ajog.org Women over 30 years old, for whom co-testing for HPV may have been performed at the time of Pap smear, would have been excluded from our analysis if their HPV testing was negative for high risk types, just as women with atypical squamous cells of undetermined significance and negative HPV or unavailable HPV testing were excluded. It was known before the most recent guidelines that LSIL on Pap smear is not always associated with high risk HPV. However, guidelines continue to advise against reflex testing for HPV with LSIL Pap smears. This is supported by data from the ASCUSUS LSIL Triage study that found that 27.6% of women with LSIL had CIN 2 within 2 years and 77% were HPV positive.2,3 As our study was retrospective, we were limited by the data that was collected on our patients. Therefore, we do not have data on the HPV types for patients with LSIL to undergo further analysis. We appreciate Dr Aderibigbe’s comment about our attempts to advance knowledge in the field of preeclampsia, and believe that further research on the association between HPV and preeclampsia is warranted. Mollie McDonnold, MD George Saade, MD
Letters to the Editors Maged Costantine, MD University of Texas Medical Branch Department of Obstetrics and Gynecology 301 University Blvd. Galveston, TX 77555-0587 [email protected] The authors report no conflict of interest.
REFERENCES 1. McDonnold M, Dunn H, Hester A, et al. High risk human papillomavirus at entry to prenatal care and risk of preeclampsia. Am J Obstet Gynecol 2014;210:138.e1-5. 2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin no. 140: management of abnormal cervical cancer screening test results and cervical cancer precursors. Obstet Gynecol 2013;122: 338-67. 3. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 2000;92:397-402. ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.05.026
Vancomycin dosage for group B streptococcus prophylaxis TO THE EDITORS: We read with interest the article by Onwuchuruba et al1 on the transplacental passage of vancomycin and its implications on vancomycin dosing for group B streptococcus (GBS) prophylaxis. Results from the study suggested that the standard dosage of 1 g intravenously every 12 hours, as recommended by guidelines from the Centers for Disease Control and Prevention, may achieve only subtherapeutic levels while higher weight-based dosages are more likely to attain levels in the therapeutic range. However, we contend that the results are over interpreted because of the definition of “therapeutic levels” that was based on an outdated understanding of vancomycin pharmacodynamics. Current guidelines on vancomycin use the ratio of area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC) of the target organism as the pharmacodynamic index for dosage guidance.2,3 This reflects the latest expert consensus that vancomycin does not exhibit simple time-dependent killing. Unfortunately, the suggested “therapeutic levels” in the study are derived from studies and guidelines before the adoption of the AUC/MIC concept. In adults, vancomycin trough level is correlated with the AUC and indeed may be used as a surrogate marker in therapeutic drug monitoring.2,3 However, this correlation is based on adult data and may not hold for exposure to the drug in utero. Moreover, commonly cited therapeutic targets for vancomycin, whether AUC/MIC ratio or trough level, were derived mainly from studies on treatment of methicillinresistant Staphylococcus aureus infections in adults. It is
uncertain whether they are applicable in the setting of neonatal GBS prophylaxis. Although we concur with the need for a better and more evidence-based dosage recommendation, much more work must be done before one can be made. The present results are insufficient to refute the utility of standard vancomycin dosage or suggest superiority of higher dosages in GBS prophylaxis. Unnecessarily high doses will lead to more infusionrelated reactions and potentially higher risks of drug toxicity4 without any definite benefit to neonatal outcome. Herman Tse, FRCPath Department of Microbiology The University of Hong Kong Pokfulam Road Hong Kong Sally C. Y. Wong, MB BChir Siddharth Sridhar, MRCP(UK) Department of Microbiology Queen Mary Hospital Pokfulam Rd. Hong Kong The authors report no conflict of interest.
