Lowering the Risk for Surgical Site Infections in Fat Folk

Image from Chopra 2010 study, link below

We've discussed prevention of surgical site infections before, often in the context of cesareans, but most recently in the context of Emergency Room visits.

Regardless of type of operation, however, accumulating evidence suggests that antibiotic regimens for "obese" people need to be adjusted.

We in the Size Acceptance Movement have been saying for years that people of size often benefit from larger or weight-based dosing for certain types of antibiotics, longer courses of antibiotics in some cases, and IV antibiotics instead of oral antibiotics for serious infections.

This was based on the anecdotal experiences of many people of size over the years, and as such, was summarily dismissed by many in the medical community.

Here is research that confirms the importance of longer courses of antibiotics and weight-based dosing, and which also suggests that more frequent dosing, administration of antibiotics by IV, and perhaps topical infusion of antibiotics into the wound  itself before closing (instead of just systemically in the IV) seem to improve outcomes.

Of course, different types of antibiotics work differently in the system. This means that some types of antibiotics need different dosing for obese people and some don't.  That's important to remember ─ the need for weight-based dosing is not universal for all drugs.  And to be fair to doctors, research has been slow to differentiate these and to provide easy-to-use guidance to doctors in their prescriptions.

Yet there is some research that addresses this issue now, but as we saw recently in the Emergency Room study, getting doctors to follow this research is difficult. In that study, simple guidelines for dosing for high-BMI patients in the E.R. were readily available, but even so, less than 5% of morbidly obese patients received the proper initial dosage of common antibiotics. And that was at a medical center that specialized in treating obese patients!

Furthermore, another study has shown that hospital pharmacists often do not catch/correct underdosing errors in high-BMI patients.  In that study, less than 1/3 of obese patients received an adequate initial dose of vancomycin, only 1% received the optimum recommended dose, and only about 3% of these underdosing cases were caught and corrected by hospital pharmacists.

Far too often, people of size are still being treated with standard antibiotic dosages instead of dosages tailored to their weight, or antibiotics given too infrequently, orally, or for an insufficient length of time.

When will doctors listen to people of size and learn from our experiences?  Heck, when will they learn from their own research?

What is the barrier to adopting these new regimens?  Why aren't they being utilized far more often?  Why aren't hospital pharmacists or medical supervisors catching more inadequate dosing and raising red flags about it?

It's frustrating that this topic is only now being researched and that many hospitals ─ even those that specialize in treating obese patients ─ have been slow to utilize the new dosing guidelines that do exist.

As people of size, we need to be our own best advocates, both before surgery and when surgical site infections occur, so don't be afraid to bring up this concern with your surgeon, or to ask for a consult with an infectious specialist.  Even with a specialist, you may have to be ready to assertively argue your case, but they are more likely to be responsive to advocacy if you can cite research like the studies below.

Providers, please press hard for more research on the most optimal antibiotic dose and regimens, and press vigorously for more caregiver education about and usage of these regimens.  If there is any question about optimal dosage, please take the time to research the issue, and don't be afraid to explore using a different timing or delivery system.  It could literally be the difference between life and death for some people of size.

Infections can be a significant problem in high-BMI patients. Part of this is because of physiological differences like decreased vascular perfusion in fat tissue, and thus decreased oxygenation.  But an under-recognized part of it is because clinicians are using the wrong dosages and treatment regimens for fat folk.

The most efficient approach to improving outcome in obese patients is still to prevent infection in the first place by using the most effective antibiotic dose and treatment protocols available for our unique needs.


References

Am J Obstet Gynecol. 2010 Mar;202(3):306.e1-9. Extended antibiotic prophylaxis for prevention of surgical-site infections in morbidly obese women who undergo combined hysterectomy and medically indicated panniculectomy: a cohort study. El-Nashar SA, et al.   PMID: 20207249

OBJECTIVE: The purpose of this study was to compare surgical-site infection rates in obese women who had extended prophylactic antibiotic (EPA) vs standard prophylactic antibiotic.
STUDY DESIGN: An electronic records-linkage system identified 145 obese women (body mass index, >30 kg/m(2)) who underwent combined hysterectomy and panniculectomy from January 1, 2005, through December 31, 2008. The EPA cohort received standard antibiotics (cefazolin, 2 g) and continued oral antibiotic (ciprofloxacin) until removal of drains. Regression models were used to adjust for known confounders. RESULTS:The mean age was 56.0 + or - 12.1 years, and mean body mass index was 42.6 + or - 8.4 kg/m(2) (range, 30-86.4 kg/m(2)). The EPA cohort experienced fewer surgical-site infections (6 [5.9%] vs 12 [27.9%]; P less than .001; adjusted odds ratio, 0.16; 95% confidence interval, 0.04-0.51; P less than .001), had lower probability of incision and drainage (3 [2.9%] vs 5 [11.6%]; P = .05), and required fewer infection-related admissions (5 [4.9%] vs 6 [13.9%]; P = .08). CONCLUSION: Extended antibiotic prophylaxis can reduce surgical-site infections in obese women after combined hysterectomy and panniculectomy.

