Christopher J. Graber, MD, MPH

METHODS

RESULTS

DISCUSSION

METHODS

RESULTS

DISCUSSION

METHODS

RESULTS

DISCUSSION

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

Methicillin‐resistant Staphylococcus aureus (MRSA) is responsible for an increasing number of invasive infections and, in the United States, may now be responsible for more deaths than disease associated with human immunodeficiency virus (HIV).1, 2 Vancomycin remains the drug of choice for invasive MRSA disease; from 1984 to 1996, its use in the United States escalated 6‐fold.3 With increased use of vancomycin, MRSA strains with partial and full resistance to vancomycin have emerged. Since 1997, S. aureus with intermediate susceptibility to vancomycin (VISA) as well as heteroresistance to vancomycin (hVISA) have been described.46 Several centers have also noted a slow rise in minimum inhibitory concentration (MIC) among clinical MRSA isolates (MIC creep).7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin‐susceptible MRSA.812 Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/MIC) 400 may be associated with improved clinical outcome,13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15‐20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.14

The effect of higher trough levels on kidney function remains poorly understood, as does the mechanism of vancomycin‐induced renal injury itself, though animal studies demonstrate oxidative damage to renal tubules with high doses of vancomycin.15, 16 In previous studies, the incidence of vancomycin nephrotoxicity with lower troughs has been reported to range from 0% to 19% with vancomycin alone, increasing up to 35% with concomitant aminoglycoside therapy.1724 Limited studies have been done to assess the risk of nephrotoxicity at higher trough levels. Lodise and colleagues identified high‐dose vancomycin (>4 gm per day) as an independent risk factor for nephrotoxicity, when compared to administration of <4 gm of vancomycin per day or use of linezolid, and showed greater risk of nephrotoxicity with increasing vancomycin trough levels within the first 96 hours of vancomycin administration.25, 26 Hidayat et al. demonstrated, in a prospective cohort analysis, that patients with mean trough levels 15 mg/L had a significantly increased incidence of nephrotoxicity. In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished.9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al. demonstrated that maximum vancomycin trough 15 mg/L was associated with nephrotoxicity in patients with healthcare‐associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.27 Pritchard et al. also retrospectively reviewed 2493 courses of vancomycin at their institution, from 2003 to 2007, and found a significant relationship between vancomycin trough 14 mg/L and nephrotoxicity. The presence of comorbid disease states and concomitant nephrotoxins was determined in a subset of 130 courses in 2007; increasing vancomycin trough was associated with nephrotoxicity in multivariable analysis.28 However, it is not clear whether troughs collected before or after nephrotoxicity onset were distinguished in this study. At least 6 other retrospective studies involving small sample size or published in abstract form have widely different results in relating high vancomycin trough or aggressive vancomycin dosing strategies to nephrotoxicity.2934

The purpose of our study was to evaluate the association between development of nephrotoxicity and trough levels obtained during vancomycin therapy at a large veterans' hospital, while accounting for other potential nephrotoxins, and to evaluate the temporal association between elevated vancomycin troughs and nephrotoxicity. We chose to focus on nephrotoxicity that occurred on, or after, 5 days of vancomycin therapy in order to reduce other confounding factors of nephrotoxicity, since short durations of vancomycin frequently represent use in surgical prophylaxis or empirical therapy for hemodynamically unstable patients at high risk for renal injury.

Patients and Methods

Results

DISCUSSION

Over the past 5 years, many institutions have adopted higher dosing guidelines for vancomycin, based on pharmacokinetic concerns related to its performance in the treatment of invasive staphylococcal disease. The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size29, 33; do not address reversibility of nephrotoxicity9, 26, 2931, 33; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels,9, 2831 or examine patient populations at relatively high27 or low30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.14 A recent review by Hazlewood et al. concluded that the incidence of nephrotoxicity remains low in patients without preexisting renal disease and those not receiving concomitant nephrotoxins.35 The aim of our study was to identify whether or not there was a correlation between high‐dose vancomycin and nephrotoxicity, while accounting for their temporal relationship, concomitant nephrotoxin use, and reversibility. In particular, we chose to focus on nephrotoxicity occurring after at least 5 days of vancomycin therapy in order to reduce confounding by other possible sources of renal injury that may have affected the decision to initially prescribe vancomycin, an approach advocated by a recent review.36 While we noted that mean and maximum vancomycin troughs were significantly higher in 2007 than 2005‐2006, incidence of nephrotoxicity was stable between the 2 time periods, with the higher rate of intravenous contrast dye in 2007 balanced in part by less aminoglycoside use. Overall, higher trough levels were not necessarily accompanied by a significant increase in nephrotoxicity, though there was a nonsignificant trend toward more nephrotoxic patients having maximum trough 15 mg/L.

The only clinical factor that was significantly associated with nephrotoxicity in multivariate analysis was receipt of intravenous contrast dye. Of the 44 patients who received intravenous contrast dye, 10 (22.7%) experienced nephrotoxicity. Interestingly, in animal studies, both intravenous contrast dye37, 38 and high‐dose vancomycin15, 16 have been demonstrated to promote free radical formation within renal tissue, which is hypothesized to cause tubular damage primarily through vascular endothelial dysfunction, vasoconstriction, and subsequent reperfusion injury. N‐acetylcysteine is frequently administered to patients about to receive intravenous contrast dye (although its benefit remains controversial37, 39); N‐acetylcysteine has also been shown in an animal model to attenuate vancomycin‐induced renal injury.40

Receipt of concomitant aminoglycosides was not significantly associated with nephrotoxicity, in contrast with previous studies. One meta‐analysis of 8 studies revealed found that the incidence of nephrotoxicity associated with combination vancomycin and aminoglycosides was 13.3% greater than with vancomycin alone (P < 0.01) and 4.3% greater than therapy with an aminoglycoside alone (P < 0.05)20; another analysis of safety data of the clinical trial comparing daptomycin to comparator therapy including initial low‐dose gentamicin therapy in the treatment of S. aureus bacteremia found renal adverse events in 10 of 53 (19%) patients receiving vancomycin and gentamicin, compared to 8 of 120 (7%) patients receiving daptomycin.41 While our findings that show no clear relationship between concomitant vancomycin and aminoglycoside use and nephrotoxicity may have been due to the relatively small number of patients in our study who received aminoglycosides, it is worth noting that more patients in our study received aminoglycosides than intravenous contrast dye (66 vs 44 patients). The 77.8% overall resolution of nephrotoxicity observed in our study is similar to that reported by Farber and Moellering in 198319 and to that reported more recently with high‐dose vancomycin by Jeffres et al. and Teng et al.27, 34

