CLINICAL PHARMACY
`CASE REPORTS
`
`
`VANCOMYCIN-INDUCED NEUTROPENIA
`
`Kenneth B. Koo, Richard L. Bachand, and Anthony W. Chow
`
`ABSTRACT: A case of vancomycin-induced neutropenia is
`presented with a review of other reported cases in the literature.
`A 59-year-old white female was started on vancomycin therapy
`for a chronic infection of a total left hip replacement.
`After 38 days of treatment, the patient developed a severe
`leukopenia with a white blood cell count of 1700/mm?andthe
`presence of only occasional neutrophils. Upon discontinuation of
`vancomycin, the leukocyte and neutrophil counts promptly
`increased with full recovery in one week. Subsequently, the
`patient was restarted on a five-day course of vancomycin at a
`lower dose that proved uneventful with no recurrence of
`neutropenia. It is unclear whether the neutropenia would have
`recurred with a longer course of vancomycin.
`A review of the literature suggests that an immunologic
`mechanism mayberesponsible for the reaction. Physicians and
`other health professionals should be aware that neutropenia is a
`potential reaction of patients receiving prolonged vancomycin
`treatment.
`
`Drug Intell Clin Pharm 1986;20:780-2.
`KEY WORDS: vancomycin, neutropenia, leukopenia.
`
`is
`VANCOMYCIN, a glycopeptide antimicrobial agent,
`bactericidal against many gram-positive cocci, with par-
`ticular potent activity against staphylococci. It is an
`effective alternative in those patients with gram-positive
`infections whoareallergic to penicillin and in the treat-
`ment of serious staphylococcal and streptococcal infec-
`tions resistant to penicillin. In recent years, vancomycin
`treatment courses have greatly increased, prompted by
`the emergence of methicillin-resistant
`strains of
`Staphylococcus aureus and an increasing prevalence of
`serious
`infections caused by penicillin-resistant
`Staphylococcus epidermidis.'
`Although the most commonly feared adverse reac-
`tions of vancomycin are ototoxicity and nephrotoxic-
`ity,
`the reported incidence of these reactions has
`decreased significantly with the reformulations of the
`
`KENNETHB. KOO,B.Sc. Pharm., and RICHARD L. BACHAND,Pharm.D., are
`with the Department of Pharmacy; and ANTHONY W. CHOW,M.D., F.R.C.P.(C),
`F.A.C.P., is with the Division of Infectious Diseases, Faculty of Medicine, Univer-
`sity of British Columbia and Vancouver General Hospital. Reprints: Richard
`Bachand, Pharmacy Department, Vancouver General Hospital, 855 West 12th Ave-
`nue, Vancouver, B.C., Canada V5Z 1M9.
`
`product. It has been postulated that the impurities con-
`tained in earlier formulations may have accounted for
`these adverse reactions.” There have been several reports
`in the recent literature of neutropenia induced by van-
`comycin.'3-? We report a case of neutropenia in a
`patient receiving vancomycin therapy during hospitali-
`zation for a revision of a total hip replacement.
`
`CASE REPORT
`
`A 59-year-old white female was admitted to the hospital for
`investigation of loosening ofa left total hip replacementrevi-
`sion. She had a revision performed 1% years before, but since
`then had developed recurrent pain andstiffness.
`On admission the patient appeared well and wasin no acute
`distress. The white blood cell count (WBC) was 7700 cells/mm?
`with 59% neutrophils, 5% bands, 33% lymphocytes, 1%
`eosinophils, and 2% monocytes; the hemoglobin (Hb) value
`was 13.1%; and the platelet count was 289 000/mm?. Serum
`creatinine and blood urea nitrogen (BUN)were 0.9 mg/100 ml
`and 20 mg/i00 ml, respectively. The patient’s past history
`revealed no known penicillin or drug allergies.
`Onhospital day 5 the patient underwent operation for resec-
`tion arthroplasty of the left total hip. At that time, the hip
`components showed evidence of chronic inflammationand
`infection. Pending the culture results of the synovium and
`acetabulum,
`the patient was empirically started on an
`antimicrobial treatment course of vancomycin 500 mg q6h and
`netilmicin 100 mg q8h (Figure 1). The patient also received three
`doses of cefazolin 1 g q8h perioperatively. Vancomycin and
`netilmicin serum concentrations were routinely monitored.
