Use of Once-Daily Dosing of Gentamicin Obstetrics …downloads.hindawi.com/journals/idog/1998/324543.pdf · The Use of Once-Daily Dosing of Gentamicin in ... culties in dosecalculation

Infectious Diseases in Obstetrics and Gynecology 6:155-159 (1998)(C) 1998 Wiley-Liss, Inc.

The Use of Once-Daily Dosing of Gentamicin inObstetrics and Gynecology

H.C. Wiesenfeld* and R.P. HeineDepartment of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of

MedMne/Magee-Womens Research Institute, Pittsburgh, PA

ABSTRACT

Gentamicin is a widely-used antimicrobial agent for obstetric and gynecologic infections. Renewedexcitement in this antibiotic has arisen from recent information supporting less frequent dosing. Inthis symposium, we will describe the pharmacokinetics of gentamicin and review new informationadvocating the use of once-daily administration of gentamicin. Infect. Dis. Obstet. Gynecol. 6:155-159, 1998. (C) 1998 Wiley-Liss, Inc.

KEY WORDS

gentamicin; antimicrobials; gynecologic infection

minoglycosides, discovered over half a centuryago, remain among the most frequently pre-

scribed antibiotic agents for serious infections.Aminoglycosides are an important component ofthe obstetrician-gynecologist’s armamentarium forobstetrical, gynecological, and postoperative infec-tions. Gentamicin is the most widely usedaminoglycoside in these settings, and thus will bethe focus of this paper. While aminoglycosideshave been in use for several decades, recent infor-mation supporting the administration of theseagents once a day has brought renewed interest inthis "older" class of compounds for this modern,cost-conscience medical era.

STRUCTURE AND DERIVATION

Gentamicin is a fermentation product derived fromthe soil actinomycetes Micromonospora purpureaand Micromonospora echinospora. All aminoglyco-sides are comprised of an essential six-memberedring with amino-group constituents bound to at

least two sugar moieties. Gentamicin is soluble inwater but insoluble in organic solvents, thereby re-

stricting permeability across the lipid-rich cellmembranes.

MECHANISM OF ACTION

Antimicrobial activity is achieved following a mul-tistep process that involves binding to the cell sur-

face, uptake into the intracellular compartment,

and, finally, binding and interaction with ribo-somes. Gentamicin binds passively to lipopolysac-charides, phospholipids, and other protein constitu-ents of the outer membrane of gram-negative bac-teria. This binding causes disruption of the outer

membrane, resulting in increased permeability ofthe cell wall. Uptake of gentamicin subsequentlyoccurs by energy-dependent processes. Genta-micin remains intracellular, with intracellular con-

centrations far greater than those found in the ex-

tracellular space. The final step culminating inantimicrobial activity occurs with binding of gen-tamicin to the bacterial ribosome (between thesmaller [30S] and larger [50S] subunits), resultingin misreading of messenger RNA and impairedprotein synthesis.

*Correspondence to: Dr. Harold C. Wiesenfeld, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, 300 Halket Street, Pittsburgh, PA 15213. E-mail: [email protected]

Received 29 April 1998Antimicrobial Symposium Accepted August 1998

ONCE-DAILY GENTAMICIN WIESENFELD AND HEINE

PHARMACOKINETICSGentamicin, as all aminoglycosides, is administeredby the parenteral route (intravenously or intramus-cularly) and is poorly absorbed when taken bymouth. Its high water solubility enables wide dis-tribution in the vascular and interstitial spaces. Thevolume of distribution (Vt)) is 0.2-0.3 L/kg but maybe greater in patients with severe infections. Thehalf-life (T1/z) of gentamicin is 2 +- hours. Elimi-nation occurs almost entirely by the kidney, whereit is excreted unchanged with minimhl reabsorp-tion. Urinary concentration typically exceeds peakplasma levels during administration, and urinarylevels following a single dose surpass therapeuticlevels for several days.The pharmacokinetics of gentamicin involve

three phases. Following parenteral administration,the drug is distributed from the intravaseular to theextravascular space over 15 to 30 minutes. Duringthe second phase, gentamicin is excreted into thekidneys, a process related to glomerular filtrationrate, with the resultant half-life closely dependenton renal function. The final phase involves the ex-cretion of gentamicin from renal tissue.