Although we attempted to account for as many confounders as possible, the retrospective nature of our study prevents us from making definitive statements regarding the role of vancomycin trough levels and nephrotoxicity. In particular, we are unable to comment on any potential role vancomycin may have on nephrotoxicity within 5 days of its start or on patients with a baseline serum creatinine >2. Other significant limitations include our small proportion of female patients, and that we were not able to calculate severity of illness or determine the presence of congestive heart failure. Also, we may be dosing vancomycin less aggressively than other centers, and thus may have reduced power in determining whether higher troughs, particularly those 20 mg/L, are associated with nephrotoxicity; identification of more patients with higher troughs and a larger overall sample size may have yielded different results. Even in the 2007 group, a significant number of patients with cellulitis, UTI, and uncomplicated bacteremia had target troughs of 8‐12 mg/L. However, taken together, our findings do not support a definite relationship between vancomycin troughs and development of nephrotoxicity, and that when it does occur, it is largely reversible. Further prospective research is needed to evaluate the effects of aggressive vancomycin dosing regimens on nephrotoxicity, particularly those regimens that include large loading doses. Trials of antioxidative agents in patients receiving aggressive dosing regimens of vancomycin who require radiology studies involving intravenous contrast dye may be indicated as well.

If you wish to receive credit for this activity, which begins on the next page, please refer to the website: www.blackwellpublishing.com/cme.

Accreditation and Designation Statement

Blackwell Futura Media Services designates this educational activity for a 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Educational Objectives

Continuous participation in the Journal of Hospital Medicine CME program will enable learners to be better able to:

• Interpret clinical guidelines and their applications for higher quality and more efficient care for all hospitalized patients.

• Describe the standard of care for common illnesses and conditions treated in the hospital; such as pneumonia, COPD exacerbation, acute coronary syndrome, HF exacerbation, glycemic control, venous thromboembolic disease, stroke, etc.

• Discuss evidence‐based recommendations involving transitions of care, including the hospital discharge process.

• Gain insights into the roles of hospitalists as medical educators, researchers, medical ethicists, palliative care providers, and hospital‐based geriatricians.

• Incorporate best practices for hospitalist administration, including quality improvement, patient safety, practice management, leadership, and demonstrating hospitalist value.

• Identify evidence‐based best practices and trends for both adult and pediatric hospital medicine.

Instructions on Receiving Credit

For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period that is noted on the title page.

Follow these steps to earn credit:

• Log on to www.blackwellpublishing.com/cme.

• Read the target audience, learning objectives, and author disclosures.

• Read the article in print or online format.

• Reflect on the article.

• Access the CME Exam, and choose the best answer to each question.

• Complete the required evaluation component of the activity.

If you wish to receive credit for this activity, which begins on the next page, please refer to the website: www.blackwellpublishing.com/cme.

Accreditation and Designation Statement

Blackwell Futura Media Services designates this educational activity for a 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Educational Objectives

Continuous participation in the Journal of Hospital Medicine CME program will enable learners to be better able to:

• Interpret clinical guidelines and their applications for higher quality and more efficient care for all hospitalized patients.

• Describe the standard of care for common illnesses and conditions treated in the hospital; such as pneumonia, COPD exacerbation, acute coronary syndrome, HF exacerbation, glycemic control, venous thromboembolic disease, stroke, etc.

• Discuss evidence‐based recommendations involving transitions of care, including the hospital discharge process.

• Gain insights into the roles of hospitalists as medical educators, researchers, medical ethicists, palliative care providers, and hospital‐based geriatricians.

• Incorporate best practices for hospitalist administration, including quality improvement, patient safety, practice management, leadership, and demonstrating hospitalist value.

• Identify evidence‐based best practices and trends for both adult and pediatric hospital medicine.

Instructions on Receiving Credit

For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period that is noted on the title page.

Follow these steps to earn credit:

• Log on to www.blackwellpublishing.com/cme.

• Read the target audience, learning objectives, and author disclosures.

• Read the article in print or online format.

• Reflect on the article.

• Access the CME Exam, and choose the best answer to each question.

• Complete the required evaluation component of the activity.

If you wish to receive credit for this activity, which begins on the next page, please refer to the website: www.blackwellpublishing.com/cme.

Accreditation and Designation Statement

Blackwell Futura Media Services designates this educational activity for a 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Educational Objectives

Continuous participation in the Journal of Hospital Medicine CME program will enable learners to be better able to:

• Interpret clinical guidelines and their applications for higher quality and more efficient care for all hospitalized patients.

• Describe the standard of care for common illnesses and conditions treated in the hospital; such as pneumonia, COPD exacerbation, acute coronary syndrome, HF exacerbation, glycemic control, venous thromboembolic disease, stroke, etc.

• Discuss evidence‐based recommendations involving transitions of care, including the hospital discharge process.

• Gain insights into the roles of hospitalists as medical educators, researchers, medical ethicists, palliative care providers, and hospital‐based geriatricians.

• Incorporate best practices for hospitalist administration, including quality improvement, patient safety, practice management, leadership, and demonstrating hospitalist value.

• Identify evidence‐based best practices and trends for both adult and pediatric hospital medicine.

Instructions on Receiving Credit

For information on applicability and acceptance of continuing medical education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period that is noted on the title page.

Follow these steps to earn credit:

• Log on to www.blackwellpublishing.com/cme.

• Read the target audience, learning objectives, and author disclosures.

• Read the article in print or online format.

• Reflect on the article.

• Access the CME Exam, and choose the best answer to each question.

• Complete the required evaluation component of the activity.

Hospitalists commonly encounter the challenges of infectious diseases in their hospitalized patients. Choosing the correct antibiotic, interpreting blood cultures, working up causes of fever, treating patients with an allergy to penicillin, and caring for patients with human immunodeficiency virus (HIV) commonly confront the hospitalist. This article presents evidence‐based pearls which will help hospitalists avoid common infectious disease pitfalls and guide their decision about when to consult an infectious diseases specialist.