`Serum creatinine and BUN were monitored twice weekly and
`auditory assessments were performed weekly. Results of the
`cultures showed twostrains of S. epidermidis resistant to
`cefazolin and penicillin but sensitive to vancomycin. Netilmi-
`cin was subsequently discontinued and the patient was main-
`tained on vancomycin alone.
`The vancomycin dosage was adjusted during the four-week
`course of therapy based on serum concentrations drawn 5
`minutes pre- and 30 minutes postvancomycin infusion. The van-
`comycin dosage was eventually reduced to 500 mg q12h. Dur-
`ing the course of therapy the serum creatininelevel increased
`to 1.3 mg/100 ml.
`On hospital day 32 the patient developed leukopenia with
`a WECof 2300/mm:?(Figure 1). The decision was made to
`stop vancomycin therapy on day 37. On day 38, the WBC was
`
`780
`
`1986 OCTOBER
`
`VOL 20
`
`Drug Intelligence and Clinical Pharmacy
`ALVOGEN, Exh. 1023, p. 0001
`
`ALVOGEN, Exh. 1023, p. 0001
`
`

`

`o— Post-dose (30 min} Desired = <50 pg /mt
`om=—o Pre-dose (5 min} Desired = <10 U9 /mL
`
` VancomycinLevels
`
`'
`20
`
`'
`24
`
`'
`28
`
`'
`32
`
`'
`36
`
`40
`
`44
`
`48
`
`1700/mm:with only occasional neutrophils, 34% bands, 70%
`lymphocytes, 24% monocytes, 1% basophils, and 3%
`eosinophils. The Hb value and platelet counts were 12.3% and
`202 000/mm?, respectively. By the next day, the WBC had
`increased to'3800/mm:with 8% neutrophils. The WBCseries
`continued to improve over the next few days with full recov-
`ery from the neutropenia in one week. Duringthis period, other
`medications that the patient received included cimetidine 300
`mg gid (which was discontinued shortly after the neutrophil
`count began to improve); and a three-day course of phenyl-
`butazone 100 mg bid that had been given prior to the onset
`of neutropenia (Figure 1).
`On hospital day 45, the patient was returned to the operat-
`ing room for removal of trochanteric wires and needle biop-
`sies of the left hip. Vancomycin therapy was reinstituted at
`a dosage of 250 mg q!2h. Cultures of the hip biopsies showed
`no evidence of anaerobic or aerobic growthafter five days and
`the vancomycin was discontinued (Figure 1). During this sec-
`ond course of vancomycin therapy,
`the patient remained
`afebrile with a stable WBC count and nosigns of neutrope-
`nia. Results of auditory tests performed during the patient’s
`therapy showed no change. Thepatient was discharged after
`63 days of hospitalization.
`
`In earlier reported cases of vancomycin-induced neu-
`tropenia, there is conflicting evidence as to whether the
`neutropenia was caused by vancomycin, since several
`of the patients had also received courses of penicillin
`or cephalosporins, both of which are reported to cause
`neutropenia.!*'! In one reported case, the neutropenia
`resolved while treatment with vancomycin was con-
`tinued.’? In the last several years, there have been 10
`additional published cases of neutropenia that, in con-
`trast to the earlier reports, more clearly indicate that
`vancomycinis the responsible agent.'-3-° In five of these
`cases, the patients had received no concurrentorprevi-
`ous courses of other antibiotics prior to vancomycin.'**
`In all cases except one,® the neutrophil count began to
`rise within one day of discontinuing vancomycin with
`complete recovery occurring in a few days. Onepatient
`receiving hemodialysis for chronic renal failure required
`15 days for his neutrophil count to recover.® Further-
`more, in 7 of the 10 cases, the neutropenia occurred
`after approximately one month of vancomycin ther-
`apy.'3-7 In two cases, the neutropenia occurred between
`two and three weeks of therapy.’° In the patient with
`chronic renal failure, the neutropenia did not occur until
`one monthafter the patient had received his last weekly
`dose of vancomycin.®
`Ourpatient displayed a similar pattern of neutrope-
`nia as shown by the development of a severe neutrope-
`nia after 38 days of vancomycin therapy (Figure 1). An
`improvementin the neutrophil count was noted within
`two days of discontinuing vancomycin with full recov-
`ery of the WBCseries in one week. The patient had
`received cimetidine 300 mg q6h until three days after
`the vancomycin wasdiscontinued. Although cimetidine
`is known to cause neutropenia,’ its role as the causa-
`tive agent is unlikely because an increase in the neu-
`trophil count occurred before it was discontinued. The
`patient received no other concurrent antibiotics. How-
`ever, four weeks before starting vancomycin, the patient
`had received one day of cefazolin and four daysofnetil-
`micin therapy. A short three-day course of phenylbuta-
`zone wastaken shortly before the onset of neutropenia.
