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American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

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The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
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American Journal of Medical Sciences and Medicine
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Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
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The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

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A Retrospective Review of Antibiotic Management of Infective Endocarditis in a Large Tertiary-Care Teaching Hospital

Anahita Mostaghim*, Hoi Yee Annie Lo, Nancy Khardori

School of Medicine, Eastern Virginia Medical School, Norfolk, USA

Abstract: This study aims to analyze duration of intravenous antimicrobial treatment and targeted antimicrobial choices after narrowing from broad-spectrum antibiotics in cases of infective endocarditis (IE) at a large teaching hospital in the U.S. Patients were retrospectively identified from 2007-2015 using appropriate ICD-9 codes. Cases that met definite Modified Duke Criteria were extracted for epidemiologic data, causative organism, antimicrobial regimen choice and length, mortality, and recurrence. Patients treated with at least 6 weeks of intravenous antibiotics had less recurrence than those who received less than 6 weeks (0% vs 9.5%, P = 0.0081) with all cases of recurrence being with Staphylococcal IE. Cefazolin showed a lower in-hospital mortality than nafcillin for methicillin-sensitive staphylococcus aureus (3.3% vs 41.2%, P = 0.0118) although statistically insignificant in coagulase negative staphylococcus IE (16.7% vs 66.7%, P = 0.0992). Cefazolin and vancomycin had similar in-hospital mortality for methicillin-susceptible coagulase-negative staphylococcus (16.7% vs 22.2%). Daptomycin and vancomycin had similar in-hospital mortality in methicillin-resistant S. aureus (0% vs 6.3%). Vancomycin and ampicillin had similar in-hospital mortalities in susceptible enterococcus (16.7% each). Recurrence was tied to use of less than 6 weeks of antibiotics in cases of staphylococcal IE. Cefazolin had lower in-hospital mortality than nafcillin in cases of methicillin-susceptible S. aureus and coagulase-negative staphylococcus. Vancomycin showed similar efficacy to cefazolin, daptomycin, and ampicillin in their respective susceptible species. Randomized control trials need to be held to confirm if antibiotic choice is tied to in-hospital mortality.

Keywords: infective endocarditis, antibiotic, cefazolin, nafcillin, duration, mortality, recurrence

Citation: Anahita Mostaghim, Hoi Yee Annie Lo, Nancy Khardori, A Retrospective Review of Antibiotic Management of Infective Endocarditis in a Large Tertiary-Care Teaching Hospital. American Journal of Infectious Diseases and Microbiology, 5 (3). 120-125. January 2017. doi:10.12691/ajidm-5-3-5

1. Introduction

Infective endocarditis (IE) was first recognized in 1885 [1], since then few advances have been made and IE still confers a high morbidity and mortality rate. With the discovery and utilization of penicillin the mortality of IE dropped by 30%, and with the institution of surgical options the mortality further decreased in the 1960s to as low as 10% [2]. Currently the mortality of IE is reported around 14-37% [3,4,5,6,7].

In 2015, the American Heart Association (AHA) released their most recent treatment guidelines. All recommendations are based on level B or C evidence and all recommend at least 4-6 weeks of antibiotics depending on causative organism [8]. Few studies exist regarding choices between these antibiotic options. One Cochrane review cites only four small randomized control trials with “high risk of bias”, concluding that limited and low quality evidence suggest no difference between a few specified antibiotic regimens in staphylococcal IE [9]. Another retrospective study showing equal failure rates of oxacillin and cefazolin in deep-seated infections such as IE (20.0% vs 15.6%, P=0.76), but insignificantly higher in-hospital mortality rate for oxacillin over cefazolin (5.3% vs 1%, P = 0.13) [10].

Given the association between ongoing antimicrobial use in the community and development of antimicrobial resistance, along with adverse effects of antibiotic use, choices for narrowing antibiotic therapy need to be studied and reevaluated. Our study observed and evaluated differences in outcomes in a large U.S. population with IE treated with different targeted antimicrobial regimen choices.

2. Materials and Methods

This study was approved by the Institutional Review Board at Eastern Virginia Medical School for retrospective study of the electronic medical record (EMR). The EMR from Sentara Norfolk General Hospital and Sentara Heart Hospital was used to identify potential cases of infective endocarditis (IE). Both hospitals make up a large tertiary care referral center for the Hampton Roads Virginia area that includes central Virginia to the coast, then expands north into the Eastern Shore and south into North Carolina. It is primarily a large inner city population with referrals from rural and suburban areas.