Surg Infect (Larchmt). 2009 Feb;10(1):53-7. Prevention of surgical site infections by an infusion of topical antibiotics in morbidly obese patients. Alexander JW, Rahn R, Goodman HR.  PMID: 19245364 

BACKGROUND: The reported incidence of surgical site infection after abdominal surgery in morbidly obese patients is high (about 15% in most studies), and this is associated with considerable disability and an increased economic burden. Topical antibiotics may reduce the incidence of serious infections. METHODS: Standard techniques for the prevention of surgical site infections were used along with the introduction of kanamycin into the subcutaneous space of morbidly obese patients at the time of closure and allowing it to dwell for 2 h. Eight hundred thirty-seven evaluable patients were followed for the development of site complications for at least six weeks postoperatively. RESULTS: One of the 65 patients with a revisional procedure had a primary deep incisional surgical site infection, as did one of the 772 patients with a primary operation. Secondary deep incisional surgical site infections occurred in four patients, two after spontaneous evacuation of a seroma, one from excessive superficial contamination, and one following separation of a nonhealing surgical site. Additionally, 21 patients had minor surgical site complications including incisional separation and stitch-related infections, which required no significant expenditure of resources. CONCLUSIONS: Prolonged contact (2 h) of topical kanamycin solution with the surgical site greatly reduces the incidence of primary infections in the deep subcutaneous space of laparotomy sites in morbidly obese patients.

Expert Rev Pharmacoecon Outcomes Res. 2010 Jun;10(3):317-28. Preventing surgical site infections after bariatric surgery: value of perioperative antibiotic regimens. Chopra T, et al.   PMID: 20545596    Full free text available here.

Kmom Summary: This paper reviews the surgical site infections (SSIs) that occur post bariatric surgery, and how to prevent SSIs. "This paper sets out to define different types of SSIs that occur following bariatric surgery and to discuss existing literature on the critical aspects of SSI prevention and the appropriate use of surgical antimicrobial prophylaxis for bariatric surgery."   

Important quote: "Most antimicrobial agents do not achieve optimal serum levels when administered orally. Although certain oral antimicrobials have comparable bioavailability with their intravenous formulation, the time to achieve maximum serum concentration is slower due to the need for absorption through the gastrointestinal tract. Intravenous antimicrobial prophylaxis is the most extensively studied route and remains the preferred route of administration."

Obes Surg. 2012 Mar;22(3):465-71. Cefepime dosing in the morbidly obese patient population. Rich BS, et al.  PMID: 22249886

Proper dosing of specific antibiotics in morbidly obese patients has been studied inadequately. However, these data are beneficial as this patient population is at an increased risk to develop postoperative infections. Cefepime is an antibiotic used for the treatment of both gram-positive and especially gram-negative infections; administration of the appropriate dose in the morbidly obese population is crucial. We therefore examined the pharmacokinetics of cefepime in patients with body mass index >40 kg/m(2). Ten morbidly obese patients, with a mean [±SD] estimated glomerular filtration rate of 108.4 ± 34.6 mL/min, undergoing elective weight loss surgical procedures were administered cefepime in addition to standard prophylactic cefazolin and studied. Serial serum cefepime concentrations were analyzed after dosing using a validated high performance liquid chromatography method. Pharmacokinetics and duration above the minimum inhibitory concentration (MIC) were determined using a protein binding value of 15% and a MIC threshold of 8 μg/mL. Mean free cefepime concentrations for t = 30, 120, and 360 min were 69.6, 31.6, and 9.2 μg/mL, respectively. The dosing interval was calculated to maintain the free concentration above the MIC (fT > MIC) for 60% of the interval. This was determined to be 10.12 h, including time for infusion. There was no toxicity. Based on this analysis, an increased dose of 2 g every 8 h is necessary to maintain an adequate fT > MIC throughout the dosing interval. Further studies are necessary to determine the efficacy of this regimen in the settings of active infections and critical illness.

Pharmacotherapy. 2007 Aug;27(8):1081-91.  Antimicrobial dosing considerations in obese adult patients. Pai MP, Bearden DT.    PMID: 17655508

As obesity continues to increase in prevalence throughout the world, it becomes important to explore the effects that obesity has on antimicrobial disposition. Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance.

Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring.

These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of beta-lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram-positive organisms-quinupristin-dalfopristin,linezolid, and daptomycin-reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials. 

An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.

Am J Med. 2008 Jun;121(6):515-8.  Multicenter evaluation of vancomycin dosing: emphasis on obesity. Hall RG 2nd, Payne KD, Bain AM, Rahman AP, Nguyen ST, Eaton SA, Busti AJ, Vu SL, Bedimo R.    PMID: 18501233 Full text available here.

BACKGROUND: There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight. METHODS: This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients greater or equal to 18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included. RESULTS: Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%).  

Adequate initial dosing (greater than or=10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P less than .0001).

Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received greater than or =15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines.

Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy.

CONCLUSION: In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.