`Neutropenia following phenylbutazone dosing is well
`recognized; however, it is more commonly reported fol-
`lowing prolonged therapy of weeks to months.'*
`
`
`
`
`
`hi Cefazolin 6
`
`efazolin
`6g
`held
`Phenylbutazone 200mg
`-— Netilmicin 300mg
`
`
`*— Total WBC Count
`o——o Neutrophil Count
`
`Vancomycin 2g
`
`2.259
`
`as
`a)
`
`0°
`
`4
`
`#8
`
`12
`
`Cimetidine 1200mg
`32
`16
`20
`24
`28
`Oay of Hospitalization
`
`36
`
`40
`
`44
`
`48
`
`% 10000
`am 8000
`§ E 6000
`@ ~ 4000
`2
`2000
`2
`0
`
`o 3
`
`3=o 6
`
`3
`3
`o
`
`s9
`
`3 =
`
`8
`
`Figure 1. Correlation between serum creatinine, pre- and postdose vancomycinlevels,
`and total WBC and neutrophil counts with vancomycin therapy.
`
`During the first course of vancomycin therapy,levels
`of vancomycin were monitored to obtain optimum ther-
`apeutic levels and at the same time to minimizetherisks
`of nephrotoxicity and ototoxicity. Desired predose levels
`were < 10 ng/mL and postdose levels were < 50 pg/mL.
`Frequent dosage adjustments based on serum concen-
`trations were madein an effort to achieve these levels
`(Figure 1). Despite these adjustments, all predose levels
`and one postdose level obtained were greater than the
`desired values. It was also noted that during this course
`of vancomycin, the serum creatinine rose from 0.9 to
`1.3 mg/100 ml. It is unknown whether the high blood
`levels of vancomycin played a contributoryrole in the
`decline in renal function and the subsequent develop-
`ment of neutropenia. The patient was rechallenged with
`a five-day course of vancomycin 250 mg ql2h that
`proved uneventful with only a slight decline in the WBC
`and no recurrence of neutropenia. This decline leads one
`to speculate that if the vancomycin course had been con-
`tinued for a longer period of time, the neutropenia may
`have recurred.