1. Avoid Spiraling Empiricism and Understand Common Fallacies in Prescribing Empiric Antimicrobial Therapy

The term spiraling empiricism describes the inappropriate treatment, or the unjustifiable escalation of treatment, of suspected but undocumented infectious diseases.1 Initiation of carefully considered empiric broad‐spectrum antibiotic therapy for an acutely ill patient is an entirely appropriate and reasonable strategy. But all too often, practitioners are confronted with clinical dilemmas such as persistent fever or lack of response to therapy. In these circumstances, clinicians are faced with deciding whether to add or change antibiotics to broaden coverage. Changes in empiric therapy should be made sparingly, and only when there is new information or symptoms to justify an addition or change. In order to make an accurate assessment of response, steady‐state levels should be achieved and usually 3 to 5 days should be allowed to pass. Lack of response to broad‐spectrum therapy should trigger further investigation for occult infection or consideration of noninfectious etiologies and not simply the addition of a new antimicrobial agent. If a microbial pathogen is isolated from a blood culture(s) or other relevant source, antimicrobials should be tailored to the narrowest spectrum and least toxic therapy based on the sensitivities of that organism. For critically ill patients or patients who do not appear to be improving, an infectious diseases consultation may be warranted.

2. Know the Important Drug‐Drug Interactions Between Antimicrobials and Commonly‐used Inpatient Medications, Particularly With Those Involving Warfarin

Most antimicrobials (especially antifungals, quinolones, metronidazole, and sulfonamides) can cause unpredictable elevations in the international normalized ratio (INR) concurrent with warfarin administration, either through inhibition of warfarin metabolism or alterations in vitamin Kproducing gut flora. When using antimicrobials in patients on warfarin, the patient's INR should be carefully monitored and adjustment of the warfarin dose may be necessary. Antimicrobials that are inhibitors of cytochrome P‐450 enzymes include ciprofloxacin, levofloxacin, isoniazid, fluconazole, and clarithromycin. In contrast, rifampin is a potent inducer of most known cytochrome P‐450 enzymes and increases the metabolism of many drugs used in patients in the hospital setting, including anticonvulsants, beta‐blockers, calcium channel blockers, and other antibiotics like fluoroquinolones, and sulfonylureas. Moreover, the concurrent oral intake of tablets or solutions (including tube feeds) with a high concentration of trivalent and divalent cations (such as aluminum, magnesium, and, to a lesser extent, calcium, iron, and zinc) impairs gastrointestinal absorption of fluoroquinolones and should be avoided or spaced apart in time. Since fluoroquinolones can potentially prolong the QT interval, careful monitoring is necessary when a patient is prescribed other QT prolonging agents. Finally, many antimicrobials reduce the effectiveness of oral or other systemic hormonal contraceptives and patients should be routinely advised to use nonhormonal methods of birth control during therapy.

3. Positive Blood Cultures for Bacteria or Fungus Should be Repeated Serially Every 24 to 48 Hours Until the Cultures Are Negative

An important step in the management of a positive blood culture for bacteria or yeast is to check follow‐up blood cultures every 24 to 48 hours until the bacteremia or fungemia has cleared. This is particularly true of bacteremia caused by Staphylococcus aureus (S. aureus), Enterococcus species, and fungemia caused by Candida species. The duration of bacteremia or fungemia has a significant impact on the predictive values of further testing for endovascular or deep‐seated sources of infection as well as treatment duration. This is particularly true for the treatment of candidemia in nonneutropenic adults and for bacterial endocarditis, in which the recommended duration of treatment starts from the day of the last positive blood culture.2, 3 In addition to repeat blood cultures, a blood culture positive for S. aureus should always prompt an aggressive workup for a source (including strong consideration of a transesophageal echocardiogram to evaluate for endocarditis). S. aureus bacteremia should never be disregarded as a contaminant, and should prompt strong consideration of removal of all indwelling intravenous lines.4

4. Removal of Indwelling Intravascular Catheters Is Essential in the Management of Patients with Candidemia. In These Patients, Retention of Central Lines Is Significantly Related to Poor Outcomes

In patients with culture‐proven Candida fungemia, all intravascular catheters must be removed if at all possible. In a study by Nguyen et al.,5 the mortality rate for patients with a catheter‐related candidemia in whom catheters were retained was significantly higher than that of patients in whom the catheters were removed (41% vs. 21%, P < 0.001). Likewise, in a separate study, Luzzati et al.6 noted that central line removal independently reduced the high mortality of the disease. This recommendation applies to all Candida species.

5. Although Candida Species Are Frequently Noted to Colonize Sputum and Urine Cultures, Their Recovery From Multiple Sites May Be an Indicator of Occult Candidemia in an Acutely Ill Patient

Candida species uncommonly cause pneumonia or urinary tract infection, so their isolation from cultures of the respiratory and genitourinary tract often represents colonization. However, the presence of Candida species at multiple sites may be an indicator of occult candidemia in a patient with multiple risk factors for candidemia, including intensive care unit (ICU) admission, immunosuppression (particularly neutropenia and recent receipt of corticosteroids), central venous catheterization, total parenteral nutrition, recent broad‐spectrum antibiotics, and recent abdominal or gastrointestinal surgery.7

6. Patients with Asymptomatic Bacteriuria, With or Without Pyuria, Should Not Be Treated with Antibiotics. Pregnant Women and Patients Undergoing a Genitourinary Procedure Are the Exception and Should Be Treated With Antibiotics

Asymptomatic bacteriuria is commonly encountered in the hospital setting, but is usually benign. Bacteriuria is defined as a voided urine specimen with 1 bacterial species isolated in a quantitative count of 10⁵ cfu/mL. Treatment of asymptomatic bacteriuria is only recommended for pregnant women or prior to invasive genitourinary procedures, including transurethral resection of the prostate. Patients with structural or functional abnormalities of the urinary tract may have a high prevalence of bacteriuria. Despite its prevalence, asymptomatic bacteriuria is seldom associated with adverse outcomes. Studies have noted that antimicrobial treatment of asymptomatic bacteriuria does not decrease recurrence. Negative outcomes with antimicrobial treatment do occur, including adverse drug reactions and reinfection with organisms of increasing resistance. Clinical trials in spinal‐cord injury patients, diabetic women, elderly patients living in the community or nursing home, and patients with indwelling urethral catheters have consistently found no benefit with treatment of asymptomatic bacteriuria.8, 9 The presence or absence of pyuria does not differentiate symptomatic from asymptomatic urinary infection. Patients with symptomatic urinary tract infection (fever and/or dysuria) should be treated after urine cultures are obtained. Other causes of pyuria in the absence of an acute urinary tract infection include urethritis, tuberculosis, prostatitis, nephrolithiasis, and malignancy.

