least two days.3 As a result, thedosage recommendations for chloramphenicolwere reduced, and now the gray syndrome occursmost frequently with accidental overdosage ofchloramphenicol. 6 With the present dosage recom-mendations the gray syndrome has not beenreported in patients with normal liver function.Mulhall et al36 reported the gray syndrome inneonates given as little as 9 mg/kg/day over therecommended 25 mg/kg/day. The pathogenesisof the gray syndrome may be related to high con-centrations of chloramphenicol interfering withtissue respiration by inhibiting mitochondrialelectron transport.37 Decreased myocardial con-tractility has been shown by echo cardiography inpatients with the gray syndrome.38 Charcoal-column hemoperfusion appears to be the besttherapy to reduce the high chloramphenicollevels39; otherwise, treatment of the gray syndromeis supportive.

Chloramphenicol-associated bone marrow sup-pression is dose-related and reversible. The com-mon sequence of suppression is (1) delayed plasmairon clearance (early), (2) rise in serum iron level(early), (3) reticulocytopenia (three to five days),(4) increased marrow myeloid/erythroid ratio andvacuolization of marrow precursors (three to sevendays), (5) hemoglobin decrease (five to ten days),and (6) thrombocytopenia (ten to 14 days).Neutropenia, which is rare, can also occur andis an indication for stopping therapy .32 Unfor-tunately, bone marrow suppression does notalways follow this sequence. In a recent study4°comparing chloramphenicol plus gentamicin, clin-damycin plus gentamicin, and ticarcillin plus gen-tamicin for abdominal or pelvic sepsis, similarrates of anemia and leukopenia were found amongthe three groups. In the chloramphenicol groupreticulocytopenia (14% vs 2% in the other groups)and thrombocytopenia (9.5% vs 2.0% in the othergroups) occurred more frequently. Completeblood counts and platelet estimates should beobtained twice weekly. If the absolute neutrophilcount falls below 500/cu mm or the platelet countfalls below 50,000/cu mm, an alternate antibioticshould be chosen.

Feder .CHLORAMPHENICOL 1131

~

Chloramphenicol has been shown to decreasethe anamnestic response to tetanus toxoid, to in-hibit neutrophil function, and to suppress in vitrocell-mediated immunity. 6 The clinical significanceof these observations is unknown. Chloram-phenicol's effectiveness in the treatment of chronicneutropenia41 may be related to its immunosup-pressant activity.

Chloramphenicol has other toxicities, which in-clude hemolytic anemia in patients with theMediterranean variant of glucose-6-phosphatedehydrogenase deficiency and optic neuritis canoccur with chronic use. Oral chloramphenicol cancause nausea, stomatitis, and diarrhea. Chloram-phenicol has been implicated as a cause of ahepatitis-pancytopenia syndrome42 and pseudo-membranous colitis,43 but these reports need tobe confirmed.

USEA 1973 Tennessee study of more than 350,000

Medicare patients showed that of the 992 patientswho received oral chloramphenicol during the yearof the study, the drug was indicated in only one. 44

In a 1976 follow-up study the authors reported afourfold decrease in the use of chloramphenicolfor outpatients.45 In a 1981 Albany College study46(verbal communication, November 1983) 14,219outpatient drug prescriptions were randomlysurveyed, and only one prescription was forchloramphenicol.

Inpatient use of chloramphenicol was studiedat the Medical Center of VermonP7 and atHartford Hospital31 where 1.6% and 1.2% ofin-patients, respectively, received chloramphenicol.Inpatient indications for chloramphenicol can in-clude serious Haemophilus influenzae infections,meningitis, brain abscess, anaerobic infections,rickettsial diseases, and typhoid. During the lastdecade, chloramphenicol therapy for meningitis,for abdominal and pelvic sepsis, and for typhoidhas been reevaluated.