Eur J Clin Pharmacol. 1998 Oct;54(8):621-5. Vancomycin dosing in morbidly obese patients. Bauer LA, Black DJ, Lill JS.   PMID: 9860149 

OBJECTIVES AND METHODS: Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal weight population.  RESULTS: Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg x kg(-1) x d(-1) TBW or 81.9 mg x kg(-1) x d(-1) IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg x kg(-1) x d(-1) to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2 = 3.3 h, V = 52 L, CL = 197 ml x min(-1); normal: t1/2=7.2 h, V=46 L, CL=77 ml x min(-1), 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW and CL, but only fair correlation between TBW and V. CONCLUSION: Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when TBW is used as a dosing weight for the obese (approximately 30 mg x kg(-1) x d(-1)). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain above 5 microg x ml(-1) in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly obese patients with renal dysfunction require further study.

Surgery. 2004 Oct;136(4):738-47. Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Edmiston CE, et al.    PMID: 15467657

BACKGROUND: Perioperative surgical antibiotic prophylaxis requires that therapeutically effective drug concentrations be present in the tissues. METHODS: Patients undergoing Roux-en-Y gastric bypass for morbid obesity were given 2 g cefazolin preoperatively, followed by a second dose at 3 hours. Thirty-eight patients were each assigned to 1 of 3 body mass index (BMI) groups: (A) BMI=40-49 (N = 17); (B) BMI=50-59 (N=11); (C) BMI > or= 60 (N=10). Multiple timed serum (baseline; incision, 15, 30, 60 minutes; prior to second prophylactic dose; and closure) and tissue (skin, subcutaneous fat, and omentum) specimens were collected and cefazolin concentration analyzed by microbiological assay. RESULTS: No significant difference was observed in intraoperative fluid replacement or blood loss among BMI groups. Serum antimicrobial concentrations exceeded resistance breakpoint (32 microg/mL) in 73%, 68%, and 52% of BMI groups A, B, and C, respectively. No significant difference in cefazolin concentration was observed in mean incisional skin and closure tissue specimens in groups A, B, and C. A significant decrease in cefazolin concentration was noted in closure adipose (p=.04), initial (p=.03) and closure omentum (p=.05) tissues in groups B and C compared with A. Over 90% of serum samples exhibited therapeutic concentrations covering 53.8% of gram-positive and 78.6% of gram-negative surgical pathogens. However, therapeutic tissue levels were achieved in only 48.1%, 28.6%, and 10.2% of groups A, B, and C, respectively. CONCLUSIONS: Pharmacokinetic analysis suggests that present dosing strategies may fail to provide adequate perioperative prophylaxis in gastric bypass patients.

Am J Emerg Med. 2011 Dec 12. Underdosing of common antibiotics for obese patients in the ED. Roe JL, Fuentes JM, Mullins ME.  PMID: 22169576

BACKGROUND: Obesity is a growing problem in the United States. Obesity alters the pharmacokinetic profiles of various drugs. Although there are guidelines for dose adjustments for many of the antibiotics commonly used in the emergency department (ED), they are seldom used. METHODS: This is an institutional review board-approved retrospective study at an American Society of Metabolic and Bariatric Surgery Center of Excellence and a level I trauma center with annual ED volumes of more than 80 000 visits. Data were retrospectively collected from ED pharmacy records during a 3-month period in 2008. Any first dose of cefepime, cefazolin, or ciprofloxacin administered in our ED to a patient recorded as both more than 100 kg and with a body mass index greater than 40 kg/m(2) was compared with our hospital guidelines and found to either adhere or not adhere to those guidelines. RESULTS: There were 1910 orders found to meet the study criteria: 775 orders for cefepime, 625 orders for cefazolin, and 510 orders for ciprofloxacin. Adherence rates for first dose of cefepime, cefazolin, and ciprofloxacin administered, respectively, were 8.0%, 3.0%, and 1.2%. CONCLUSION: Emergency physicians frequently underdose cefepime, cefazolin, and ciprofloxacin in obese patients. Underdosing antimicrobials presents risk of treatment failure and may promote antimicrobial resistance. Education is necessary to improve early antibiotic administration to obese patients.

Obese Patients Undertreated for Infection in the Emergency Room

The following study shows just how badly obese patients are underdosed with antibiotics in the Emergency Room (E.R.).

Terri of the FattiesUnited blog brought this study to the attention of the fatosphere briefly several months ago, just as I was about to write a post about this study too, so I put the post on the back burner.

However, in writing an upcoming post on treating Surgical Site Infections in people of size, I came across the study again and decided it was important enough to be highlighted once more.  Any of us can end in the Emergency Room at any time, regardless of size.  But those of us who are fat need to be aware of the possibility of underdosing and to be able to advocate for ourselves as needed.  Perhaps sharing the full details of this study will help in that process.

In this study, the initial antibiotic dosages of "morbidly obese" folks (BMI over 40) who visited the E.R. and were prescribed 3 common antibiotics were analyzed retrospectively for a 3-month period.  The doses were compared with internal hospital guidelines for antibiotic dose adjustments for obese folks.

Less than 5% of morbidly obese patients were given the correct antibiotic dose for their weight.