A search was performed for admission with ICD9 codes 421.0-421.9, 391.1, 424.90-99, 017.90-96, 074.22, 098.84, 115.04, 115.14, 036.42, 112.81, and 093.20-4, from when the EMR went live on July 16, 2007 to August 13, 2015. Only those age 18+ were included. Patient files were extracted for pertinent information including age, culture and serology results, echocardiography, comorbidities, risk factors, valve type, recurrence, and mortality.

Each admission was characterized based on Modified Duke Criteria (Figure 1) and only those meeting definite criteria were included. Definite cases of IE that did not have culture results, susceptibilities, or documented antibiotic treatment were excluded. Groups were then assigned for analysis in by length of intravenous antibiotic treatment as well as antibiotic management by causative organism.

Figure 1. Modified Duke Criteria (adapted from Topan et al [11])

When analyzing for length of intravenous antibiotic treatment, cases were classified as either received at least 6 weeks of treatment or less than 6 weeks of treatment. Each set was then reviewed for 30-day, 90-day, and 180-day mortality from the date of admission. Recurrence was also reviewed and was defined as an episode of IE within 6 months of a previous episode of IE, unless disproved by culture results. Patients that died prior to completing their fully prescribed course of antibiotics were excluded from results.

When analyzing for antibiotic management by organism, causative organism was assessed based on culture results and susceptibilities, and was then compared with provider notes to confirm their agreement of the identified causative organism. The specific causative organisms looked at were methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Viridans group Streptococci (VGS), coagulase-negative staphylococcus (CoNS), methicillin-resistant CoNS, and non-vancomycin resistant enterococcus. Each group was then divided into subgroups based on the long-term intravenous antibiotic they were treated with. These antibiotics were chosen by the provider based on the same culture results and susceptibilities. Use of synergistic combinations, such as rifampin or gentamicin, was also noted in each subgroup. These subgroups were then reviewed for recurrence and in-hospital mortality as well as 30-day, 90-day, and 180-day mortality after admission.

Odds ratio were calculated for all comparisons. 95% Confidence intervals were determined and significance was defined as P ≤ 0.05.

3. Results

A total of 492 potential admissions were identified using the mentioned ICD9 codes. Of these admissions, 363 met definite criteria for IE. They showed a 19.8% 30-day mortality, 24.5% 90-day mortality, and 27.5% 180-day mortality. Cultures were positive for methicillin-susceptible S. aureus (MSSA) in 65 (17.9%) cases, methicillin-resistant S. aureus (MRSA) in 67 (18.5%) cases, Viridans Group Streptococci (VGS) in 59 (16.3%) cases, coagulase-negative Staphylococci (CoNS) in 27 (7.4%) cases, methicillin-resistant CoNS in 23 (6.3%) cases, and vancomycin-susceptible enterococcus in 41 (11.3%) cases.

3.1. Antimicrobial Duration

A total of 352 cases had a documented length of antibiotic therapy. Of these, 106 (30.1%) received less than 6 weeks of intravenous treatment. Eighty-one (76.4%) of these due to patient demise on treatment and four (3.8%) were due to discharge against medical advice, and both sets were excluded from analysis. Of the remaining 21 cases that did not receive full 6 weeks of intravenous treatment, 19 received 4 weeks and two received 5 weeks. Two cases were continued on suppressive oral antibiotics. Of these 21 cases, 9 (42.9%) were treated for Staphylococcal species. Two (9.5%) cases had 90-day mortality (1 VGS, 1 CoNS), with no additional mortality by 180 days. There was 1 (4.8%) case involving a prosthetic valve. Two (9.5%) were associated with recurrence, with both receiving 4 weeks of antibiotics. One was caused by CoNS and the other by MRSA.

The remaining 246 (67.8%) cases each received 6+ weeks of intravenous antimicrobial therapy. Ten (4.1%) died within 90 days, and 11 (4.5%) more within 180 days. Those that received 6+ weeks of antibiotics had a similar 90-day mortality (4.1% vs 9.5%, OR=0.4, 95%CI 0.08-1.97, P=0.2615) and similar 180-day mortality (8.5% vs 9.5%) to those who received less than 6 weeks. Of the 246 cases, none were associated with recurrence, this is significantly less than those that received less than 6 weeks (OR=0.02, 95%CI 0.0007-0.34, P=0.0081). Thirty-seven (15.0%) had prosthetic valve endocarditis.

