Timing is everything: Delivering drug prophylaxis to prevent SSIs

Researchers find it is done right only half of the time

The chances that a surgical patient in a U.S. hospital will receive appropriate antibiotic prophylaxis — with drugs both administered and discontinued in a timely fashion — remains essentially a flip of the coin.

A recently published study of more than 30,000 patients found that the antimicrobial dose was administered appropriately within one hour of the surgical incision only 55.7% of the time.1 Worse still, antimicrobial prophylaxis was discontinued appropriately within 24 hours after the surgery for only 40.7% of the patients.

The timely administration of antibiotics prior to a procedure has been shown to reduce subsequent surgical-site infections (SSIs). On the other hand, inappropriately prolonging antibiotics provides no prevention benefit, wastes resources, and increases the likelihood that any infection the patient develops will be of the drug-resistant variety. One of the first questions that arise is whether this matter of timing is a systems problem or an education problem.

"I think its both — that’s a personal opinion," says E. Patchen Dellinger, MD, co-author of the study and chief of general surgery at the University of Washington in Seattle.

"But to say that it’s a settled issue — I don’t really know. There are many ways to do this, and I think what works in one hospital sometimes doesn’t work in another hospital. You have to figure out what works in what setting. This is an issue that is very unsettled [regarding] why the stats are as bad as they are. There are a number of national projects going on to try and improve this," Dellinger explains.

Indeed, in an age of patient safety, timing of surgical antibiotic prophylaxis now is blinking brightly on the radar screen. As usual, infection control professionals and hospital epidemiologists find themselves with key roles in addressing the problem.

"Infection control practitioners often have the responsibility of doing surveillance and are perhaps more knowledgeable about the infection rate postoperatively than anybody else in the hospital system," says Dale Bratzler, DO, MPH, lead author of the study and director of the health care quality improvement program at the Oklahoma Foundation for Medical Quality in Oklahoma City.

"They can’t do it themselves, but they can bring together the groups of surgeons, pharmacists, nurses, and others to focus on practices that reduce infection rates. They have the opportunity to play a real leadership role in the hospital in terms of driving practices to reduce [SSIs]."

And there are plenty to reduce. Of the nearly 30 million operations in the United States each year, more than 2% are complicated by an SSI, the authors report. Mortality rates are two to three times higher in patients who develop an SSI, and hospital readmission rates are significantly increased.

Moreover, SSIs increase length of stay by an average of seven days and charges by approximately $3,000, they report.2,3

Lax compliance despite data

The effectiveness of antimicrobials administered shortly before skin incision for prevention of SSIs was established in the 1960s and has been demonstrated repeatedly since, the authors emphasize.

However, adherence remains poor despite evidence of effectiveness and the publication of guidelines for antimicrobial prophylaxis.

In 2002, the Centers for Medicare & Medicaid Services, in collaboration with the Centers for Disease Control and Prevention (CDC), implemented the National Surgical Infection Prevention Project.

The project promotes prophylactic practices that have been shown to reduce the risk of SSI, and thus reduce morbidity and mortality in the Medicare population. (See recommendations, below.)

The aforementioned study describes the baseline results on the use of antimicrobial prophylaxis for a national sample of Medicare patients undergoing five types of major surgery during 2001.

The researchers conducted a systematic random sample of 34,133 Medicare inpatients undergoing coronary artery bypass grafting; other open-chest cardiac surgery; vascular surgery; general abdominal colorectal surgery; hip and knee total joint arthroplasty; and abdominal and vaginal hysterectomy. A total of 2,965 hospitals were involved in the effort to assess the baseline levels for antibiotic prophylaxis.

Overall, 55.7% of patients received prophylactic antimicrobials during the 60 minutes (120 minutes for vancomycin) before incision, the authors report.

Prior studies have demonstrated that timing is critical to the effectiveness of prophylaxis, and current guidelines recommend dosing within one hour before incision.

Of particular concern, the authors found that 9.6% of the patients received their first antimicrobial dose more than four hours after the incision when little if any benefit would be expected based previously on published studies.4-6

The authors clarify that an explicit incision time was documented for only 11,220 patients (32.9%). Of those, the aforementioned 55.7% received an antimicrobial dose in the recommended time frame. What about the other two-thirds of patients?

To get at those data, the researchers randomly selected 1,728 cases for which an explicit incision time was missing. Using proxy times to approximate the incision time, they estimated that 54.3% of these patients received their antimicrobial dose within one hour before incision. So again, we’re still in the range of a coin flip.

"I think it is a systems problem," says Donald E. Fry, MD, co-author of the paper and chairman of the department of surgery at the University of New Mexico in Albuquerque.

"It comes down to the fact that we set out schedules for our operating rooms, but sometimes I think they are only advisory — if you will," he continues.

"In the sense that things do not always happen on the exact time schedule that they are supposed to happen. Operations don’t start exactly when we expect they do, and there is the error of drugs being given too soon."