7. Evaluate All Patients Who Have a History of Penicillin Allergy and Consider Desensitization for Patients With a History Consistent With Immunoglobulin Emediated Allergy Who Require Treatment With a Beta‐Lactam Antibiotic

Patients commonly claim to have an allergy to penicillin. True penicillin allergy is very serious and can be life‐threatening. Because of this, patients labeled as penicillin allergic are typically not treated with beta‐lactam antibiotics. Instead, they may be prescribed medications which are typically less effective, more toxic, have a broader spectrum, or are more expensive.10, 11 Many patients are inappropriately labeled as having a penicillin allergy. A history of penicillin allergy is reported in approximately 10% of hospitalized patients, but only approximately 10% of those who report a history of penicillin allergy actually have an allergic reaction when treated with penicillin. Exanthems are frequently associated with beta‐lactam use during an episode of infectious mononucleosis but these are not considered an allergic reaction. Such patients are generally able to tolerate beta‐lactams subsequent to this episode. Nonpruritic maculopapular rashes are also reported in 3% to 7% of children taking amoxicillin and are not a contraindication for future beta‐lactam or cephalosporin use.12 All patients who describe an allergy should be questioned in detail about the type of penicillin received, as well as the type, severity, and timing of the reaction. Typical immunoglobulin E (IgE)‐mediated severe reactions to penicillin include urticaria, pruritus, angioedema, bronchospasm, and hypotension. These patients should not be given other agents that share the same beta‐lactam ring, including cephalosporins (risk of cross‐reactivity is greatest with first‐generation and second‐generation cephalosporins). Carbapenems have minimal cross‐reactivity, particularly meropenem.13 Monobactams (eg, aztreonam) do not cross‐react. While skin testing to penicillin can be considered in patients with a history of a severe reaction to penicillin, neither the major nor minor determinants are commercially available at this time. In patients with a history of a possible IgE‐mediated reaction and when there is no suitable alternative antibiotic (usually determined from infectious diseases consultation), desensitization to beta‐lactams or carbapenems can be considered. Desensitization should be reserved only for clinicians experienced with these techniques, preferably in consultation with a specialist in allergy and immunology. Patients who report a non‐IgE‐mediated reaction may be prescribed a cephalosporin if necessary (preferably a third‐generation or fourth‐generation).14

8. An Abrupt Increase in Leukocytosis In a Hospitalized Patient Should Prompt Consideration of Clostridium difficile Infection

In recent years, there has been a marked increase in the incidence and severity of Clostridium difficile (C. difficile) infection (CDI). A new hypervirulent strain, NAP1/BI/027, has emerged and is becoming endemic in the United States, Canada, and Europe. Typically C. difficile causes diarrhea, abdominal pain, and fever. Often patients have received antibiotics in the recent past, placing them at higher risk, but cases can occur sporadically (even in the community setting) or be transmitted nosocomially. Early detection appears to be essential in reducing the serious morbidity and mortality associated with this disease. Observational studies suggested that C. difficile infection is a common cause of unexplained leukocytosis or a sudden worsening of preexisting leukocytosis.15, 16 In a prospective study evaluating 60 patients with unexplained leukocytosis (white blood cell count 15,000/mm³), 58% of patients with leukocytosis in the absence of localizing symptoms and signs of infection were subsequently diagnosed with CDI. The authors believe that the percent may have been as high as 73% when they included patients with a negative toxin assay who rapidly responded to metronidazole therapy.17 White blood cell counts can range from 10,000 to 20,000/mm³ in moderate disease. Counts as high as 40,000/mm³ can occur, especially in patients with severe disease. Although the use of clindamycin and cephalosporins have been classically associated with the subsequent development of CDI, the current widespread use of fluoroquinolones has led to significant fluoroquinolone resistance among strains of C. difficile, especially the hypervirulent NAP1/BI/027 strain.18 The judicious use of antibiotics, especially fluoroquinolones, remains the cornerstone in preventing CDI. Remember that hand washing with soap and water is essential as alcohol‐based hand sanitizers do not eradicate the C. difficile spores. The drug of choice for initial treatment of mild to moderate CDI remains oral metronidazole, and it may be used for a first recurrence of CDI. Increasing data support the use of oral vancomycin for moderately severe to severe CDI or for multiple recurrences.19 Intravenous metronidazole is often added to oral vancomycin in patients with ileus, but it is not reliably effective alone for CDI.

9. Fever Is Common in the First 48 Hours After a Major Surgical Procedure, and Is a Poor Indicator of Infection. The use of Antibiotics in Response to Fever in the Absence of Other Localizing Signs and Symptoms of Infection Should Be Avoided

Early postoperative fever is relatively common but most fevers that develop within the first 48 hours after surgery do not have an infectious etiology.2023 However, fever that begins or persists beyond the fifth postoperative day is much more likely to represent a clinically significant infection. The continued use of antibiotics outside the window for wound prophylaxis (>24 hours) does not decrease the risk of postoperative infection but it does increase the risk of acquiring resistant bacteria and adverse drug reactions, including CDI.

10. Facts All Clinicians Should Know About Patients with HIV Infection

The 2 most common laboratory abnormalities routinely associated with antiretroviral therapy for HIV infection are unconjugated hyperbilirubinemia associated with atazanavir and an elevated mean corpuscular volume (MCV) associated with zidovudine (and, to a lesser extent, stavudine). Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in patients with advanced acquired immune deficiency syndrome (AIDS) who have recently started antiretroviral therapy. As the immune system begins to recover, it may respond to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. IRIS is associated with a pathological inflammatory response that can have substantial morbidity and mortality.24 For this reason, when considering whether to start or stop continuous or highly active antiretroviral therapy (also known as HAART), an infectious diseases consult is recommended. Pneumocystis jiroveci (PCP) remains a cause of pneumonia in patients with advanced AIDS' though in the era of HAART, its presentation may be more subtle. Finally, the principle of parsimony (Occam's razor) often does not hold in the diagnosis of opportunistic infections in patients with advanced AIDS, as these patients can often present with multiple infections simultaneously.25, 26

Conclusion

Infectious diseases are commonly encountered by physicians who care for hospitalized patients. Early recognition, evaluation, and appropriate treatment and/or referral to an infectious diseases specialist are necessary to moderate the significant morbidity and mortality that are often associated with infectious diseases.

Hospitalists commonly encounter the challenges of infectious diseases in their hospitalized patients. Choosing the correct antibiotic, interpreting blood cultures, working up causes of fever, treating patients with an allergy to penicillin, and caring for patients with human immunodeficiency virus (HIV) commonly confront the hospitalist. This article presents evidence‐based pearls which will help hospitalists avoid common infectious disease pitfalls and guide their decision about when to consult an infectious diseases specialist.