Gentamicin is widely used in obstetrics and gy-necology, as gram-negative organisms are fre-quently implicated in reproductive tract infections,either alone or as part of a polymicrobial process.Gentamicin is often selected to treat chorioamni-onitis, postpartum endometritis, pyelonephritis,pelvic inflammatory disease, and tuboovarian ab-scesses. Among obstetric patients there are widevariations in gentamicin elimination, posing diffi-culties in dose calculation. Using a dose of mg/kgevery 8 hours, Duff et al. found that one-third ofwomen with postpartum endometritis had sub-therapeutic levels of gentamicin. Zaske et al. es-timated that 49% of patients receiving standarddoses of gentamicin would have subtherapeuticlevels, z Establishing therapeutic levels required awide range of doses of gentamicin (3.0 to 11.6 mg/kg/d). Given the wide variation of doses amongobstetric patients, when multiple daily dosing ofgentamicin is used, serum concentrations shouldbe monitored in patients who do not quickly re-

spond to therapy.

SIDE EFFECTSThe clinician’s main concern regarding the use ofgentamicin (and other aminoglycosides) is the risk

of toxicity, specifically nephrotoxicity and ototox-

icity. The incidence of nephrotoxicity is between 5and 10% and is even less frequently seen in other-wise healthy individuals receiving gentamicin.Risk factors for nephrotoxicity include older age,multisystem disease, preexisting renal disease, con-comitant administration of nephrotoxic agents (eg,cis-platinum, amphotericin-B), and multiple dailydosing (see below). Aminoglycoside-related neph-rotoxicity rarely results in severe renal compromiserequiring dialysis. Gentamicin should be discontin-ued if nephrotoxicity occurs; resolution of renalfunction will subsequently follow over severaldays. When it is ill-advised to stop aminoglycosideadministration, the dosage should be adjusted to

reduce the risk of increasing toxicity.

SPECTRUM OF ACTIVITYGentamicin is active against the majority of gram-negative bacteria, such as Escherichia coli, Klebsiellasp, Proteus mirabilis, Citrobacter sp, Serratia sp, En-terobacter sp, Hemophilus influenzae, and some strainsof Pseudomonas aeruginosa. It possesses some activ-ity against gram-positive organisms, particularlymethicillin-susceptible Staphylococcus aureus. Gen-tamicin is not active against anaerobic organisms.

RESISTANCE

Resistance against aminoglycosides occurs by sev-

eral mechanisms, including enzymatic alteration ofthe aminoglycoside by aerobic gram-negative bac-teria, altered bacterial uptake, and by modificationof ribosomal binding sites. Resistance of a particu-lar organism to gentamicin is slow in development,therefore resistance rarely emerges during a thera-peutic course of gentamicin. Resistance to genta-micin is observed in many strains of enterococci,Pseudomonas aeruginosa, and methicillin-resistantStaphylococcus aureus.

ONCE-DAILY DOSING OF GENTAMICINRecently developed broad-spectrum antimicrobialagents (eg, cephalosporins and fluoroquinolones)with less frequent dosing requirements and favor-able safety profiles have supplanted aminoglyco-sides in many clinical settings. However, over theyears new information on the pharmacokineticproperties and killing parameters of gentamicinhave enabled the development of alternative, lessfrequent dosing regimens with lower risk of toxic-

156 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY


ity. Aminoglycosides possess concentration, ordose-dependent killing properties, with greaterbacteriocidal activity associated with higher con-

centrations of drug (eg, 10 times the minimum in-hibitory concentration [MIC]). This contrasts with

13-1actam agents that possess time-dependent kill-ing, where maximum antibacterial activity occurs

during prolonged periods of drug concentrationabove the MIC. Additionally, gentamicin has a

"postantibiotic effect" (PAE), which is defined as

persistent bacterial growth inhibition after antibi-otic exposure has ceased. In vitro and animal stud-ies have documented equivalent or greater antimi-crobial activity with once-daily dosing versus

smaller, more-frequent doses of aminoglyco-sides.3,4 The PAE of aminoglycosides pertains to

several different microbial species, and the higherthe initial aminoglycoside level, the greater thePAE. Both the PAE and the concentration-dependent killing properties of aminoglycosidesare the rationale behind the utilization of once-

daily dosing of gentamicin. Specifically, the singlelarge daily dose maximizes bacterial killing, whilethe PAE during the extended dosing interval,when the drug level in the serum is low, wouldeither allow for ongoing killing or at least prevent

regrowth of bacteria.There has been a rapid accumulation of pub-

lished trials of once-daily dosing of aminoglyco-sides, including netilmicin, amikacin, and gentami-cin. A small randomized study comparing once-and thrice-daily dosing of gentamicin or netilmicinin sixty patients demonstrated similar efficacy, butthe study was limited by small sample size.s Prinset al. compared once-daily dosing of gentamicin,using a dose of 4 mg/kg/d, to thrice-daily doses of1.33 mg/kg of gentamicin among 67 adult patientswith serious infections. Once-daily dosing was aseffective as thrice-daily doses, with favorable clini-cal outcomes seen in 91% of patients receivingonce-daily dosing and in 78% of those receivingconventional dosing.6 Similar results have been ob-tained with netilmicin and other aminoglycosides.7

Metaanalyses have repeatedly demonstrated equalefficacy of once-daily dosing of aminoglycosidescompared with multiple daily dosing in both clini-cal and microbiologic cure rates.8-1z Additionalstudies are needed among certain populations, par-ticularly pregnant women, children, and patientswith endocarditis.