REFERENCES 1. Onwuchuruba CN, Towers CV, Howard BC, Hennessy MD, Wolfe L, Brown MS. Transplacental passage of vancomycin from mother to neonate. Am J Obstet Gynecol 2014;210:352.e1-4. 2. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American
NOVEMBER 2014 American Journal of Obstetrics & Gynecology
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ajog.org
Letters to the Editors Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66:82-98. 3. Matsumoto K, Takesue Y, Ohmagari N, et al. Practice guidelines for therapeutic drug monitoring of vancomycin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J Infect Chemother 2013;19:365-80. 4. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008;52: 1330-6. ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.06.039
REPLY We thank Tse, Wong, and Sridhar for their question regarding the use of vancomycin serum levels that were obtained at the time of delivery in an attempt to assess a “therapeutic” drug level. The current guidelines on vancomycin monitoring do recommend the use of area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC).1 However, the AUC/MIC value is recommended for use in the evaluation of vancomycin “treatment” effectiveness rather than prophylaxis. In using the AUC/MIC, one starts with a mathematic calculation that involves the determination of an estimated creatinine clearance, an estimate of the vancomycin clearance with conversion to liters per hour, the chosen vancomycin dosing regimen, followed by an estimate of the AUC/MIC.2 Once treatment is initiated, >1 serum level is then obtained to verify (through further mathematic computation) that the chosen dosing regimen is adequate. This AUC/MIC verification is not feasible in the evaluation of fetal levels at the time of birth because only 1 cord blood value can be obtained at delivery. Likewise, most pregnant women receive only 1 dose before delivery (29 of 55 patients in our study), thereby negating the possibility of obtaining multiple serum levels. The MIC of the infecting organism is also required for the AUC/MIC to be accurate,2 and the MIC for group B streptococcus usually is not obtained or is unavailable, unless one were to assume that all isolates have an MIC of 1 mg/mL. However, 2 cases of vancomycin-resistant group B streptococcus were reported recently with MICs of 4 mg/mL.3 Additionally, the AUC/MIC evaluation also uses the best estimate of vancomycin volume of distribution, and the volume of distribution in pregnancy has never been addressed. This value would most likely be elevated in pregnancy because the antimicrobial was shown to cross the placenta and enter the fetal circulation, thereby adding to the volume of distribution. The guidelines discuss several very important issues. To begin, an AUC/MIC of 400 mg/mL is the target for Staphylococcus aureus infections.1 The target AUC/MIC for group B streptococcus is unknown. Second, serum vancomycin trough levels are considered the most accurate and practical way to
574 American Journal of Obstetrics & Gynecology NOVEMBER 2014
evaluate efficacy and are the recommended therapeutic drug monitoring parameter to use.1 Third, the guidelines state that “minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance” (milligrams per liter is equivalent to micrograms per milliliter).1 Last, to achieve the optimal trough levels, the recommended dosing regimen is 15-20 mg/kg (using actual body weight) administered every 8-12 hours in patients with normal renal function for a bacteria with an MIC of 1 mg/mL.1 In reference to this last statement, renal function (creatinine clearance) usually increases above normal in most pregnancies, which may explain the reason that our study found that 20 mg/kg intravenously every 8 hours was needed to obtain a cord blood level of >10 mg/mL in most patients.4 There actually has been some discussion of using higher vancomycin trough levels of 15-20 mg/mL in cases of serious infections (ie, sepsis, endocarditis, meningitis).1,2 In conclusion, if vancomycin “treatment” is needed in a pregnant patient with a serious bacterial infection, then our study data would suggest the use of 20 mg/kg intravenously every 8 hours (maximum individual dose of 2 g) to obtain the greatest number of serum values of >10 mg/mL. At the present time, the AUC/MIC value is not likely to be obtained when treating pregnant patients. Regarding group B streptococcus “prophylaxis,” the standard regimen of 1 g intravenously every 12 hours may be adequate; however, one must wonder whether this protocol potentially could lead to the advancement of resistance in group B streptococcus and other significant bacteria because of a high frequency of serum levels below the recommended 10 mg/mL. We concur that further research on these topics is needed. Craig V. Towers, MD Bobby C. Howard, MD Cheryl N. Onwuchuruba, MD Division of Maternal-Fetal Medicine University of Tennessee Medical Center Knoxville, TN The authors report no conflict of interest.