1. Avoid Spiraling Empiricism and Understand Common Fallacies in Prescribing Empiric Antimicrobial Therapy

The term spiraling empiricism describes the inappropriate treatment, or the unjustifiable escalation of treatment, of suspected but undocumented infectious diseases.1 Initiation of carefully considered empiric broad‐spectrum antibiotic therapy for an acutely ill patient is an entirely appropriate and reasonable strategy. But all too often, practitioners are confronted with clinical dilemmas such as persistent fever or lack of response to therapy. In these circumstances, clinicians are faced with deciding whether to add or change antibiotics to broaden coverage. Changes in empiric therapy should be made sparingly, and only when there is new information or symptoms to justify an addition or change. In order to make an accurate assessment of response, steady‐state levels should be achieved and usually 3 to 5 days should be allowed to pass. Lack of response to broad‐spectrum therapy should trigger further investigation for occult infection or consideration of noninfectious etiologies and not simply the addition of a new antimicrobial agent. If a microbial pathogen is isolated from a blood culture(s) or other relevant source, antimicrobials should be tailored to the narrowest spectrum and least toxic therapy based on the sensitivities of that organism. For critically ill patients or patients who do not appear to be improving, an infectious diseases consultation may be warranted.

2. Know the Important Drug‐Drug Interactions Between Antimicrobials and Commonly‐used Inpatient Medications, Particularly With Those Involving Warfarin

Most antimicrobials (especially antifungals, quinolones, metronidazole, and sulfonamides) can cause unpredictable elevations in the international normalized ratio (INR) concurrent with warfarin administration, either through inhibition of warfarin metabolism or alterations in vitamin Kproducing gut flora. When using antimicrobials in patients on warfarin, the patient's INR should be carefully monitored and adjustment of the warfarin dose may be necessary. Antimicrobials that are inhibitors of cytochrome P‐450 enzymes include ciprofloxacin, levofloxacin, isoniazid, fluconazole, and clarithromycin. In contrast, rifampin is a potent inducer of most known cytochrome P‐450 enzymes and increases the metabolism of many drugs used in patients in the hospital setting, including anticonvulsants, beta‐blockers, calcium channel blockers, and other antibiotics like fluoroquinolones, and sulfonylureas. Moreover, the concurrent oral intake of tablets or solutions (including tube feeds) with a high concentration of trivalent and divalent cations (such as aluminum, magnesium, and, to a lesser extent, calcium, iron, and zinc) impairs gastrointestinal absorption of fluoroquinolones and should be avoided or spaced apart in time. Since fluoroquinolones can potentially prolong the QT interval, careful monitoring is necessary when a patient is prescribed other QT prolonging agents. Finally, many antimicrobials reduce the effectiveness of oral or other systemic hormonal contraceptives and patients should be routinely advised to use nonhormonal methods of birth control during therapy.

3. Positive Blood Cultures for Bacteria or Fungus Should be Repeated Serially Every 24 to 48 Hours Until the Cultures Are Negative

An important step in the management of a positive blood culture for bacteria or yeast is to check follow‐up blood cultures every 24 to 48 hours until the bacteremia or fungemia has cleared. This is particularly true of bacteremia caused by Staphylococcus aureus (S. aureus), Enterococcus species, and fungemia caused by Candida species. The duration of bacteremia or fungemia has a significant impact on the predictive values of further testing for endovascular or deep‐seated sources of infection as well as treatment duration. This is particularly true for the treatment of candidemia in nonneutropenic adults and for bacterial endocarditis, in which the recommended duration of treatment starts from the day of the last positive blood culture.2, 3 In addition to repeat blood cultures, a blood culture positive for S. aureus should always prompt an aggressive workup for a source (including strong consideration of a transesophageal echocardiogram to evaluate for endocarditis). S. aureus bacteremia should never be disregarded as a contaminant, and should prompt strong consideration of removal of all indwelling intravenous lines.4

4. Removal of Indwelling Intravascular Catheters Is Essential in the Management of Patients with Candidemia. In These Patients, Retention of Central Lines Is Significantly Related to Poor Outcomes

In patients with culture‐proven Candida fungemia, all intravascular catheters must be removed if at all possible. In a study by Nguyen et al.,5 the mortality rate for patients with a catheter‐related candidemia in whom catheters were retained was significantly higher than that of patients in whom the catheters were removed (41% vs. 21%, P < 0.001). Likewise, in a separate study, Luzzati et al.6 noted that central line removal independently reduced the high mortality of the disease. This recommendation applies to all Candida species.

5. Although Candida Species Are Frequently Noted to Colonize Sputum and Urine Cultures, Their Recovery From Multiple Sites May Be an Indicator of Occult Candidemia in an Acutely Ill Patient

Candida species uncommonly cause pneumonia or urinary tract infection, so their isolation from cultures of the respiratory and genitourinary tract often represents colonization. However, the presence of Candida species at multiple sites may be an indicator of occult candidemia in a patient with multiple risk factors for candidemia, including intensive care unit (ICU) admission, immunosuppression (particularly neutropenia and recent receipt of corticosteroids), central venous catheterization, total parenteral nutrition, recent broad‐spectrum antibiotics, and recent abdominal or gastrointestinal surgery.7

6. Patients with Asymptomatic Bacteriuria, With or Without Pyuria, Should Not Be Treated with Antibiotics. Pregnant Women and Patients Undergoing a Genitourinary Procedure Are the Exception and Should Be Treated With Antibiotics

Asymptomatic bacteriuria is commonly encountered in the hospital setting, but is usually benign. Bacteriuria is defined as a voided urine specimen with 1 bacterial species isolated in a quantitative count of 10⁵ cfu/mL. Treatment of asymptomatic bacteriuria is only recommended for pregnant women or prior to invasive genitourinary procedures, including transurethral resection of the prostate. Patients with structural or functional abnormalities of the urinary tract may have a high prevalence of bacteriuria. Despite its prevalence, asymptomatic bacteriuria is seldom associated with adverse outcomes. Studies have noted that antimicrobial treatment of asymptomatic bacteriuria does not decrease recurrence. Negative outcomes with antimicrobial treatment do occur, including adverse drug reactions and reinfection with organisms of increasing resistance. Clinical trials in spinal‐cord injury patients, diabetic women, elderly patients living in the community or nursing home, and patients with indwelling urethral catheters have consistently found no benefit with treatment of asymptomatic bacteriuria.8, 9 The presence or absence of pyuria does not differentiate symptomatic from asymptomatic urinary infection. Patients with symptomatic urinary tract infection (fever and/or dysuria) should be treated after urine cultures are obtained. Other causes of pyuria in the absence of an acute urinary tract infection include urethritis, tuberculosis, prostatitis, nephrolithiasis, and malignancy.