The treatment of bacterial meningitis requiresbactericidal antibiotics. Chloramphenicol failurescan oc(:ur when chloramphenicol is bacteriostaticagainst the meningeal pathogen.48 Also, in a studyof gram -negative bacilli meningitis in 19 patientstreated with chloramphenicol, six patients de-veloped resistant organisms during therapy. 49

Chloramphenicol is bactericidal against Hae-moPhilus influenzaeJ Streptococcus pneumoniae , andNeisseria meningitidisJ and its efficacy against thesepathogens is well established. 6.12 Chloram -

phenicol can be used in penicillin-allergic adultswith suspected pneumococcal or meningococcalmeningitis and can be used to treat meningitis

caused by relatively penicillin-resistant pneumo-cocci (MIC 0.12 to 1.0 p,g/m1). Cefuroxime, a sec-ond generation cephalosporin, and ceftriaxone andmoxalactam, third generation cephalosporins, allachieve higher Haemophilus influenzae bactericidaltiters in the cerebrospinal fluid than chloram-phenicol or ampicillin; however, in prospectivestudies of meningitis,5°-52 clinical efficacy andtime required to sterilize the cerebrospinal fluidwas not different in patients treated with acephalosporin or conventional therapy ( chloram-phenicol plus ampicillin initially, then continuingonly one antibiotic when susceptibilities areavailable). In many institutions cephalosporinshave replaced chloramphenicol for initial men-ingitis therapy because the new cephalosporinshave less toxicity and levels do not have to bemonitored.

The antibiotics of choice for the treatment ofbrain abscesses usually include a penicillin pluschloramphenicol or metronidazole. Chloramphen-icol can be used because of its central nervoussystem penetration and its anaerobic spectrum,and because it has been effective even withoutsurgery .53 Chloramphenicol, however, is onlybacteriostatic against anaerobes12 and can be in-activated in abscesses.54 Some physicians prefermetronidazole over chloramphenicol because theformer is bactericidal against anaerobes6 and whencombined with penicillin has resulted in amortality of less than 10% .55 Unfortunately, noprospective studies have compared different an-tibiotics in the treatment of brain abscesses.

For suspected abdominal or pelvic sepsis, anti-biotic therapy should be directed against gram-positive cocci including enterococci, gram-negativeenterics, and anaerobes including Bacteroides fragilis.Prospective controlled studies have shown severalprotocols to be effective for abdominal or pelvicsepsis: a penicillin, an aminoglycoside, andchloramphenicoI4°; a penicillin, an aminoglyco-side, and clindamycin4°; clindamycin, and anaminoglycoside56-58; metronidazole and anaminoglycoside56; cefoxitin57; cefoxitin and anaminoglycoside57; cefoperazone58; and cefotax-ime.59 Of the protocols for treatment of abdominalor pelvic sepsis, the combination of ampicillin,clindamycin, and an aminoglycoside has the invitro advantage of the best spe:ctrum, and thus isthe commonly recommended protocol,6° thoughclinical data demonstrating superiority of this com-bination are lacking. c

Pillay et al61 reported no difference in efficacybetween oral chloramphenicol and oral amoxicillinin the treatment of typhoid fever. In anothertyphoid study, Snyder et al62 reported a fever

1132 September 1986 .SOUTHERN MEDICAL JOURNAL. Vol. 79, No.9

duration of 122 hours in patients treated with oralchloramphenicol, 150 hours with intramuscularampicillin, and 166 hours with oral trimethoprim-sulfamethoxazole. Outcome was not differentamong the three treatment groups. Butler et al63compared intravenous trimethoprim-sulfamethox-azole to intravenous chloramphenicol for the treat-ment of typhoid fever and found no difference inclinical efficacy. Chloramphenicol as well asampicillin, amoxicillin, and trimethoprim-sulfa-methoxazole are all effec;tive for typhoid fever .Salmonella typhi can be resistant to any of theseantibiotics, and susceptibilities must always bedetermined.

Chloramphenicol or tetracycline is effectivetherapy for rickettsial infections.6 In children lessthan 9 years old and in pregnant women, forwhom tetracycline, is contraindicated, chloram-phenicol should be used.