3.2. Species-based Therapy

3.2.1. Staphylococcus Aureus

Of 65 MSSA cases, 30 used Cefazolin as the long-term antibiotic with only 1 (3.3%) showing in-hospital mortality. Nafcillin was used in 17 cases with 7 (41.2%) showing in-hospital mortality. Patients treated with cefazolin were significantly less likely to have in-hospital mortality than patients treated with nafcillin (OR = 0.06, 95%CI 0.01-0.53, P = 0.0118). As cefazolin and nafcillin showed a striking difference in mortality with a larger number of patients treated, characteristics of patients treated with cefazolin and nafcillin were reviewed for differences that could possibly explain the mortality difference (Figure 2). Fourteen cases were treated with a broader spectrum antibiotic, such as vancomycin or daptomycin, with 5 (35.7%) in-hospital mortalities. The other choices were split between third generation cephalosporins or a combination of 3rd generation cephalosporins and nafcillin. Both nafcillin and cefazolin had an additional 30-day mortality not occurring in the hospital. One case showed 90-day mortality using a combination of ceftriaxone and nafcillin. Two cases showed 180-day mortality, one used cefazolin and the other used vancomycin. None of the MSSA cases showed recurrence. Five cases were associated with use of a synergistic antibiotic combination, such as gentamicin or rifampin; 3 of these showed in-hospital mortality with 1 having cefazolin as the main antibiotic, 1 with combination broad spectrum, and 1 with nafcillin. The remaining two were paired with cefazolin with no associated 180-day mortality.

Of 67 MRSA cases, 30 used vancomycin as the long-term antibiotic, with 5 (16.7%) cases of in-hospital mortality and 1 (3.3%) more 30-day mortality not occurring in the hospital. Daptomycin was used in 18 cases by itself, and in 4 cases in combination with another broad-spectrum antibiotic. Four cases had in-hospital mortality associated with daptomycin, 3 of these cases were in association with other broad-spectrum antibiotics giving sole daptomycin an in-hospital mortality of 5.6% and combination 75%. The rest of the cases used either a different anti-MRSA or broad spectrum antibiotic, or different combinations of broad-spectrum antibiotics. One (1.5%) case had documented recurrence and was associated with sole daptomycin use for 4 weeks. Thirteen cases used a synergistic combination. Three (23.1%) of these were in-hospital mortalities, the others showed no 30/90/180-day mortality.

Figure 2. Methicillin-susceptible S. aureus infective endocarditis patient characteristics

3.2.2. Viridans Group Streptococci

Of the 59 cases of Viridans group streptococci (VGS), 27 were received ceftriaxone as the long term antibiotic with no in-hospital mortality and two (7.4%) 90-day mortalities. Penicillin was used in 8 cases, with no in-hospital mortality and two (25%) 90-day mortalities. Vancomycin was the sole long-term antibiotic in 7 (11.9%) cases, with no in-hospital mortality or 180-day mortality. There were three cases each for ampicillin, cefazolin, and vancomycin/ceftriaxone combination; all were alive at 180 days. Other patients received unasyn, clindamycin, moxifloxacin, or combinations of these. Of all VGS cases, 4 (6.9%) had in hospital mortality. Synergistic combinations were used in 5 cases, with 1 showing in-hospital mortality and the other 4 showing no mortality by 180 days.

3.2.3. Coagulase-negative Staphylococci

Of 27 cases of methicillin susceptible coagulase-negative staphylococcus (CoNS), 6 used cefazolin as the long-term antibiotic with 1 (16.7%) in-hospital mortality. Six used nafcillin with 4 (66.7%) in-hospital mortality. Eleven used vancomycin with 2 cases using it in combination with another broad-spectrum antibiotic. Two (22.2%) of cases using solely vancomycin had in-hospital mortality and 1 (50%) of combination use had in-hospital mortality. One case used ceftriaxone with in-hospital mortality. Patients treated with cefazolin were similarly likely to have in-hospital mortality as those treated with nafcillin (OR = 0.1, 95%CI 0.01-1.54, P = 0.0992) and vancomycin (OR = 0.7, 95%CI 0.05-10.01, P=0.7928). Both cefazolin and nafcillin had one case of 90-day mortality outside of the hospital. Other antibiotics used included tobramycin, unasyn, and ceftriaxone. One case had recurrence after being treated with nafcillin and rifampin for 4 weeks. Fourteen cases used synergistic combinations with 4 (28.6%) associated with in-hospital mortality and others showing no mortality by 180 days. Three cases dropped the synergistic agent prior to in-hospital death by either narrowing in one case, or going to broad spectrum antibiotics in 2 cases.