7. Evaluate All Patients Who Have a History of Penicillin Allergy and Consider Desensitization for Patients With a History Consistent With Immunoglobulin Emediated Allergy Who Require Treatment With a Beta‐Lactam Antibiotic

Patients commonly claim to have an allergy to penicillin. True penicillin allergy is very serious and can be life‐threatening. Because of this, patients labeled as penicillin allergic are typically not treated with beta‐lactam antibiotics. Instead, they may be prescribed medications which are typically less effective, more toxic, have a broader spectrum, or are more expensive.10, 11 Many patients are inappropriately labeled as having a penicillin allergy. A history of penicillin allergy is reported in approximately 10% of hospitalized patients, but only approximately 10% of those who report a history of penicillin allergy actually have an allergic reaction when treated with penicillin. Exanthems are frequently associated with beta‐lactam use during an episode of infectious mononucleosis but these are not considered an allergic reaction. Such patients are generally able to tolerate beta‐lactams subsequent to this episode. Nonpruritic maculopapular rashes are also reported in 3% to 7% of children taking amoxicillin and are not a contraindication for future beta‐lactam or cephalosporin use.12 All patients who describe an allergy should be questioned in detail about the type of penicillin received, as well as the type, severity, and timing of the reaction. Typical immunoglobulin E (IgE)‐mediated severe reactions to penicillin include urticaria, pruritus, angioedema, bronchospasm, and hypotension. These patients should not be given other agents that share the same beta‐lactam ring, including cephalosporins (risk of cross‐reactivity is greatest with first‐generation and second‐generation cephalosporins). Carbapenems have minimal cross‐reactivity, particularly meropenem.13 Monobactams (eg, aztreonam) do not cross‐react. While skin testing to penicillin can be considered in patients with a history of a severe reaction to penicillin, neither the major nor minor determinants are commercially available at this time. In patients with a history of a possible IgE‐mediated reaction and when there is no suitable alternative antibiotic (usually determined from infectious diseases consultation), desensitization to beta‐lactams or carbapenems can be considered. Desensitization should be reserved only for clinicians experienced with these techniques, preferably in consultation with a specialist in allergy and immunology. Patients who report a non‐IgE‐mediated reaction may be prescribed a cephalosporin if necessary (preferably a third‐generation or fourth‐generation).14

8. An Abrupt Increase in Leukocytosis In a Hospitalized Patient Should Prompt Consideration of Clostridium difficile Infection

In recent years, there has been a marked increase in the incidence and severity of Clostridium difficile (C. difficile) infection (CDI). A new hypervirulent strain, NAP1/BI/027, has emerged and is becoming endemic in the United States, Canada, and Europe. Typically C. difficile causes diarrhea, abdominal pain, and fever. Often patients have received antibiotics in the recent past, placing them at higher risk, but cases can occur sporadically (even in the community setting) or be transmitted nosocomially. Early detection appears to be essential in reducing the serious morbidity and mortality associated with this disease. Observational studies suggested that C. difficile infection is a common cause of unexplained leukocytosis or a sudden worsening of preexisting leukocytosis.15, 16 In a prospective study evaluating 60 patients with unexplained leukocytosis (white blood cell count 15,000/mm³), 58% of patients with leukocytosis in the absence of localizing symptoms and signs of infection were subsequently diagnosed with CDI. The authors believe that the percent may have been as high as 73% when they included patients with a negative toxin assay who rapidly responded to metronidazole therapy.17 White blood cell counts can range from 10,000 to 20,000/mm³ in moderate disease. Counts as high as 40,000/mm³ can occur, especially in patients with severe disease. Although the use of clindamycin and cephalosporins have been classically associated with the subsequent development of CDI, the current widespread use of fluoroquinolones has led to significant fluoroquinolone resistance among strains of C. difficile, especially the hypervirulent NAP1/BI/027 strain.18 The judicious use of antibiotics, especially fluoroquinolones, remains the cornerstone in preventing CDI. Remember that hand washing with soap and water is essential as alcohol‐based hand sanitizers do not eradicate the C. difficile spores. The drug of choice for initial treatment of mild to moderate CDI remains oral metronidazole, and it may be used for a first recurrence of CDI. Increasing data support the use of oral vancomycin for moderately severe to severe CDI or for multiple recurrences.19 Intravenous metronidazole is often added to oral vancomycin in patients with ileus, but it is not reliably effective alone for CDI.

9. Fever Is Common in the First 48 Hours After a Major Surgical Procedure, and Is a Poor Indicator of Infection. The use of Antibiotics in Response to Fever in the Absence of Other Localizing Signs and Symptoms of Infection Should Be Avoided

Early postoperative fever is relatively common but most fevers that develop within the first 48 hours after surgery do not have an infectious etiology.2023 However, fever that begins or persists beyond the fifth postoperative day is much more likely to represent a clinically significant infection. The continued use of antibiotics outside the window for wound prophylaxis (>24 hours) does not decrease the risk of postoperative infection but it does increase the risk of acquiring resistant bacteria and adverse drug reactions, including CDI.

10. Facts All Clinicians Should Know About Patients with HIV Infection

The 2 most common laboratory abnormalities routinely associated with antiretroviral therapy for HIV infection are unconjugated hyperbilirubinemia associated with atazanavir and an elevated mean corpuscular volume (MCV) associated with zidovudine (and, to a lesser extent, stavudine). Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in patients with advanced acquired immune deficiency syndrome (AIDS) who have recently started antiretroviral therapy. As the immune system begins to recover, it may respond to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. IRIS is associated with a pathological inflammatory response that can have substantial morbidity and mortality.24 For this reason, when considering whether to start or stop continuous or highly active antiretroviral therapy (also known as HAART), an infectious diseases consult is recommended. Pneumocystis jiroveci (PCP) remains a cause of pneumonia in patients with advanced AIDS' though in the era of HAART, its presentation may be more subtle. Finally, the principle of parsimony (Occam's razor) often does not hold in the diagnosis of opportunistic infections in patients with advanced AIDS, as these patients can often present with multiple infections simultaneously.25, 26

Conclusion

Infectious diseases are commonly encountered by physicians who care for hospitalized patients. Early recognition, evaluation, and appropriate treatment and/or referral to an infectious diseases specialist are necessary to moderate the significant morbidity and mortality that are often associated with infectious diseases.

Hospitalists commonly encounter the challenges of infectious diseases in their hospitalized patients. Choosing the correct antibiotic, interpreting blood cultures, working up causes of fever, treating patients with an allergy to penicillin, and caring for patients with human immunodeficiency virus (HIV) commonly confront the hospitalist. This article presents evidence‐based pearls which will help hospitalists avoid common infectious disease pitfalls and guide their decision about when to consult an infectious diseases specialist.