CONCLUSIONIn the 1970s there was a renaissance in the use

of chloramphenicol. During this last decade theclinical efficacy of chloramphenicol has beenreestablished and chloramphenicol's pharma-cokinetics have been better defined. With properdosing and careful monitoring of serum levels,serious toxicity is infrequent; however, withimproper dosing or with failure to follow levels,serious toxicity can result. Now with the availabi-lity of less toxic alternatives, the indications forchloramphenicol have again narrowed. Re-

membering chloramphenicol's unique spectrum,pharmacokinetics, and clinical efficacy, it is possi-ble that there will be a second chloramphenicolrenaissance in the future.

12. M~~tin W], Gard~er M, v:-'a~hington]A: In vitro antimicrobial suscep-tlblhty of anaerobic bacteria Isolated from clinical specimens. AntimiCTobAgents Chemother 1:148-158, 1972

13. Rocco V, Overlurf G: Chloramphenicol inhibition of the bactericidal ef-fect of ampicillin against HaemoPhilus influenzae. Antimicrob Agents Chemother21:349-351,1982

14. Weeks ]L, ~ason EO Jr, B":ker C]: Antagonism of ampicillin andchloramphenicol for menmgeallsolates of group B streptococci. AntimiCTobAgents Chemother 20:281-285, 1981

15. Sande MA, Overton]W: In vivo antagonism between gentamicin andchloramphenicol in neutropenic mice. ] Infect Dis 128:247-250, 1973

16. Asmar BI, Dajani AS: Ampicillin-chloramphenicol interaction againstenteric gram-negative organisms. Pediatr Infect Dis 2:39-42, 1983

17. Kauffman RE, Thirumoorthi MC, Buckley ]A, et al: Relativebioavailability of intravenous chloramphenicol succinate and oral chloram-phenicol palmitate in infants and children. ] Pediatr 99:963-967, 1981

18. Kauffman RE, Mceli]N, Strebel L, et aI: Pharmacokinetics of chloram-phenicol and chloramphenicol succinate in infants and children.] Pediatr98:315-320, 1981

191 Dupont HL, Hornick RB, Weiss CF, et al: Evaluation of chloramphenicolacid succinate therapy of induced typhoid fever and Rocky Mountainspotted fever. N Engl] Med 282;53-57, 1970

20. Shann F, Linnemann V, Mackenzie A, et aI: Absorption ofchloramphenicol sodium succinate after intramuscular administration inchildren. N Engl] Med 313:410-414, 1985

21. Narang APS, DattaDV, Nath N, et al: Pharmacokinetic study ofchloram-phenicol in patients with liver disease. Eur] Clin PharmacoI20;479-483, 1981

22. Lindberg AA, Nilsson LH, Bucht H, et al: Concentration of chloram-phenicol in the urine and blood in relation to renal function. Br Med]2;724-728, 1966

23. Krasinski K, Kusmiesz H, Nelson]D: Pharmacologic interactions amongchloramphenicol, phenytoin and phenobarbital. Pediatr lrifect Dis 1 :232-235,1982

24. Powell DA, Nahata MC, Durrell DC, et al: Interactions among chloram-phenicol, phenytoin, and phenobarbital in a pediatric patient. ] Pedialr98:1001-1003, 1981

25. Wallerstein RO, Condit PK, Kasper CK, et aI: Statewide study ofchloramphenicol therapy and fatal aplastic anemia.]AMA 208;2045-2050,1969

26. Daum RS, Cohen DL, Smith AL: Fatal aplastic anemia following ap-parent "dose related" chloramphenicol toxicity. ] Pedialr 94:403, 1979

27. Farber BF, Brody ]P: Rapid development of aplastic anemia after in-travenous chloramphenicol and cimetidine therapy. South Med ]74:1257-1258, 1981 ,

28. Plaut ME, Best WR: Aplastic anemia after parenteral chloramphenicol:warning renewed (Letter). N Engl] Med 24:1486, 1982

29. Alavi]B: Aplastic anemia associated with intravenous chloramphenicol.Am] HematoI15:375-379, 1983

30. Feder HM]r, Osier C, Maderazo EG: An audit of chloramphenicol usein a large community hospital. Arch lnlern Med 141:597-598, 1981