REFERENCES 1. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Disease Pharmacists. Am J Health Syst Pharm 2009;66:82-98. 2. DeRyke CA, Alexander DP. Optimizing vancomycin dosing through pharmacodynamic assessment targeting area under the concentrationtime curve/minimum inhibitory concentration. Hosp Pharm 2009;44: 751-65. 3. Nichols M, Schrag SJ. Two cases of invasive vancomycin-resistant group B streptococcus infection. N Engl J Med 2014;370:885-6. 4. Onwuchuruba CN, Towers CV, Howard BC, Hennessy MD, Wolfe L, Brown MS. Transplacental passage of vancomycin from mother to neonate. Am J Obstet Gynecol 2014;210:352.e1-4. ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.06.040
Letters to the Editors Maged Costantine, MD University of Texas Medical Branch Department of Obstetrics and Gynecology 301 University Blvd. Galveston, TX 77555-0587 [email protected] The authors report no conflict of interest.
REFERENCES 1. McDonnold M, Dunn H, Hester A, et al. High risk human papillomavirus at entry to prenatal care and risk of preeclampsia. Am J Obstet Gynecol 2014;210:138.e1-5. 2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin no. 140: management of abnormal cervical cancer screening test results and cervical cancer precursors. Obstet Gynecol 2013;122: 338-67. 3. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 2000;92:397-402. ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.05.026
Vancomycin dosage for group B streptococcus prophylaxis TO THE EDITORS: We read with interest the article by Onwuchuruba et al1 on the transplacental passage of vancomycin and its implications on vancomycin dosing for group B streptococcus (GBS) prophylaxis. Results from the study suggested that the standard dosage of 1 g intravenously every 12 hours, as recommended by guidelines from the Centers for Disease Control and Prevention, may achieve only subtherapeutic levels while higher weight-based dosages are more likely to attain levels in the therapeutic range. However, we contend that the results are over interpreted because of the definition of “therapeutic levels” that was based on an outdated understanding of vancomycin pharmacodynamics. Current guidelines on vancomycin use the ratio of area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC) of the target organism as the pharmacodynamic index for dosage guidance.2,3 This reflects the latest expert consensus that vancomycin does not exhibit simple time-dependent killing. Unfortunately, the suggested “therapeutic levels” in the study are derived from studies and guidelines before the adoption of the AUC/MIC concept. In adults, vancomycin trough level is correlated with the AUC and indeed may be used as a surrogate marker in therapeutic drug monitoring.2,3 However, this correlation is based on adult data and may not hold for exposure to the drug in utero. Moreover, commonly cited therapeutic targets for vancomycin, whether AUC/MIC ratio or trough level, were derived mainly from studies on treatment of methicillinresistant Staphylococcus aureus infections in adults. It is
uncertain whether they are applicable in the setting of neonatal GBS prophylaxis. Although we concur with the need for a better and more evidence-based dosage recommendation, much more work must be done before one can be made. The present results are insufficient to refute the utility of standard vancomycin dosage or suggest superiority of higher dosages in GBS prophylaxis. Unnecessarily high doses will lead to more infusionrelated reactions and potentially higher risks of drug toxicity4 without any definite benefit to neonatal outcome. Herman Tse, FRCPath Department of Microbiology The University of Hong Kong Pokfulam Road Hong Kong Sally C. Y. Wong, MB BChir Siddharth Sridhar, MRCP(UK) Department of Microbiology Queen Mary Hospital Pokfulam Rd. Hong Kong The authors report no conflict of interest.