Toxicity studies of once-daily dosing ofaminoglycosides have not revealed an increasedrisk of either nephrotoxicity or ototoxicity. Whileaminoglycosides are accumulated in the renal cor-

tex, the uptake is saturable, with greater accumu-lation occurring in continuous or divided-dose in-fusions than in one large dose. Less nephrotoxicitywas observed in laboratory animals receiving once-

daily dosing. In a review of once-daily aminoglyco-side administration to over 2,000 adult patients,nephrotoxicity was observed in 1.2% of patients,and only three patients exhibited clinical ototoxic-ity. 13 Prins et al. noted significantly less nephrotox-icity in patients with serious infections receivingthe once-daily dose of gentamicin compared with

thrice-daily dosing (5% vs. 24%, P 0.016) and no

difference in ototoxicity as assessed clinically andby audiometry.6 Similarly, several metaanalyses ofsingle daily dosing of aminoglycosides failed to

demonstrate increased nephrotoxicity or ototoxic-ity.8,9,1,1z However, in patients with preexistingrenal failure, there are limited data on the safety ofonce-daily dosing.A consensus is lacking regarding the timing, and

even utility, of monitoring aminoglycoside levels.After 48 hours of therapy, Prins et al. obtainedtrough levels immediately preceding and peak lev-els 30 minutes following the next dose.6 The dosewas subsequently lowered when the trough levelswere above 2 rag/L; no adjustment was made forpeak levels. In a large series of adult patients re-

ceiving once-daily aminoglycosides (mostly genta-micin), Nicolau et al. reported that only 5% of pa-tients required a dose adjustment.1 Based on hisresults, the following patient criteria for withhold-ing aminoglycoside levels were identified: age lessthan 60 years, no concurrent therapy with nephro-toxic agents, no exposure to contrast media, no re-

quirement for intensive care support, and not

quadriplegics nor amputees. Nonetheless, serumcreatinine was monitored every 2 to 3 days.

Experience with single-dose gentamicin amonggeneral adult populations has been the foundationfor its use for reproductive tract infections. In our

report in this issue of the journal, we evaluated thepharmacokinetics of once-daily gentamicin inwomen with postpartum endometritis.4 Using a

single daily dose of 4.5 mg/kg actual body weight,peak gentamicin levels were above 10 mg/L, with

consistently low trough levels. Clinical efficacy of

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 157

ONCE-DAlLY GENTAMICIN WIESENFELD AND HEINE

this regimen in this preliminary study was excel-lent, with no nephrotoxicity or clinical ototoxicity.A recently published randomized trial of once-daily(5 mg/kg/d) vs. 8-hour dosing (1.75 mg/kg every 8hours) of gentamicin for the treatment of postpar-tum endometritis demonstrated equal efficacy andcost savings with the once-daily regimen, is Mitra et

al. reported on once-daily gentamicin with twice-daily clindamycin versus gentamicin and clindamy-cin each administered three times a day for puer-peral endometritis. The less-freqtent dosingschedule was associated with similar outcomes to

those with conventional dosing. 16 Given the diffi-culty in establishing therapeutic levels with mul-tiple daily doses in obstetric patients, once-dailydosing of gentamicin is appealing in this popula-tion. There are no data on once-daily gentamicinfor gynecologic infections, although this regimen isbecoming widely used in many centers. Similarly,once-daily dosing has not been well studied inpregnant women. Its safety in breastfeedingwomen remains to be established, however infantabsorption from breast milk should not be a con-cern due to the inability of gentamicin to be ab-sorbed from the gastrointestinal tract. There arelimited data on the utility of performing routinepeak and trough levels. As noted above, levels are

likely unwarranted in otherwise healthy adults re-

ceiving once-a-day gentamicin for limited periodsof time.