Use narrow window to start and stop surgical antibiotics

Consensus is one hour before, one day after

As part of the Medicare National Surgical Infection Prevention Project, a guideline working group was formed to develop consensus recommendations for surgical antimicrobial prophylaxis.1 Key recommendations regarding the timing of antibiotic administration include the following:

  1. Before surgery
    On the basis of published evidence, the work group endorsed the national performance measure that infusion of the first antimicrobial dose should begin within 60 minutes before incision. However, when a fluoroquinolone or vancomycin is indicated, the infusion should begin within 120 minutes before incision to prevent antibiotic-associated reactions. Although research has demonstrated that administration of the antimicrobial at the time of anesthesia induction is safe and results in adequate serum and tissue drug levels at the time of incision, there was no consensus that the infusion must be completed before incision. When a proximal tourniquet is required, however, the entire antimicrobial dose should be administered before the tourniquet is inflated.

  2. After surgery
    The majority of published evidence demonstrates that antimicrobial prophylaxis after wound closure is unnecessary, and most studies comparing single-dose prophylaxis with multiple-dose prophylaxis have not shown the benefit of additional doses. Prolonged use of prophylactic antimicrobials is associated with emergence of resistant bacterial strains. For the majority of operations, prophylaxis should end within 24 hours after the operation.


  1. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: An advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis 2004; 38:1,706-1,715.

Trying to create a new surgical culture

Patients awaiting surgery may be administered the antibiotics in a holding area in the hospital, but the critical one-hour time frame may tick away before they get under the OR lights.

There also is the issue that many surgeons have become accustomed to the antibiotics traditionally being given "on call on the floor," Fry says.

"So we are trying to create a new culture of people understanding better that if the drug is given too soon — or if the drug is forgotten and not given until after the incision, or God forbid, after the operation — it will have a potential consequence as far as outcomes," he says. "We have to overcome a culture of many decades, and we have to overcome some of the vagaries of operations being delayed," he adds.

Antibiotic prophylaxis decisions could be incorporated into a surgical timeout, with the timing of the dose being verified along with the correct surgical site and other important factors, Fry says.

"Re-identify the patient and confirm that antibiotics, if indicated, have in fact been given," he notes. "[That] hopefully is a systems approach to try and remedy the fact that in the past, the drugs were either given entirely too soon, were omitted, or started too late."

The researchers found that patients undergoing cardiac and orthopedic surgery were more likely to receive an antimicrobial dose within one hour before incision.

That may reflect the much more common use of pre-printed care plans or order forms (50% of patients undergoing hip or knee arthroplasty and 36.6% of patients undergoing cardiac surgery), which often included antimicrobial protocols, they report.

However, such pre-printed care plans or order forms were found in only 4% of colorectal surgery cases, 4.5% of hysterectomy cases, and 5.3% of vascular surgery cases.

"A lot of hospitals around the country now have created standard protocols for prophylaxis, which incorporate preoperative administration and limited postoperative doses," Bratzler says. "[They allow] less exceptions and opt-outs by surgeons."

Fry says he favors that approach, particularly because only 40.7% of the patients had their antimicrobial prophylaxis discontinued within 24 hours after the procedure.

Patients undergoing cardiac surgery (34.4%) and hip or knee arthroplasty (36.7%) were least likely to have antimicrobial prophylaxis discontinued. The median duration of antimicrobial prophylaxis was longest (57 hours) for patients undergoing colon surgery.

A counterintuitive decision

"I have been screaming about this subject for 25 years now, and I am actually convinced that perhaps the only solution is to protocol preventive antibiotics within the institution and do not allow it to be a free and independent decision of the surgeon," Fry explains.

"In some institutions, they have just adopted a protocol and taken that decision out of the hands of the individual surgeon. I think individual surgeons want the best for their patients. I truly believe that," he continues. "But [discontinuing antibiotics] is a counterintuitive thing, so I don’t think it is too surprising that there would be resistance to it."

The optimal duration of prophylaxis has been controversial, especially for cardiovascular and orthopedic surgery, where many surgeons prefer to continue prophylaxis until all drains and tubes have been removed, the researchers acknowledge.

"The antibiotic discontinuation [issue] is largely a function, I believe, of the surgeons," Bratzler says. "They control the orders about the antibiotics that are given postoperatively. Here we targeted a lot of our educational efforts toward making sure that surgeons understand there is really no data that support prolonged postoperative antibiotics, despite the way they may have been trained or the way they have always done it. We are trying to provide a lot of education on that point."

The notion is dead wrong

Indeed, many could argue with apparent logic that keeping antibiotics in the bloodstream of a post-op patient is a good precaution against infection. But that notion is dead wrong for a number of reasons, according to Fry.

"Nearly 60% of patients [in our study] had their drugs extended beyond any period of time for which there would be any benefit to be derived from them," he says.

"The literature is very replete in showing that the critical time, the decisive time for having antibiotics present during an operation, is while it is being conducted. Extending the antibiotics for indefinite periods after the operation — there is just no evidence that that is of any value. On the other hand, it is counterintuitive for surgeons to accept that," Fry adds.

It is true that bacteria cause SSIs and antibiotics kill bacteria, but drugs administered after the surgical wound is closed cannot reach the site, he continues. The reason is fibrin, a protein involved in blood clotting that forms a barrier at the wound site that antibiotics cannot penetrate.