REFERENCES 1. Onwuchuruba CN, Towers CV, Howard BC, Hennessy MD, Wolfe L, Brown MS. Transplacental passage of vancomycin from mother to neonate. Am J Obstet Gynecol 2014;210:352.e1-4. 2. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American
NOVEMBER 2014 American Journal of Obstetrics & Gynecology
573
ajog.org
Letters to the Editors Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66:82-98. 3. Matsumoto K, Takesue Y, Ohmagari N, et al. Practice guidelines for therapeutic drug monitoring of vancomycin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J Infect Chemother 2013;19:365-80. 4. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008;52: 1330-6. ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.06.039
REPLY We thank Tse, Wong, and Sridhar for their question regarding the use of vancomycin serum levels that were obtained at the time of delivery in an attempt to assess a “therapeutic” drug level. The current guidelines on vancomycin monitoring do recommend the use of area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC).1 However, the AUC/MIC value is recommended for use in the evaluation of vancomycin “treatment” effectiveness rather than prophylaxis. In using the AUC/MIC, one starts with a mathematic calculation that involves the determination of an estimated creatinine clearance, an estimate of the vancomycin clearance with conversion to liters per hour, the chosen vancomycin dosing regimen, followed by an estimate of the AUC/MIC.2 Once treatment is initiated, >1 serum level is then obtained to verify (through further mathematic computation) that the chosen dosing regimen is adequate. This AUC/MIC verification is not feasible in the evaluation of fetal levels at the time of birth because only 1 cord blood value can be obtained at delivery. Likewise, most pregnant women receive only 1 dose before delivery (29 of 55 patients in our study), thereby negating the possibility of obtaining multiple serum levels. The MIC of the infecting organism is also required for the AUC/MIC to be accurate,2 and the MIC for group B streptococcus usually is not obtained or is unavailable, unless one were to assume that all isolates have an MIC of 1 mg/mL. However, 2 cases of vancomycin-resistant group B streptococcus were reported recently with MICs of 4 mg/mL.3 Additionally, the AUC/MIC evaluation also uses the best estimate of vancomycin volume of distribution, and the volume of distribution in pregnancy has never been addressed. This value would most likely be elevated in pregnancy because the antimicrobial was shown to cross the placenta and enter the fetal circulation, thereby adding to the volume of distribution. The guidelines discuss several very important issues. To begin, an AUC/MIC of 400 mg/mL is the target for Staphylococcus aureus infections.1 The target AUC/MIC for group B streptococcus is unknown. Second, serum vancomycin trough levels are considered the most accurate and practical way to
574 American Journal of Obstetrics & Gynecology NOVEMBER 2014
evaluate efficacy and are the recommended therapeutic drug monitoring parameter to use.1 Third, the guidelines state that “minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance” (milligrams per liter is equivalent to micrograms per milliliter).1 Last, to achieve the optimal trough levels, the recommended dosing regimen is 15-20 mg/kg (using actual body weight) administered every 8-12 hours in patients with normal renal function for a bacteria with an MIC of 1 mg/mL.1 In reference to this last statement, renal function (creatinine clearance) usually increases above normal in most pregnancies, which may explain the reason that our study found that 20 mg/kg intravenously every 8 hours was needed to obtain a cord blood level of >10 mg/mL in most patients.4 There actually has been some discussion of using higher vancomycin trough levels of 15-20 mg/mL in cases of serious infections (ie, sepsis, endocarditis, meningitis).1,2 In conclusion, if vancomycin “treatment” is needed in a pregnant patient with a serious bacterial infection, then our study data would suggest the use of 20 mg/kg intravenously every 8 hours (maximum individual dose of 2 g) to obtain the greatest number of serum values of >10 mg/mL. At the present time, the AUC/MIC value is not likely to be obtained when treating pregnant patients. Regarding group B streptococcus “prophylaxis,” the standard regimen of 1 g intravenously every 12 hours may be adequate; however, one must wonder whether this protocol potentially could lead to the advancement of resistance in group B streptococcus and other significant bacteria because of a high frequency of serum levels below the recommended 10 mg/mL. We concur that further research on these topics is needed. Craig V. Towers, MD Bobby C. Howard, MD Cheryl N. Onwuchuruba, MD Division of Maternal-Fetal Medicine University of Tennessee Medical Center Knoxville, TN The authors report no conflict of interest.
REFERENCES 1. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Disease Pharmacists. Am J Health Syst Pharm 2009;66:82-98. 2. DeRyke CA, Alexander DP. Optimizing vancomycin dosing through pharmacodynamic assessment targeting area under the concentrationtime curve/minimum inhibitory concentration. Hosp Pharm 2009;44: 751-65. 3. Nichols M, Schrag SJ. Two cases of invasive vancomycin-resistant group B streptococcus infection. N Engl J Med 2014;370:885-6. 4. Onwuchuruba CN, Towers CV, Howard BC, Hennessy MD, Wolfe L, Brown MS. Transplacental passage of vancomycin from mother to neonate. Am J Obstet Gynecol 2014;210:352.e1-4. ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.06.040