That's right, more than 95% of high BMI patients were underdosed with antibiotics, putting them at significant risk for serious complications.

The study notes:

Although there are guidelines for dose adjustments for many of the antibiotics commonly used in the emergency department (ED), they are seldom used...Underdosing antimicrobials presents risk of treatment failure and may promote antimicrobial resistance. Education is necessary to improve early antibiotic administration to obese patients.

Study Details

This study was done as a quality improvement review at an urban Level I trauma center with an emergency medicine residency.

In the study, pharmacy records were collected retrospectively to identify the initial dose of cefazolin, cefepime, or ciproflaxin given in the E.R. to patients with a BMI greater than 40 and who weighed more than 100 kg.

These three drugs were chosen because they are used so frequently and because, unlike many antibiotics, there are readily-available guidelines for dosing obese folks without having to do a bunch of complicated extra calculations first.  The guidelines are distributed in a handbook each year to every resident and are also always available on the hospital's internal website, so there was no excuse for not knowing or not checking the recommended dosages.

The study looked at only the initial dose given (and to be fair, any additional dose within 4 hours, as sometimes doctors self-correct dosing when they have a chance to look up the guidelines).

This attention to the initial dose is important because the first dose of antibiotics is the most important in knocking down an infection.  According to the study, the effectiveness of this class of antibiotics (cephalosporins) is proportional to the amount of time kept above the Minimum Inhibitory Concentration (MIC). If the initial dose does not achieve MIC, then the patient may develop resistance to the antibiotics, not to mention serious complications, longer hospital stays, or even death.

In the study, there were 1,910 orders that fit the criteria in the 3-month study period. Of these, only 4.6% of the antibiotic orders were dosed appropriately for morbidly obese patients.

For cefepime, the adherence rate was 8%.  For cefazolin, the adherence rate was 3%, and for ciproflaxin the adherence rate was only 1.2%.

This is an appallingly poor adherence rate to readily-available, simple dosing guidelines. The study notes this and emphasizes how important it is to ensure adequate dosing in morbidly obese patients:

Attaining therapeutic dosing in [morbidly obese] patients is especially important.  Obese patients present a greater risk of infection and a higher morbidity and mortality associated with infection than does the general population.  Subtherapeutic dosing increases the risk of treatment failure, unnecessary escalation to broader-spectrum antibiotics, and selection of resistant pathogens...Because early antibiotic administration reduces mortality in life-threatening infections, meeting proper dosing guidelines in the [Emergency Department] should be of the highest priority.

The authors go on to cite another study which found that when the perioperative dose of cefazolin was doubled to 2g in obese patients, the postoperative infection rate dropped from 16.5% to 5.6%.  This shows that increased dosages of this antibiotic in heavier patients do result in improved outcomes.

Interestingly, there is recent data (Pevzner 2011) on cesareans in morbidly obese patients suggesting that even a doubled, 2g dose of cefazolin may not be enough, and that further research is needed to figure out the most effective perioperative dose in this group.  What implications this has for E.R. usage is unknown but suggests doses bigger than 2g may also need to be considered. Research needs to be done to find the optimal dose for each size.

Concluding Thoughts

Sooner or later, people of every size end up in the E.R., especially as they age.  Different populations present different care challenges; obese people present a unique subset whose care challenges are often under-recognized and under-addressed.

Bottom line, the best care protocols for obese people are yet to be determined because research on the topic has been woefully inadequate.  Furthermore, even when the best care protocols are known, they are often not followed by medical personnel.  Therefore, it is critical as people of size that we know about key care issues in our own care and how to advocate for ourselves when we interact with medical personnel.  

One of the most understudied areas in the care of obese patients is optimal medication dosage.  Research shows that obese patients (and especially morbidly obese patients) are often dosed inappropriately with a variety of drugs, from chemotherapy to anti-coagulants to antibiotics, and this may be correlated to poorer outcomes among these groups.

Clearly, it is imperative that more research and physician education be done on appropriate medication dosage for people of size as quickly as possible.

In this study, only initial antibiotic dosing at the Emergency Room was examined, using only common antibiotics with easily-available dose adjustments.  Even so, less than 5% of the morbidly obese patients were given dosages that adhered to the internal guidelines of the hospital.

One has to wonder how adequate the dosing was in very fat patients for the rest of their hospital stays and how that impacted their outcomes.

Ironically, this was in a hospital that is a regional referral center for fat patients and is recognized as a Bariatric Surgery "Center of Excellence" (ugh).  That makes the findings even more alarming.

If a teaching hospital that specializes in the treatment of very fat people doesn't routinely use the correct antibiotic dosing in their E.R., what are the underdosing rates in community hospitals that don't specialize in fat patients at all?

This study has lessons both for people of size and for the medical community.

Fat people should know that if they end up in the E.R. for an infection of some sort, they need to ask their physician to check into adjusted antibiotic doses for weight.  Not every type of antibiotic needs dose adjustment, mind ─ it all depends on how they are designed to work in the body.  But this study indicates that you may really have to push your physician to find out about dose adjustments and to use them when they are indicated.