Of 23 methicillin-resistant CoNS cases, 18 were treated with long-term vancomycin, with 4 of these using it in combination with another broad-spectrum antibiotic. Six vancomycin cases showed in-hospital mortality with 4 using it in combination (6.3% of sole vancomycin use, 100% of combination use). Daptomycin was used in 4 cases and doripenem in 1 case, with the doripenem case showing in-hospital mortality. Four cases used synergistic antibiotics. All were paired with vancomycin, and none of them showed in-hospital or 30/90/180-day mortality.

3.2.4. Enterococcus

Of the 41 vancomycin susceptible enterococcus cases, 24 (58.5%) received ampicillin as the long-term antibiotic. Four of these (16.7%) showed in-hospital mortality, one (4.2%) showed 30-day mortality, one 180-day mortality. Of the remaining cases, ampicillin was paired with ceftriaxone in 7 cases with one (14.3%) in-hospital mortality and one 180-day mortality. Vancomycin was used as the only long-term antibiotic in 6 (14.6%) cases, with one (16.7%) in-hospital mortality using streptomycin synergistically and no other mortality by 180 days. Other antibiotic choices included unasyn, daptomycin, and broad-spectrum combinations. There was one 30-day mortality occurring outside the hospital associated with ampicillin and gentamicin use, with the gentamicin discontinued early due to ototoxicity. Of the 16 using synergistic combinations, 4 (25%) had in-hospital mortality, 1 had 30-day mortality outside the hospital mentioned above, and the rest did not show 30/90/180-day mortality.

4. Discussion

Antibiotic management shows a statistically significant difference in recurrence with relation to the length of treatment. A longer regimen likely reduces recurrence, although those more likely to follow-up as an outpatient may be more likely to have a longer regimen. Staphylococcus IE has a recommended 6 weeks or more of treatment [8] and our findings support this. Current AHA recommendations also recommend 4 or more weeks in cases of streptococcal or enterococcal IE [8]. This is also supported in this study as all cases of streptococcal or enterococcal IE treated with 4 weeks of antibiotics did not experience recurrence. It was noticed that certain cases were prescribed a shorter length of antibiotics because of a healthier appearing patient, “early endocarditis”, or fear of long term adverse effects. In the event of recurrent staphylococcal IE, a patient experiences more than 6 weeks of antibiotics and we would suggest adhering to current AHA guidelines in these cases. Recurrence was limited in our study due to needing to be seen at our facility for documentation, which may underestimate recurrence rate in all populations. There was no statistically significant difference in 30/90/180-day mortality for those who received 6+ weeks of antibiotics or less than 6 weeks, showing that antibiotic regimen length after 4 weeks is tied to recurrence rather than mortality.

In methicillin-susceptible S. aureus (MSSA) cases, the most frequently used antibiotic was cefazolin. Cefazolin use was significantly associated with less in-hospital mortality than nafcillin (P = 0.0118) with similar out-of-hospital mortality. This mortality finding also paralleled with cases of non-methicillin-resistant CoNS, although the difference here was statistically insignificant (P = 0.0992) it may become significant with a larger study population. These results could signify better mortality outcomes using cefazolin as possibly seen in a previous study whose results had near significance (P = 0.13) [10]. It may be that penicillin class adverse effects are amplified in the beta-lactamase resistant subclass. This could lead organ damage and failure during admission, which is detrimental to patient outcome as one study showed renal failure increases post-operative mortality in IE patients [12]. There may also be provider bias, as nafcillin could be chosen more frequently in cases where the patient is perceived to be in a worse overall state. We looked at age and comorbidities between the two groups to possibly uncover other causes of this difference. This showed that cefazolin had an overall younger group with slightly less comorbidities but significantly more patients on chronic hemodialysis which confers lower likelihood of surgical intervention and higher risk of death (Figure 2). When divided into mortality groups, cefazolin-treated patients that survived had similar average age and number of comorbidities compared to nafcillin-treated patients that died. Nafcillin-treated patients that survived had a greater average age and number of comorbidities than either those that died or in cefazolin-treated patients. The number of comorbidities for each group depends heavily on accurate documentation of ongoing health problems and can include diagnoses that may have resolved or did not contribute to mortality, such as gout and asthma. While we do not have the patient picture as seen by the provider, it may be that mortality difference is inherent to the antibiotic choice. Randomized-control study of nafcillin versus cefazolin needs to be done to determine if cefazolin has better outcomes than nafcillin.