"The facts are that the bacteria that contaminate the surgical wound are embedded in a matrix of fibrin from the coagulation cascade during the onset of human inflammation," he points out.

"The antibiotics simply do not penetrate the fibrin. Secondly, when we close the surgical wound, the human inflammatory process continues, and we end up with increasing hydrostatic pressure in and about the wound following the wound closure from the natural and continued evolution of edema [swelling]," Fry notes. "The systemic drug does not get to the wound interface. It is a plain and simple issue."

Fry, for his part, says he sees no benefit in even the 24 post-op time frame, noting that it was something of a compromise in the quest toward eliminating post-op drug administration entirely.

"I am even more adamant in my personal feeling," he points out.

"I think any antibiotic given after wound closure has no benefit. So the surgical infection prevention project opted for 24 hours, feeling if we got everybody to a 24-hour standard that it would be a tremendous accomplishment. I believe that that is true. Maybe at some future time, we can get surgeons to ratchet down, hopefully, to reaching the day where there would be no re-dosing of the drug after the operation is over," Fry says.

No good and some harm

Not only does the post-op dosing of antibiotics do no good, it does harm in the form of selecting out resistant bacteria. There is clear evidence that prolonged antimicrobial administration can be harmful to patients by promoting antimicrobial-resistant bacteria and increasing the incidence of antibiotic-associated complications, the authors note.7-10

"There is no question that it contributes to resistance," Fry explains. "If you look at patients who have prolonged preventive antibiotics, who develop nosocomial infections, they always do so with organisms that are resistant to whatever the preventive drug that was used. The patient ends up having more resistant organisms with any infectious complications that occur in the wake of the procedure."

Toxicity and drug reactions are a concern as well, and blasting the system with antibiotics is an infamous prelude to a nasty Clostridium difficile infection. The C. diff already may be present, and wiping out the rest of the bacterial flora will give it ample room to grow and cause diarrhea and other problems.

"Then there is simply the issue of why are we continuing to waste resources [on practices] that are of no benefit," Fry adds.

"In a given patient, somebody may say, What is an extra hundred bucks?’ Well, an extra hundred dollars when there are 30 million operations performed annually in the United States comes to a staggering sum of money," he stresses. "There are a lot of reasons to stop the drugs within 24 hours. The patient benefits, wound infections will not be higher, and drug morbidity will be less."

The nation’s major surgical societies are on board with the issue, though the Society for Thoracic Surgery originally suggested antibiotics be given for 48 hours rather than the 24-hour post-op limit, Fry says.

"There is no evidence that 48 is better than 24," he notes. "When you extend the drugs postoperatively, you buy a measure of risk with no measure of benefit. I think the surgical societies are working hard to try to bring up compliance."

Going to a standard protocol

The use of standard protocols is the way to go, Fry argues, noting that a study published way back in 1982 showed multiple benefits to taking the decision out of the surgeon’s hands.11

"When they went to a protocol, they brought compliance with accepted standards in using preventive antibiotics from 30% to 40% up to almost 100%," he explains.

"And in a specialty like orthopedics, that actually showed that overall wound infection rates dropped by 80% and days of antibiotics dropped by 80%," Fry points out.

"Well, that’s the best deal I know of: improving outcomes and reducing resource utilization. The hospitals [should] say, This is the way we are going to do it.’ It makes for less cost and better results," he adds.


  1. Bratzler DW, Houck PM, Richards C, et al. Use of antimicrobial prophylaxis for major surgery baseline results from the National Surgical Infection Prevention Project. Arch Surg2005; 140:174-182
  2. Kirkland KB, Briggs JP, Trivette SL, et al. The impact of surgical-site infections in the 1990s: Attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol 1999; 20:725-730.
  3. Martone WJ, Jarvis WR, Culver DH, et al. "Incidence and Nature of Endemic and Epidemic Nosocomial Infections." In: Bennett JV, Brachman PS, eds. Hospital Infections. 3rd ed. Boston: Little Brown & Co. Inc.; 1992, pp. 577-596.
  4. Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 1961; 50:161-168.
  5. Stone HH, Hooper CA, Kolb LD, et al. Antibiotic prophylaxis in gastric, biliary and colonic surgery. Ann Surg 1976; 184:443-452.
  6. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992; 326:281-286.
  7. Harbarth S, Samore MH, Lichtenberg D, et al. Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance. Circulation 2000; 101:2,916-2,921.
  8. Takesue Y, Yokoyama T, Akagi S, et al. Changes in the intestinal flora after the administration of prophylactic antibiotics to patients undergoing a gastrectomy. Surg Today 2002; 32:581-586.
  9. Hecker MT, Aron DC, Patel NP, et al. Unnecessary use of antimicrobials in hospitalized patients: Current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med 2003; 163:972-978.
  10. Hoth JJ, Franklin GA, Stassen NA, et al. Prophylactic antibiotics adversely affect nosocomial pneumonia in trauma patients. J Trauma 2003; 55:249-254.
  11. Shapiro M. Perioperative prophylactic use of antibacterials in surgery: Principles and practice. Infect Control 1982; 3:38-40.