`The mechanism of vancomycin-induced neutropenia
`is not well understood. It has been proposed that an
`immunologic mechanism may be responsible for this
`reaction. In 5 of the 10 published cases, the patients were
`knownto havea history of penicillin allergy.'.°-”.? Fur-
`thermore, in two of the remaining cases, an erythema-
`tous rash occurred during the courses of vancomycin
`therapy.”® Weitzman et al. found antineutrophil anti-
`bodies capable of opsonizing neutrophils in their
`patients who received vancomycin and a cephalosporin.’°
`However, Kauffmanet al. were unable to demonstrate
`the presence of circulating antineutrophil antibodies by
`two different assay methodsin a patient receiving van-
`comycin therapy only. Most recently, Mackett and
`Guay used a lymphocyte transformation test, which
`measures the integrity of cell-mediated immunity and
`T-lymphocyte sensitization to antigen, to provide fur-
`ther support for the theory that an immunologic mech-
`
`Drug Intelligence and Clinical Pharmacy
`
`1986 OCTOBER
`
`VOL 20
`
`781
`ALVOGEN, Exh. 1023, p. 0002
`
`o
`
`4
`
`8
`
`12
`
`16
`
`ALVOGEN, Exh. 1023, p. 0002
`
`

`

`anism is responsible for the neutropenia.’ They were
`able to demonstrate lymphocyte transformation in the
`presence of vancomycin 0.1-100 ng/mL. But, because
`the authors were unable to document the presence of
`vancomycin-dependent antibodies, they were unable to
`conclude that hypersensitivity was the mechanism ofthe
`reaction.® West has postulated that the neutropenia may
`be causally related to the current method of vancomy-
`cin production, which involves purification by an ion
`exchange resin. The use of vancomycin purified by
`earlier methods of production with picric acid had not
`been reported to cause neutropenia.'* Althoughthis is
`a possibility, it is more likely that this adverse reaction
`is caused by the drugitself as a reflection of increased
`usage and recognition of neutropenia, rather than an
`association with the current method of production.
`Regardless of the exact mechanism for the develop-
`ment of neutropenia, it appears to be an immunologic-
`based reaction.In all clearly documentedcases, the neu-
`tropenia did not occur until after two to four weeksof
`therapy—with the majority of cases occurring after four
`weeks.'3-79 Results in our patient parallel these reports
`with the development of severe neutropenia after 38
`days of treatment. Although our patient did not develop
`neutropenia upon rechallenge with a five-day course of
`vancomycin, it remains unclear whether the neutrope-
`nia would have recurred with a longer course of higher
`dosage. If the reaction is immunologic, it would be
`expected to recur since the response mediators should
`still be present. It also remains unclear if the sustained
`elevated predose levels of vancomycin are a significant
`factor in the developmentof neutropenia. This sugges-
`tion implies the reaction is concentration related and
`could be affected either by dosage and/or renal func-
`tion. Other published case reports have not included
`data on serum vancomycin levels, thereby making it
`impossible to correlate the importance of this factor.
`
`Summary
`A case of vancomycin-induced neutropenia has been
`reported with a review of previously documented cases
`in the literature. This case strongly supports that the
`reaction is immunologic based.
`Neutropenia is becoming a recognized but infrequent
`adverse reaction associated with vancomycin therapyin
`recent years. However, at the present time, neutrope-
`nia is not included as an adverse reaction of vancomy-
`cin in the product drug monograph, the Compendium
`of Pharmaceuticals & Specialties, or the Physician’s
`Desk Reference. In view ofthis fact and the increasing
`trend of vancomycin use, physicians and other health
`professionals must be cognizant of this potential reac-
`tion and monitorall patients receiving prolonged van-
`comycin treatment with periodic WBCs. =
`
`References
`1. FARBER BF, MOELLERINGRC. Retrospective study of the toxicity
`of preparations of vancomycin from 1974 to 1981. Antimicrob
`Agents Chemother 1983;23:138-41.
`2. WOODLEY DW, HALL WH. Treatment of severe staphylococcal
`infections with vancomycin. Ann Intern Med 1961;55:235-49.
`
`3. BORLAND CDR, FARRAR WEJR.Reversible neutropenia from van-
`comycin (letter). JAMA 1979;242:2392-3.
`4. KESARWALA HH, RAHIL WJ, AMARAM N. Vancomycin-induced
`neutropenia (letter). Lancet 1981;1/:1423.
`5, WEST BC. Vancomycin-induced neutropenia. South Med J 1981;
`74:1255-6.
`6. KAUFFMANCA, SEVERANCEPJ, SILVA J JR, HUARDTK. Neutrope-
`nia associated with vancomycin therapy. South Med J 1982;
`75:1131-3.
`7. STRIKAS R, STUDLO J, VENEZIO FR, O'KEEFE JP. Vancomycin-
`induced neutropenia (letter). J Infect Dis 1982;146:575.