In MRSA cases, vancomycin in-hospital mortality rate is similar to the overall 30-day mortality rate and to the Daptomycin in-hospital mortality rate (16.7% vs 5.6%, OR = 3.4, 95%CI 0.36-31.74, P = 0.28). This may support a previous study showing daptomycin to be a good alternate to standard staphylococcal IE therapy [13]. This would be even more important if it had better outcomes as it is currently the only Class IIb recommendation surrounded by Class I recommendations in the MRSA IE group, meaning it is currently not recommended as highly as other anti-MRSA antibiotics [8]. This could also be supported by the similar in-hospital mortality of sole vancomycin or daptomycin use in cases of methicillin-resistant CoNS (6.3% vs 0%, OR = 1.4, 95%CI 0.05-33.80, P = 0.8498). The daptomycin data is limited by having fewer cases. One MRSA case treated with daptomycin did show recurrence, but this was in the setting of only 4 weeks of antibiotics and it is unclear as to whether this recurrence would have happened with the recommended 6 weeks of treatment. Most of the in-hospital mortality in methicillin-resistant staphylococcal species cases were on combinations of broad-spectrum antibiotics. This is likely be due to patients being in poorer health, prompting providers to continue broad-spectrum antibiotics over narrowing.

VGS IE had the lowest mortality. The majority of VGS IE was treated with ceftriaxone which only showed 10% 90-day mortality and this is the choice antibiotic according to AHA guidelines [8]. On the other hand, vancomycin-susceptible enterococcal IE was treated with ampicillin in most cases, either by itself or with a synergistic or non-synergistic antibiotic. In enterococcal cases, ampicillin and vancomycin showed similar in-hospital mortality (16.7% each).

Methicillin susceptible CoNS was also most likely to be treated with vancomycin despite in-vitro susceptibility to other non-broad spectrum antibiotics. These cases showed similar in-hospital mortality using vancomycin alone versus cefazolin (22.2% vs 16.7%, P=0.7928). It may be that providers were more likely to believe CoNS was a culture contaminant and would rather treat broadly or it may be that the patient seemed to be in a poorer condition. Either way, with the reported higher incidences of IE caused by CoNS in the literature, we should consider further narrowing in the event of a culture growing methicillin-sensitive CoNS, especially those sensitive to cefazolin. This could aid in combating antimicrobial resistance and reducing costs.

Synergistic antibiotics, such as gentamicin and rifampin, show a disparate effectiveness. There were a total of 57 cases using synergistic combinations. All cases, with the exception of one, either showed in-hospital mortality (26.3%) or 180-day survival. The outlier had early discontinuation due to adverse effects. In cases that did not have in-hospital mortality, synergistic antibiotic usage varied from 2 weeks to the duration of IE treatment. If in-hospital mortality can be accounted for by provider choice of in patients that were more ill-appearing, this finding may show the role of synergistic antibiotics in long-term survival. Otherwise, the average in-hospital mortality for synergistic combinations is higher than the 30-day mortality of all definite IE cases. It must be noted that gentamicin also has the same ability to damage the kidneys as nafcillin. If synergistic combination reduces mortality, it further supports the guidelines for at least 2 weeks of synergistic combination. But if synergistic combinations increase in-hospital mortality while decreasing long-term mortality, finding the appropriate time to use them would be prudent although difficult.

5. Conclusions

Recurrence was tied to use of less than 6 weeks of antibiotics in cases of staphylococcal IE. Cefazolin had lower in-hospital mortality than nafcillin in cases of methicillin-susceptible IE. Vancomycin showed similar efficacy to cefazolin, daptomycin, and ampicillin in their respective susceptible species. Synergistic combinations should be reviewed further for outcome benefit as it showed either in-hospital mortality or no mortality by 180 days. Randomized control trials need to be held to confirm if antibiotic choice is tied to in-hospital mortality.

Acknowledgements

None.

Statement of Competing Interests

The authors have no competing interests.

List of Abbreviations

IE – infective endocarditis

AHA – American Heart Association

MSSA – methicillin susceptible staphylococcus aureus

MRSA – methicillin resistant staphylococcus aureus

VGS – Viridans group streptococci

CoNS – coagulase negative staphylococcus.

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