COST

Once-daily dosing of gentamicin offers importantcost savings over traditional dosing schedules. Re-duced costs are realized by a reduction in laborcosts, particularly in pharmacist time and nursinglabor, and material costs (intravenous tubing andbags). In contrast to the thrice-daily regimen,single-daily dosing does not require monitoring se-

rum levels of gentamicin, resulting in further cost

savings. We calculated a 44% reduction in patientcharges with once-daily dosing of gentamicin for 72hours of therapy. 14 Substantial cost savings were

similarly noted in the studies by Del Priore et al.and Mitra et al. as,16

SUMMARY

Gentamicin remains a widely used antibiotic fortreating obstetric and gynecologic infections be-cause of its activity against gram-negative organ-

isms. Among obstetric patients, serum levels are

varied, requiring monitoring of serum gentamicinconcentrations to ensure therapeutic levels. Thereis substantial evidence among general adult popu-lations documenting equal efficacy and reducedtoxicity with once-daily dosing compared to stan-

dard multidose regimens. Limited data support theuse of single-daily dose gentamicin for the treat-

ment of postpartum endometritis. Using this famil-iar antibiotic in a new way results in an equallyeffective, safer, and less costly approach to thetreatment of gram-negative infections.

REFERENCES

1. Duff P, Jorgensen JH, Gibbs RS, Blanco JD, AlexanderG, Castaneda YS: Serum gentamicin levels in patientswith post-cesarean endomyometritis. Obstet Gynecol61:723-727, 1983.

2. Zaske DE, Cipolle RJ, Strate RG, Malo JW, KoszalkaMF Jr: Rapid gentamicin elimination in obstetric pa-tients. Obstet Gynecol 56:559-564, 1980.

3. Blaser J, Stone BB, Zinner SH: Efficacy of intermittentversus continuous administration of netilmicin in a two-

compartment in vitro model. Antimicrob Agents Che-mother 27:343-349, 1985.

4. Herscovici L, Grise G, Thauvin C, Lemeland JF, Fil-lastre JP: Efficacy and safety of once daily versus

intermittent dosing of tobramycin in rabbits withacute pyelonephritis. Stand J Infect Dis 20:205-212,1988.

5. Nordstrom L, Ringberg H, Cronberg S, Tjernstrom O,Walder M: Does administration of an aminoglycoside ina single daily dose affect its efficacy and toxicity? J An-timicrob Chemother 25:159-173, 1990.

6. Prins JM, Bullet HR, Kuijper EJ, Tange RA, SpeelmanP: Once versus thrice daily gentamicin in patients withserious infections. Lancet 341:335-339, 1993.

7. de Vries PJ, Verkooyen RP, Leguit P, Verbrugh HA:Prospective randomized study of once-daily versus

thrice-daily netilmicin regimens in patients with intra-abdominal infections. Eur J Clin Microbiol Infect Dis9:161-168, 1990.

8. Ali MZ, Goetz MB: A recta-analysis of the relative ef-ficacy and toxicity of single daily dosing versus multipledaily dosing of aminoglycosides. Clin Infect Dis 24:796-809, 1997.

9. Bailey TC, Little JR, Littenberg B, Reichley RM, Du-nagan WC: A recta-analysis of extended-interval dosingversus multiple daily dosing of aminoglycosides. ClinInfect Dis 24:786-795, 1997.

10. Barza M, Ioannidis JP, Cappelleri JC, Lau J: Single or

multiple daily doses of aminoglycosides: a meta-analysisBMJ 312:338-345, 1996.

158 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY


11. Hatala R, Dinh T, Cook DJ: Once-daily aminoglycosidedosing in immunocompetent adults: a meta-analysis.Ann Intern Med 124:717-725, 1996.

12. Hatala R, Dinh TT, Cook DJ: Single daily dosing ofaminoglycosides in immunocompromised adults: a sys-tematic review. Clin Infect Dis 24:810-815, 1997.

13. Nicolau DP, Wu AH, Finocchiaro S, et al.: Once-dailyaminoglycoside dosing: impact on requests and costs fortherapeutic drug monitoring. Ther Drug Monitoring 18:263-266, 1996.

14. Sunyecz JA, Wiesenfeld HC, Heine RP: The pharma-cokinetics of once-daily dosing with gentamicin in

women with postpartum endometritis. Infect Dis Ob-stet Gynecol 6:160-162, 1998.

15. Del Priore G, Jackson-Stone M, Shim EK, Garfinkel J,Eichmann MA, Frederiksen MC: A comparison of once-daily and 8-hour gentamicin dosing in the treatment ofpostpartum endometritis. Obstet Gynecol 87:994-1000,1996.

16. Mitra AG, Whitten AG, Laurent SL, Anderson WE: Arandomized, prospective study comparing once-dailygentamicin versus thrice-daily gentamicin in the treat-

ment of puerperal infection. Am J Obstet Gynecol 177:786-791, 1997.

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 159

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Documents

Use of Once-Daily Dosing of Gentamicin Obstetrics …downloads.hindawi.com/journals/idog/1998/324543.pdf · The Use of Once-Daily Dosing of Gentamicin in ... culties in dosecalculation