Most physicians truly want their patients to get better, so it's really OK to ask about whether weight-based dosing is needed for you. However, don't be afraid to ask for a consult with an infections specialist if you feel your E.R. doctor is not attentive to your concerns, or to involve the hospital's Patient Advocate in getting your concerns heard.  There are measures in place to help patients advocate for their own needs, and you don't have to go it alone.

But the first step is self-education, to know where the potential issues may lie, to know to ask questions about dosages, and to feel empowered enough to do so.

For medical professionals, the associated lesson is that they must aggressively press for better research on optimal medication dosage in obese patients, and to continue to push for more physician education and accountability on these matters.

*Next post.....other ways to improve response to infections in people of size, including IV antibiotics, more frequent dosings, and topical infusions.



References

Am J Emerg Med. 2011 Dec 12. Underdosing of common antibiotics for obese patients in the ED. Roe JL, Fuentes JM, Mullins ME.  PMID: 22169576

BACKGROUND: Obesity is a growing problem in the United States. Obesity alters the pharmacokinetic profiles of various drugs. Although there are guidelines for dose adjustments for many of the antibiotics commonly used in the emergency department (ED), they are seldom used. METHODS: This is an institutional review board-approved retrospective study at an American Society of Metabolic and Bariatric Surgery Center of Excellence and a level I trauma center with annual ED volumes of more than 80 000 visits. Data were retrospectively collected from ED pharmacy records during a 3-month period in 2008. Any first dose of cefepime, cefazolin, or ciprofloxacin administered in our ED to a patient recorded as both more than 100 kg and with a body mass index greater than 40 kg/m(2) was compared with our hospital guidelines and found to either adhere or not adhere to those guidelines. RESULTS: There were 1910 orders found to meet the study criteria: 775 orders for cefepime, 625 orders for cefazolin, and 510 orders for ciprofloxacin. Adherence rates for first dose of cefepime, cefazolin, and ciprofloxacin administered, respectively, were 8.0%, 3.0%, and 1.2%. CONCLUSION: Emergency physicians frequently underdose cefepime, cefazolin, and ciprofloxacin in obese patients. Underdosing antimicrobials presents risk of treatment failure and may promote antimicrobial resistance. Education is necessary to improve early antibiotic administration to obese patients.

Surgery. 2004 Oct;136(4):738-47. Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Edmiston CE, et al.  PMID: 15467657

BACKGROUND: Perioperative surgical antibiotic prophylaxis requires that therapeutically effective drug concentrations be present in the tissues. METHODS: Patients undergoing Roux-en-Y gastric bypass for morbid obesity were given 2 g cefazolin preoperatively, followed by a second dose at 3 hours. Thirty-eight patients were each assigned to 1 of 3 body mass index (BMI) groups: (A) BMI=40-49 (N = 17); (B) BMI=50-59 (N=11); (C) BMI > or= 60 (N=10). Multiple timed serum (baseline; incision, 15, 30, 60 minutes; prior to second prophylactic dose; and closure) and tissue (skin, subcutaneous fat, and omentum) specimens were collected and cefazolin concentration analyzed by microbiological assay. RESULTS: ...Over 90% of serum samples exhibited therapeutic concentrations covering 53.8% of gram-positive and 78.6% of gram-negative surgical pathogens. However, therapeutic tissue levels were achieved in only 48.1%, 28.6%, and 10.2% of groups A, B, and C, respectively. CONCLUSIONS: Pharmacokinetic analysis suggests that present dosing strategies may fail to provide adequate perioperative prophylaxis in gastric bypass patients.

Obstet Gynecol. 2011 Apr;117(4):877-82. Effects of maternal obesity on tissue concentrations of prophylactic cefazolin during cesarean delivery. Pevzner L, et al.  PMID: 21422859

OBJECTIVE: To estimate the adequacy of antimicrobial activity of preoperative antibiotics at the time of cesarean delivery as a function of maternal obesity. METHODS: Twenty-nine patients scheduled for cesarean delivery were stratified according to body mass index (BMI) category, with 10 study participants classified as lean (BMI less than 30), 10 as obese (BMI 30-39.9), and nine as extremely obese (BMI 40 or higher). All patients were given a dose of 2 g cefazolin 30-60 minutes before skin incision. Antibiotic concentrations from adipose samples, collected after skin incision and before skin closure, along with myometrial and serum samples, were analyzed with microbiological agar diffusion assay. RESULTS: Cefazolin concentrations within adipose tissue obtained at skin incision were inversely proportional to maternal BMI (r=-0.67, P<.001)...Although all specimens demonstrated therapeutic cefazolin levels for gram-positive cocci (greater than 1 microgram/g), a considerable portion of obese and extremely obese did not achieve minimal inhibitory concentrations of greater than 4 micrograms/g for Gram-negative rods in adipose samples at skin incision (20% and 33.3%, respectively) or closure (20.0% and 44.4%, respectively)... CONCLUSION: Pharmacokinetic analysis suggests that present antibiotic prophylaxis dosing may fail to provide adequate antimicrobial coverage in obese patients during cesarean delivery.