`8. FARWELL AP, KENDALL LG JR, VAKIL RD, GLEW RH. Delayed
`appearance of vancomycin-induced neutropenia in a patient with
`chronic renal failure. South Med J 1984;77:664-5.
`9. MACKETT RL, GUAY DRP. Vancomycin-induced neutropenia. Can
`Med Assoc J 1985;132:39-40.
`10. WEITZMAN SA, STOSSEL TP, DESMOND M. Drug-induced immuno-
`logical neutropenia. Lancet 1978; 1:1068-72.
`11. GOPALV, BISNO AL, SILVERBLATT FJ. Failure of vancomycin treat-
`ment
`in staphylococcus aureus endocarditis. JAMA 1976;
`236:1604-6.
`:
`12. HOOK EW III, JOHNSON WD JR. Vancomycin therapy of bacterial
`endocarditis. Am J Med 1978;65:411-5.
`13. POSNETT DN, STEIN RS, GRABER SE, KRANTZ SB. Cimetidine-
`induced neutropenia. Arch Intern Med 1979; 139:584-6.
`14. McCARTHY DD, CHALMERSTM. Hematological complications of
`phenylbutazone therapy. Can Med Assoc J 1964;90:1061-7.
`15. WEST BC. Vancomycin-induced neutropenia (letter). South Med
`J 1982;75:1576.
`
`EXTRACTO
`
`Los autores presentan un caso de neutropenia inducida por vancomi-
`cina en conjunto con unarevisién de otros casos reportadosenla liter-
`atura. Una mujer blanca de 59 afios de edad se comenz6 en tratamiento
`con vancomicina para unainfeccién crénica en el drea de reemplazo
`total de la cadera izquierda. Luego de 38 dias de tratamiento, la
`paciente desarrollé leucopenia severa con un contaje de células blancas
`de 1700/mm?y la presencia de neutréfilos ocasionalmente. Después
`de descontinuar la vancomicina, los contajes de leucocitos y neutrofilos
`aumentaron rd4pidamente con una recuperaci6n completa en una
`semana. Subsiguientemente, la paciente se comenzé nuevamente en
`vancomicina en dosis reducida por sélo cinco dias sin experimentar
`mayor complicacién y sin recurrencia de neutropenia. Nose tiene claro
`si la neutropenia hubiése recurrido con un curso mas prolongado de
`vancomicina.
`Unarevision dela literatura sugiere que un mecanismo inmunoldgico
`podria ser el responsable de la reacciédn. Médicos y otros profesion-
`ales de la salud deben estar conscientes de que la neutropenia es una
`reaccién potencial en pacientes recibiendo tratamiento prolongado
`con vancomicina.
`
`BRENDA R. MORAND
`
`RESUME
`
`Cet article décrit un cas de neutropénie chez une patiente de 59 ans
`traitée avec la vancomycine pour uneinfection chronique suite a un
`remplacementtotal de la hanche. Aprés 38 jours de thérapie, la patiente
`a développé une leucopénie sévére avec un compte de globules blancs
`de 1700/mm)!et de rares neutrophiles au frottis sanguin. La formule
`blanche est revenue rapidement 4 la normale en une semainesuite a
`Parrét de l’antibiotique. Par la suite, la vancomycine a été recommencée
`pour une durée de 5 jours et a faible dose. Aucune récurrence de la
`neutropénie n’est survenue. Cependant, une plus longue durée de
`traitement aurait peut-étre causé de nouveau cette réaction adverse.
`La patiente a aussi recu de la cimétidine et de la phénylbutazone peu
`avantle début de la neutropénie. Cependant, les auteurs considérent
`improbable le lien de causalité.
`Unerevuedelittérature suggére qu’un mécanisme immunologique
`peut étre responsable de cette réaction. La possibilité de neutropénie
`chez des patients recevant de la vancomycine de facon prolongéeest
`a retenir.
`
`MICHELE BALLY
`
`782
`
`1986 OCTOBER
`
`VOL 20
`
`Drug Intelligence and Clinical Pharmacy
`ALVOGEN, Exh. 1023, p. 0003
`
`ALVOGEN, Exh. 1023, p. 0003
`
`