1. Avoid Spiraling Empiricism and Understand Common Fallacies in Prescribing Empiric Antimicrobial Therapy

The term spiraling empiricism describes the inappropriate treatment, or the unjustifiable escalation of treatment, of suspected but undocumented infectious diseases.1 Initiation of carefully considered empiric broad‐spectrum antibiotic therapy for an acutely ill patient is an entirely appropriate and reasonable strategy. But all too often, practitioners are confronted with clinical dilemmas such as persistent fever or lack of response to therapy. In these circumstances, clinicians are faced with deciding whether to add or change antibiotics to broaden coverage. Changes in empiric therapy should be made sparingly, and only when there is new information or symptoms to justify an addition or change. In order to make an accurate assessment of response, steady‐state levels should be achieved and usually 3 to 5 days should be allowed to pass. Lack of response to broad‐spectrum therapy should trigger further investigation for occult infection or consideration of noninfectious etiologies and not simply the addition of a new antimicrobial agent. If a microbial pathogen is isolated from a blood culture(s) or other relevant source, antimicrobials should be tailored to the narrowest spectrum and least toxic therapy based on the sensitivities of that organism. For critically ill patients or patients who do not appear to be improving, an infectious diseases consultation may be warranted.

2. Know the Important Drug‐Drug Interactions Between Antimicrobials and Commonly‐used Inpatient Medications, Particularly With Those Involving Warfarin

Most antimicrobials (especially antifungals, quinolones, metronidazole, and sulfonamides) can cause unpredictable elevations in the international normalized ratio (INR) concurrent with warfarin administration, either through inhibition of warfarin metabolism or alterations in vitamin Kproducing gut flora. When using antimicrobials in patients on warfarin, the patient's INR should be carefully monitored and adjustment of the warfarin dose may be necessary. Antimicrobials that are inhibitors of cytochrome P‐450 enzymes include ciprofloxacin, levofloxacin, isoniazid, fluconazole, and clarithromycin. In contrast, rifampin is a potent inducer of most known cytochrome P‐450 enzymes and increases the metabolism of many drugs used in patients in the hospital setting, including anticonvulsants, beta‐blockers, calcium channel blockers, and other antibiotics like fluoroquinolones, and sulfonylureas. Moreover, the concurrent oral intake of tablets or solutions (including tube feeds) with a high concentration of trivalent and divalent cations (such as aluminum, magnesium, and, to a lesser extent, calcium, iron, and zinc) impairs gastrointestinal absorption of fluoroquinolones and should be avoided or spaced apart in time. Since fluoroquinolones can potentially prolong the QT interval, careful monitoring is necessary when a patient is prescribed other QT prolonging agents. Finally, many antimicrobials reduce the effectiveness of oral or other systemic hormonal contraceptives and patients should be routinely advised to use nonhormonal methods of birth control during therapy.

3. Positive Blood Cultures for Bacteria or Fungus Should be Repeated Serially Every 24 to 48 Hours Until the Cultures Are Negative

An important step in the management of a positive blood culture for bacteria or yeast is to check follow‐up blood cultures every 24 to 48 hours until the bacteremia or fungemia has cleared. This is particularly true of bacteremia caused by Staphylococcus aureus (S. aureus), Enterococcus species, and fungemia caused by Candida species. The duration of bacteremia or fungemia has a significant impact on the predictive values of further testing for endovascular or deep‐seated sources of infection as well as treatment duration. This is particularly true for the treatment of candidemia in nonneutropenic adults and for bacterial endocarditis, in which the recommended duration of treatment starts from the day of the last positive blood culture.2, 3 In addition to repeat blood cultures, a blood culture positive for S. aureus should always prompt an aggressive workup for a source (including strong consideration of a transesophageal echocardiogram to evaluate for endocarditis). S. aureus bacteremia should never be disregarded as a contaminant, and should prompt strong consideration of removal of all indwelling intravenous lines.4

4. Removal of Indwelling Intravascular Catheters Is Essential in the Management of Patients with Candidemia. In These Patients, Retention of Central Lines Is Significantly Related to Poor Outcomes

In patients with culture‐proven Candida fungemia, all intravascular catheters must be removed if at all possible. In a study by Nguyen et al.,5 the mortality rate for patients with a catheter‐related candidemia in whom catheters were retained was significantly higher than that of patients in whom the catheters were removed (41% vs. 21%, P < 0.001). Likewise, in a separate study, Luzzati et al.6 noted that central line removal independently reduced the high mortality of the disease. This recommendation applies to all Candida species.

5. Although Candida Species Are Frequently Noted to Colonize Sputum and Urine Cultures, Their Recovery From Multiple Sites May Be an Indicator of Occult Candidemia in an Acutely Ill Patient

Candida species uncommonly cause pneumonia or urinary tract infection, so their isolation from cultures of the respiratory and genitourinary tract often represents colonization. However, the presence of Candida species at multiple sites may be an indicator of occult candidemia in a patient with multiple risk factors for candidemia, including intensive care unit (ICU) admission, immunosuppression (particularly neutropenia and recent receipt of corticosteroids), central venous catheterization, total parenteral nutrition, recent broad‐spectrum antibiotics, and recent abdominal or gastrointestinal surgery.7

6. Patients with Asymptomatic Bacteriuria, With or Without Pyuria, Should Not Be Treated with Antibiotics. Pregnant Women and Patients Undergoing a Genitourinary Procedure Are the Exception and Should Be Treated With Antibiotics

Asymptomatic bacteriuria is commonly encountered in the hospital setting, but is usually benign. Bacteriuria is defined as a voided urine specimen with 1 bacterial species isolated in a quantitative count of 10⁵ cfu/mL. Treatment of asymptomatic bacteriuria is only recommended for pregnant women or prior to invasive genitourinary procedures, including transurethral resection of the prostate. Patients with structural or functional abnormalities of the urinary tract may have a high prevalence of bacteriuria. Despite its prevalence, asymptomatic bacteriuria is seldom associated with adverse outcomes. Studies have noted that antimicrobial treatment of asymptomatic bacteriuria does not decrease recurrence. Negative outcomes with antimicrobial treatment do occur, including adverse drug reactions and reinfection with organisms of increasing resistance. Clinical trials in spinal‐cord injury patients, diabetic women, elderly patients living in the community or nursing home, and patients with indwelling urethral catheters have consistently found no benefit with treatment of asymptomatic bacteriuria.8, 9 The presence or absence of pyuria does not differentiate symptomatic from asymptomatic urinary infection. Patients with symptomatic urinary tract infection (fever and/or dysuria) should be treated after urine cultures are obtained. Other causes of pyuria in the absence of an acute urinary tract infection include urethritis, tuberculosis, prostatitis, nephrolithiasis, and malignancy.