Bigger Dose of Antibiotics Needed For Women of Size?

It's time to finish our focus this Cesarean Awareness Month on the over-utilization of cesareans in women of size and the burdens this high rate imposes on this group.

Consider a new study just out that suggests that women of size might benefit from a bigger dose of antibiotics if they undergo a cesarean. 

This further supports the idea of the importance of weight-based dosing of certain types of antibiotics when people of size undergo other surgeries as well. 

Wound infection is a very significant risk of cesarean sections in women of size, especially "morbidly obese" women.  Part of the reason for this is that adipose tissue tends to be poorly vascularized and oxygenated, which makes it harder for that area to heal as effectively.

However, another reason for a higher infection risk may be that "obese" women are being under-dosed with antibiotics when standardized dosing (the same for all weights) is used instead of weight-based dosing. 

In this new study, the same standardized antibiotic regime was given to all women (regardless of size) undergoing a planned cesarean delivery.  Women were categorized by BMI, and then tested to see how well the dosage was working at different times during the delivery (incision time, closure time). 

The antibiotic dosage was fine for everyone for gram-positive bacteria, but the story was considerably different for gram-negative bacteria.

One-third of the "extremely obese" women (BMI greater than 40 in this study) did not achieve minimal inhibitory concentrations at skin incision, and 44% did not achieve minimal inhibitory concentrations at closure. 

So by the end of the surgery, nearly HALF of the women with BMI greater than 40 did not have enough concentration of antibiotics in their tissue to effectively ward off a gram-negative infection. 

Reflections on the Study

For years, doctors have blamed all kinds of factors for the higher rate of wound infection in fat women. And to be fair, many of these factors are relevant.

However, this study shows it's likely that fat women also have higher rates of wound infections because their doctors are inadvertently underdosing them with antibiotics.

We in the fat acceptance community have been telling them this for years, but on the whole doctors have been very slow to listen and heed our feedback. Why has it taken the medical community so long to listen?  Will this study finally change the standard of care? 

Only time will tell...but I'm not holding my breath.  In the meantime, in light of just how high the cesarean rate (both planned and unplanned) is among women of size in the USA....consider the implications of such an excessive cesarean rate for infectious burden, healthcare costs, and disruptions to the mother's life just as she is trying to bond with her newborn.

The lessons from this study are twofold. 

First, for when a "morbidly obese" mother truly needs a cesarean, doctors should explore weight-based dosing with certain types of antibiotics, and then study this practice to see if this lessens the risk of infection. 

Second, because the risk for infection/wound complications is increased in "morbidly obese" women, doctors should stop doing things that increase the cesarean rate in this group.  For example, doctors need to stop scheduling this group for routine "elective" cesareans, and stop practices (like induction for suspected "big baby") that increase the risk for cesarean during labor. 

The medical, financial, and personal burdens that result from infections and wound complications after cesarean are clear. 

Stop placing fat women at increased risk of these burdensome complications by over-utilizing cesareans and inductions in this group.



Study Abstract

Pevzner L, Swank M, Krepel C, Wing DA, Chan K, Edmiston CE Jr. Effects of maternal obesity on tissue concentrations of prophylactic cefazolin during cesarean delivery.  Obstet Gynecol. 2011 Apr;117(4):877-82.

From the Department of Obstetrics and Gynecology, University of California, Irvine, Orange, California; Surgical Microbiology Research Laboratory, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; and the Department of Obstetrics and Gynecology, Long Beach Memorial Medical Center, Long Beach, California.

Abstract

OBJECTIVE:  To estimate the adequacy of antimicrobial activity of preoperative antibiotics at the time of cesarean delivery as a function of maternal obesity.

METHODS:  Twenty-nine patients scheduled for cesarean delivery were stratified according to body mass index (BMI) category, with 10 study participants classified as lean (BMI less than 30), 10 as obese (BMI 30-39.9), and nine as extremely obese (BMI 40 or higher). All patients were given a dose of 2 g cefazolin 30-60 minutes before skin incision. Antibiotic concentrations from adipose samples, collected after skin incision and before skin closure, along with myometrial and serum samples, were analyzed with microbiological agar diffusion assay.

RESULTS:  Cefazolin concentrations within adipose tissue obtained at skin incision were inversely proportional to maternal BMI (r=-0.67, P less than .001). The mean adipose concentration was 9.4 plus or minus 2.7 micrograms/g in the lean group of women compared with 6.4 plus or minus 2.3 micrograms/g in the obese group (P=.009) and 4.4 plus or minus 1.2 micrograms/g in the extremely obese group (P less than .001).

Although all specimens demonstrated therapeutic cefazolin levels for gram-positive cocci (greater than 1 microgram/g), a considerable portion of obese and extremely obese did not achieve minimal inhibitory concentrations of greater than 4 micrograms/g for Gram-negative rods in adipose samples at skin incision (20% and 33.3%, respectively) or closure (20.0% and 44.4%, respectively).

No significant difference in cefazolin concentration was observed in mean closure adipose, myometrial, or serum specimens across the BMI categories.