31. Smith DH, Ingram DL, Smith AL, etal: Bacterial meningitis-a sym-posium. Pediatrics 52:586-600, 1973

32. Oski FA: Hematologic consequences of chloramphenicol therapy. ] Pediatr94:515-516,1979

33. Gleckman RA: Warning-chloramphenicol may be good for your health.]AMA 135;1125-1126,1975

34. Lietman PS: Oral chloramphenicol therapy. ] Pedialr 99;905-906, 198135. Fraunfelder FT , Bagby GC: Ocular chloramphenicol and aplastic anemia

(Letter). N Engl] Med 308:1536, 198336. Mulhall A, de Louvois], Hurley R: Chloramphenicol toxicity in neonates:

its incidence and prevention. Br Med] 287: 1424-1427, 198337. Hallman M: Oxygen uptake in neonatal rats: a developmental study with

particular reference to the effects of chloramphenicol. Pediatr Res 7:923-930,1973

38. Fripp RR, Carter MC, Werner ]C, et al: Cardiac function and acutechloramphenicol toxicity. ] Pediatr 103:487-490, 1983

39. Mauer SM, Chavers BM, Kjellstrand CM: Treatment of an infant withsevere chloramphenicol intoxication using charcoal-column hemoperfu-sion. ] Pediatr 96:136-139, 1980

40. Harding GKM, Buckwold F], Ronald AR, et al: Prospective, randomizedcomparative study of clindamycin, chloramphenicol, and ticarcillin, eachin combination with gentamicin, in therapy for intraabdominal and femalegenital tract sepsis. ] Infect Dis 142:384-393, 1980

41. Adams GA, Pearson HA: Chloramphenicol-responsive chronicneutropenia. N Engl] Med 309:1039-1041, 1983

42. Feder HM ]r: Do we really need to monitor liver function in patientsreceiving chloramphenicol (Letter)? ] Pedialr 103:341-342, 1983

43. Feigin R: Antimicrobial agent-induced pseudomembranous colitis. PediatrRev 3:147-152,1981

44. Ray W A, Federspie1 CF, Schaffner W: Prescribing of chloramphenicolin ambulatory practice-an epidemiologic study among TennesseeMedicaid recipients. Ann lnlern Med 84:266-270, 1976

References1. Volini IF, Greenspan I, Ehrlich L, et aI: Hemopoietic changes during

administration of chloramphenicol (Ghloromycetin).JAMA 142:1333-1335,1950

2. Rich ML, Ritterhoff RJ, Hoffman RJ: A fatal case of aplastic anemiafoUowing chloramphenicol (Ghloromycetin) therapy. Ann Intem Med33:1459-1467, 1950

3. Sutherland JM: Fatal cardiovascular collapse of infants receiving largeamounts of chloramphenicol. AmJDis Child 97:761-767, 1959

4. Gherubin GE, Neu HG, Rahal JJ, et aI: Emergence of resistance tochloramphenicol in Salmonella. J Infect Dis 135:807-812, 1977

5. Lorian V: Antibiotics in Laboratory Medicine. Baltimore, Williams & WilkinsGo, 1980, pp 618-655

6. Feder HM Jr, Osier G, Maderazo EG: Chloramphenicol: a review ofits use in clinical practice. Rev Infect Dis 3:479-491, 1981

7. Edelstein PH, Meyer RD: Susceptibility of Legionella pneumophila to 20antimicrobial agents. Antimicrob Agents Chemother 18:405-408, 1980

8. Hill JG: Summary of a workshop on Haemophilus influenzae type b vac-ciru,s. J Infect Vis 148:167-175, 1983

9. Roberts MG, Swenson CD, Owens LM, et aI: Characterization ofchlorampheniciil-resistant Haemophilus in.fluenzae. Antimicrob Agents Chemother18:610-615, 1980

10. WalterspielJN, Kaplan SL, Kessler MJ, et aI: Ampicillin and chloram-phenicol resistance in systemic Haemophilus influenzae disease. MMWR33:35-37, 1984