7. Evaluate All Patients Who Have a History of Penicillin Allergy and Consider Desensitization for Patients With a History Consistent With Immunoglobulin Emediated Allergy Who Require Treatment With a Beta‐Lactam Antibiotic

Patients commonly claim to have an allergy to penicillin. True penicillin allergy is very serious and can be life‐threatening. Because of this, patients labeled as penicillin allergic are typically not treated with beta‐lactam antibiotics. Instead, they may be prescribed medications which are typically less effective, more toxic, have a broader spectrum, or are more expensive.10, 11 Many patients are inappropriately labeled as having a penicillin allergy. A history of penicillin allergy is reported in approximately 10% of hospitalized patients, but only approximately 10% of those who report a history of penicillin allergy actually have an allergic reaction when treated with penicillin. Exanthems are frequently associated with beta‐lactam use during an episode of infectious mononucleosis but these are not considered an allergic reaction. Such patients are generally able to tolerate beta‐lactams subsequent to this episode. Nonpruritic maculopapular rashes are also reported in 3% to 7% of children taking amoxicillin and are not a contraindication for future beta‐lactam or cephalosporin use.12 All patients who describe an allergy should be questioned in detail about the type of penicillin received, as well as the type, severity, and timing of the reaction. Typical immunoglobulin E (IgE)‐mediated severe reactions to penicillin include urticaria, pruritus, angioedema, bronchospasm, and hypotension. These patients should not be given other agents that share the same beta‐lactam ring, including cephalosporins (risk of cross‐reactivity is greatest with first‐generation and second‐generation cephalosporins). Carbapenems have minimal cross‐reactivity, particularly meropenem.13 Monobactams (eg, aztreonam) do not cross‐react. While skin testing to penicillin can be considered in patients with a history of a severe reaction to penicillin, neither the major nor minor determinants are commercially available at this time. In patients with a history of a possible IgE‐mediated reaction and when there is no suitable alternative antibiotic (usually determined from infectious diseases consultation), desensitization to beta‐lactams or carbapenems can be considered. Desensitization should be reserved only for clinicians experienced with these techniques, preferably in consultation with a specialist in allergy and immunology. Patients who report a non‐IgE‐mediated reaction may be prescribed a cephalosporin if necessary (preferably a third‐generation or fourth‐generation).14

8. An Abrupt Increase in Leukocytosis In a Hospitalized Patient Should Prompt Consideration of Clostridium difficile Infection

In recent years, there has been a marked increase in the incidence and severity of Clostridium difficile (C. difficile) infection (CDI). A new hypervirulent strain, NAP1/BI/027, has emerged and is becoming endemic in the United States, Canada, and Europe. Typically C. difficile causes diarrhea, abdominal pain, and fever. Often patients have received antibiotics in the recent past, placing them at higher risk, but cases can occur sporadically (even in the community setting) or be transmitted nosocomially. Early detection appears to be essential in reducing the serious morbidity and mortality associated with this disease. Observational studies suggested that C. difficile infection is a common cause of unexplained leukocytosis or a sudden worsening of preexisting leukocytosis.15, 16 In a prospective study evaluating 60 patients with unexplained leukocytosis (white blood cell count 15,000/mm³), 58% of patients with leukocytosis in the absence of localizing symptoms and signs of infection were subsequently diagnosed with CDI. The authors believe that the percent may have been as high as 73% when they included patients with a negative toxin assay who rapidly responded to metronidazole therapy.17 White blood cell counts can range from 10,000 to 20,000/mm³ in moderate disease. Counts as high as 40,000/mm³ can occur, especially in patients with severe disease. Although the use of clindamycin and cephalosporins have been classically associated with the subsequent development of CDI, the current widespread use of fluoroquinolones has led to significant fluoroquinolone resistance among strains of C. difficile, especially the hypervirulent NAP1/BI/027 strain.18 The judicious use of antibiotics, especially fluoroquinolones, remains the cornerstone in preventing CDI. Remember that hand washing with soap and water is essential as alcohol‐based hand sanitizers do not eradicate the C. difficile spores. The drug of choice for initial treatment of mild to moderate CDI remains oral metronidazole, and it may be used for a first recurrence of CDI. Increasing data support the use of oral vancomycin for moderately severe to severe CDI or for multiple recurrences.19 Intravenous metronidazole is often added to oral vancomycin in patients with ileus, but it is not reliably effective alone for CDI.

9. Fever Is Common in the First 48 Hours After a Major Surgical Procedure, and Is a Poor Indicator of Infection. The use of Antibiotics in Response to Fever in the Absence of Other Localizing Signs and Symptoms of Infection Should Be Avoided

Early postoperative fever is relatively common but most fevers that develop within the first 48 hours after surgery do not have an infectious etiology.2023 However, fever that begins or persists beyond the fifth postoperative day is much more likely to represent a clinically significant infection. The continued use of antibiotics outside the window for wound prophylaxis (>24 hours) does not decrease the risk of postoperative infection but it does increase the risk of acquiring resistant bacteria and adverse drug reactions, including CDI.

10. Facts All Clinicians Should Know About Patients with HIV Infection

The 2 most common laboratory abnormalities routinely associated with antiretroviral therapy for HIV infection are unconjugated hyperbilirubinemia associated with atazanavir and an elevated mean corpuscular volume (MCV) associated with zidovudine (and, to a lesser extent, stavudine). Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in patients with advanced acquired immune deficiency syndrome (AIDS) who have recently started antiretroviral therapy. As the immune system begins to recover, it may respond to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. IRIS is associated with a pathological inflammatory response that can have substantial morbidity and mortality.24 For this reason, when considering whether to start or stop continuous or highly active antiretroviral therapy (also known as HAART), an infectious diseases consult is recommended. Pneumocystis jiroveci (PCP) remains a cause of pneumonia in patients with advanced AIDS' though in the era of HAART, its presentation may be more subtle. Finally, the principle of parsimony (Occam's razor) often does not hold in the diagnosis of opportunistic infections in patients with advanced AIDS, as these patients can often present with multiple infections simultaneously.25, 26

Conclusion

Infectious diseases are commonly encountered by physicians who care for hospitalized patients. Early recognition, evaluation, and appropriate treatment and/or referral to an infectious diseases specialist are necessary to moderate the significant morbidity and mortality that are often associated with infectious diseases.