CONCLUSION:  Pharmacokinetic analysis suggests that present antibiotic prophylaxis dosing may fail to provide adequate antimicrobial coverage in obese patients during cesarean delivery.

PMID: 21422859

Antibiotic Underdosing in "Obesity"

One of the most critical areas of research in improving treatment and outcomes for "obese" people is the issue of weight-based dosing. 

In many drugs, dosages have been determined based on the norm of average-sized people.  This means that people who are significantly under or over this "norm" may not be receiving the dosage most optimal for their size, with lean folk potentially being overtreated and fat folk likely being vastly undertreated. 

Underdosing is of particular concern for "obese" people because it may lead to subtherapeutic concentrations of drugs and deteriorating outcomes over time.

However, deciding on optimal drug dosages is not a simple task.  Concern for obtaining the most effective dose must be balanced against concern over toxicity from a too-large dose. 

In the past, doctors were understandably reluctant to prescribe a very large dose of various medications for people with larger bodyweights because they were concerned about the potential for massive toxicity. 

In fact, doctors sometimes intentionally reduced the dose because they were concerned about greater possible toxicity in "obese" people.

Now, however, there is emerging evidence that in many drugs, outcomes are improved with the larger doses and suboptimal with smaller doses. 

This is one of the most pressing issues in pharmocotherapy because extensive research is needed to determine optimal dosing and which drugs benefit most from weight-based dosing, but this research has been slow to happen.  And even when the research is there, some doctors have been slow to adopt new guidelines. 

Let's look at several critical areas in which underdosing is a major issue.  First up.....antibiotics.

Antibiotic Underdosing

Antibiotic underdosing in "obese" people may be one reason why fat people have poorer outcomes after surgery and/or infections.  Furthermore, underdosing may be a particularly serious problem in very fat people. 

Remember, when you are on antibiotics, you are cautioned to take the entire prescription, not to stop when you start feeling well.  If you stop too soon, the bug may still be there at low levels. Then, when the antibiotics are stopped, the bug may opportunistically spring back to life in a more severe or antibiotic-resistant form. 

A similar effect may happen when "obese" people are underdosed with antibiotics.  The bug may be only partially knocked out, return in time stronger than before, or worse, develop a resistance to the subtherapeutic-level antibiotic.

This may be one reason (among several) why infection is a particular problem for "obese" people after surgery....the antibiotic dosages given to them may not be strong enough. 

Of course, different drugs work by different mechanisms.  Therefore, not all drugs need weight-based dosing because of the unique way they work........but it's clear that some do, and that the importance of this factor is only now becoming more recognized in the medical field. 

For example, even recent research (see study abstracts below) shows that:

• Many "obese" people are still routinely underdosed with antibiotics, especially "morbidly" and "super-obese" people
• Revised guidelines for weight-based dosing are underutilized by healthcare professionals
• Far more research needs to be done into the most effective drug dosages for people of varying sizes, but particularly for very fat people

It's very disappointing that there isn't more definitive information on this topic in this day and age.  You would think that this would have been well-studied by now.....or that there would be a tremendous push for more research on this right now, given recent studies showing the problem. 

Yet there really doesn't seem to be a sense of urgency or priority on this in the research.  There are a number of studies noting the paucity of research on the topic and pointing out the need for more, but there are few studies actually conducting research into this important area. 

[Ironically, what studies there are often are on weight-loss surgery patients. We may finally be starting to get data on drug dosages for very fat people, if only because bariatric surgeons need to improve their surgery stats.]

At the very least, more doctors should be aware of what research and guidelines we do have for more effective dosing...but they apparently aren't because it doesn't seem to be affecting the way many of them prescribe (see vancomycin study below).

You have to wonder how many fat people have died or been gravely ill because their doctors didn't utilize the most effective dosage for them.

This is really a critical area for future research and education among health-care professionals. But until they start paying more attention to this issue, it's up to us, as fat consumers, to push for more action and to advocate strongly for ourselves if we get sick. 

Standardized Dosing

Another problem that commonly leads to chronic underdosing of "obese" people is standardized dosing, where little or no flexibility is offered to the doctors regarding dose size. 

Weight-based dosing is all well and good when it's easy to adjust dosages (as in IV antibiotic therapy in the hospital) but many commonly-prescribed antibiotics are only offered in a "one-size-fits-all" package.

For example, a few years ago, I developed a roaring secondary bacterial infection around a holiday and went to an emergent care center to get quick treatment for it.  They recognized I really needed antibiotics at that point.  I asked them about weight-based dosing, and the doctor admitted that weight-based dosing probably would be more beneficial for someone of my size.  However, he pointed out that he had no choice because the medication only came in one dosage.  It was that or nothing. 

I needed two rounds of antibiotics to beat that bug.  The first one started to knock it out, and then it came back a couple of weeks later, stronger than ever (at which point I started coughing up blood). I'm lucky the bug got wiped out by the second dose of antibiotics. If I had been older or more fragile, that bug might easily have gotten me because it was a really nasty one.