11. Rahal JJ, Simberkoff MS: Bactericidal and bacteriostatic action ofchloramphenicol against meningeal pathogens. Antimicrob Agents Chemother16:13-18, 1979

1133Feder .CHLORAMPHENICOL

.15. Alderson D, Strong AJ, Ingham HR, et al: Fifteen-year review of themortality of brain abscesses; Neurosurgery 8: 1-6, 1981

56. SmithJA, Skidmore AG, Forward AD, et al: Prospective, randomized,double-blind comparison of metronidazole and tobramycin and clin-damycin and tobramycin in the treatment of intra-abdominal sepsis. AnnSurg 192:213-220, 1980

57. Tally FP, McGowan K, Kelluffi JM, et al: A randomized comparisonof cefoxitin with or without amikacin and clindamycin plus amikacin insurgical sepsisc Ann Surg 193:318-323, 1981

58. Berne TV, Yellin AW, Appleman MD, et al: Comparison of gentamicinand clindamycin versus cefamandole versus cefoperazone. Am J Surg

1~~:8-13,198259. Smith CR, Ambinder R, Lipsky J , et al: Cefotaxime compared with naf-

cillin plus tobramycin for serious bacterial infections: a randomized double-blind trial. Ann Intern Med 101 :~69-~77 , 198~

60. Siegel JD: Intra abdominal sepsis. Pediatr Infect Dis ~:SI8-S21, 198~61. Pillay N, Adams EB, North-Coombies D: Comparative trial of amox.

icillin and chloramphenicol in treatment of typhoid fever in adults. Lancet2:333-33~, 1975

62. Snyder MJ, Gonzalez 0, Palomino C,et al: Comparative efficacy ofchloramphenicol, ampicillin, and co-trimoxazole in the treatment oftyphoid fever. Lancet 2:1155-1157, 1976

63. Butler T, Ruffians L, Arnold K: Response of typhoid fever caused bychloramphenicol-susceptible and chloramphenicol resistant strains ofSalmonella typhi to treatment with trimethopriffi.sulfamethoxazole. Rev InfectDis ~.551.561 , 1982

45. SchaffneI W, Ray WA, Federspiel CF: Chloramphenicol and tetracyclineusage in outpatient practice. Quality Rev Bull 5:28-31, 1979

46. DeNuzzo RV: Tylenol with codeine leads the way. Medical Marketing andMedia, April 1982, pp 36-66

47 Fink TJ, Gump DW: Chloramphenicol: an inpatient study of use andabuse. ] Infect Dis 138:690-694, 1978

48 Rahal 11, Simberkoff MS: Host defense and antimicrobial therapy in adultgram-negative bacillary meningitis. Ann Intern Med 96:468-474, 1982

49 McGee ZA, Kaiser AB, Rubens C, et ai: Emergence of chloramphenicolresistan<:e during chloramphenicol therapy of gram-negative bacillary men-ingitis (Abstract No.4). Proceedings of the lnterscience Conference onAntimicrobial Agents Chemotherapy, 1977. Washington, DC, AmericanSociety for Microbiology, 1977

50 Swedish Study Group: Cefuroxime versus ampicillin and chloramphenicolfor the treatment of bacterial meningitis. Lancet 1 :295-298, 1982

51. Del Rio MA, Chrane D, Shelton S, et ai: Ceftriaxone versus ampicillinand chloramphenicol for treatment of bacterial meningitis in children.Lancet 1 :1241-1244, 1983

52. Kaplan SL, Mason EO 1r, Mason SK, et ai: Prospective comparativetrial of moxalactam ver~us ampicillin or chloramphenicol for treatmentof Hemophilus injluenzat type b meningitis in children.] Pediatr 104:447-453,1984

53. Boom WH, Tuazon CU: Successful treatment of multiple brain abscesseswith antibiotics alone. Rev Infect Dis 7:189-199, 1985

54. Onderdonk AB, Kasper DL, Mansheim B1, et ai: Experimental animalmodels for anaerobic infections. Rev Infect Dis 1:291-301, 1979

September 1986 .SOUTHERN MEDICAL JOURNAL. Vol. 79, No.91134