Was my delayed recovery because I was underdosed due to standardized dosing?  Hard to know for sure because I've not found a lot of dosing information about that particular antibiotic, but I suspect underdosing might well have played a role. And how even more undertreated might I have been had I been truly supersized?

Of course, sometimes standardized dosing is logical.  In an emergency, no one has time to stop and figure out weight-based dosing and dispense it.  In situations where time is of the essence (i.e. trauma surgery, emergent cesareans), having standardized doses available makes sense. 

But many surgeries are pre-planned and there is plenty of time to figure out the proper dosage of antibiotic to really lower the chances of wound infection.  Yet, hospital protocol or lack of knowledge/data about weight-based dosing often prevents its use even when time allows for it. 

So although I'm still learning about this topic (and welcome feedback from healthcare professionals who are well-versed in pharmocotherapy), I think it's important to:

• Start raising awareness among fat people to ask more questions from their healthcare providers about weight-based dosing and when it's needed
• Ask healthcare professionals to raise their awareness of the issue
• Start pressuring healthcare researchers to do further study of this important topic

If half of Americans are "overweight" or "obese," then prompt attention to this issue is quite pressing so that outcomes can be improved in this group.

This problem is also pressing to the general public because antibiotic resistance is on the rise. If subtherapeutic levels lead to more antibiotic resistance, then underdosing "obese" people may be adding to the critical public health issue of antibiotic resistance.

Therefore, finding out and promoting the proper dosages for people of size may benefit not only fat people, but society as a whole. 

Research on Antibiotic Underdosing

In the meantime, here are two recent study abstracts on the topic of antibiotic underdosing in "obese" people. I was particularly struck by the vancomycin study. 

Vancomycin is a very strong antibiotic, typically used for severe infections; in the past it was often a drug of last resort.  Therefore, proper dosing of it is critical, especially the initial dose to "knock out" the infection, and then therapeutic dosages to keep the infection down and out afterwards.

Yet in the study, only 1/3 of "obese" patients received an "adequate" initial dose of vancomycin.

If you look at the full text of the study (available here), you see that when they further examined dosage by class of obesity, NONE of the people with BMI greater than 40 received an adequate initial dosage.

Furthermore, less than 1% of the whole "obese" group received the recommended weight-based dose.

They concluded: 

Our results highlight the fact that obese patients may be routinely underdosed as a result of the widespread practice of prescribing fixed-dose vancomycin.

The authors also noted that another study has suggested that dosing intervals may need to be more frequent in the "obese" population in order to maintain minimum therapeutic levels, which is another intriguing consideration. 

Other studies have found that it's not only the dosage of antibiotics that counts, it's also the length of treatment.  "Morbidly obese" people may benefit from a longer course of antibiotics than is standard.

Furthermore, recent studies have found that in particularly infection-prone areas, application of additional topical antibiotics into the surgical incision area significantly reduces the rate of post-operative infection. 

So the the concept of antibiotic underdosing may not just be about how much antibiotics should be given to fat people, but also where they are given, how often they should be given, and for how long. 

I'd love to see more specific studies devoted to these questions.

Final Thoughts

If antibiotic underdosing is so common in people of size, is it any wonder that "obese" patients have poorer outcomes from infections and after surgery? 

Granted, many variables factor into why "obese" people respond less effectively to wounds and infections, and antibiotic underdosing is definitely not the only issue.  It's important to be fair about that.  It's not only about antibiotic dosing.

However, underdosing is quite likely a vastly underestimated reason for poorer outcomes, and one that should be relatively easy to fix, given more awareness of and research into the problem.  We can't do a lot about other factors that cause poorer outcomes and higher infection rates, but dosing is a relatively easy problem to fix.

Therefore, it seems extremely important to me to raise more awareness around this issue and start pressing for more and better research on the topic.


Here are the research abstracts.  (Obviously, highlights and emphasis are mine.)

Multicenter evaluation of vancomycin dosing: emphasis on obesity. Hall RG 2nd, Payne KD, Bain AM, Rahman AP, Nguyen ST, Eaton SA, Busti AJ, Vu SL, Bedimo R.  Am J Med. 2008 Jun;121(6):515-8.

Department of Pharmacy Practice, Texas Tech University Health Sciences Center, School of Pharmacy, Dallas, Texas, USA.

BACKGROUND: There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight.

METHODS: This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients greater or equal to 18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included.

RESULTS: Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%).

Adequate initial dosing (greater than or=10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P less than .0001).

Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received greater than or =15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines.

Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy.

CONCLUSION: In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.

PMID: 18501233   Full text available here. 

Antimicrobial dosing considerations in obese adult patients. Pai MP, Bearden DT.  Pharmacotherapy. 2007 Aug;27(8):1081-91.

Division of Pharmacy Practice, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.

As obesity continues to increase in prevalence throughout the world, it becomes important to explore the effects that obesity has on antimicrobial disposition. Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance.

Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring.

These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of beta-lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram-positive organisms-quinupristin-dalfopristin, linezolid, and daptomycin-reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials.

An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.

PMID: 17655508