Antibiotics issues in infective endocarditis.pdf

Patient
Name WHAI
Age 63
Gender M
Race Malay
DOA 18/2/24 -> T/I 9A 14/3/24
Chief Complaint left shoulder pain which radiates to right shoulder
History of Presenting Illness left shoulder pain 1/52
generalized weakness
fever
lethargy

Past Medical History DM
HPT
IHD - 3VD (COROS 2020) , refused CABG
Valvular heart disease - severe MR, moderate TR
CKD
Past Medication History T Vastarel MR 35mg OD
T Bisoprolol 1.25mg OD
s/c Insugen R 20u TDS
s/c Insugen N 20u ON
T Lasix 40mg OD
T Cardiprin 100mg OD
T Amlodipine 10mg OD
T Atozet 1/1 OD
T Ferrous fumarate 200mg OD
Allergies NKDA
Social History ADL Independent
Diagnosis 1. Disseminated MSSA bacteremia with severe IE
and distant metastatic infection to lung and
complicated with (Resolved) extensive
multiloculated abscess at left axilla,upper arm
region and sub-coracoid

Diagnosis
1.Disseminated MSSA bacteremia with severe IE and distant
metastatic infection to lung and complicated with (Resolved)
extensive multiloculated abscess at left axilla, upper arm region
and sub-coracoid.
2.Non-oligouric AKI on CKD secondary to 1 with metabolic
acidosis.
3.NCNC anemia.
4.Tinea pedis over right foot.
5.Hypoalbuminemia secondary chronic illness/sepsis.
6.Sacral sore grade (II).

Review of System
BP (mmHg) 106/53
PR (bpm) 82
RR (breath/min) 33
Temp (°C) 36.2
SpO2 (%) 99% under NpO2 3L
RBS 14
Lungs Clear
CVS Pansystolic murmur
PA Soft non tender
General Alert,
Lethargic,
Warm peripheries,
Good PV,
CRT< 2 secs.

Case Timeline
16/2/24
•Shoulder pain
•GP > KPJ Seremban
•given pain relievers
•advised to go to IJN in
view of patient already
under IJN follow up
KPJ Ix:
•Xray Left Shoulder (KPJ) -
normal
•Xray Cervical Spine (KPJ) -
suggestive of changes of
cervical spondylosis
18/2/24 @ IJN (1am)
•Tachypnic and lethargic
looking.
•Had temp 38.8.
•VBG acidotic with
glucose 31.6 + ketone: 3
•Given IV Rocephine 2g
stat + T paracetamol 1g
stat
•Complete 1.5L NS bolus
•Started IVI sliding scale
as well
•Planned for referral to
HKL : Patient took AOR
discharge to come here
due to logistic issue
18/2/24 @ HASA
(11am)
•Patient admitted to ICU
HASA with on HFNC and
subsequently manage to
wean down to nasal
prong O2.
•1/ Septic shock 2nd to
?CAP
•2/ DKA 2nd to sepsis
•CXR: left LZ consolidation
•IV Rocephin 2g OD -> 1g
BD

ICU Progress
18/2
• CTA Thorax and abdomen:
• No evidence of aortic dissection or
aneurysm.
• Multiple lung nodules of varying sizes
with larger peripheral mass-like
opacity in the left apex.
• DDx include malignancy and
infection.
• As the patient is currently admitted
for pneumonia, suggest for repeat CT
after treatment completion to
reassess.
20/2
• Respi: TRO PTB
• CXR: patchy opacity bilateral lung
fields
• CTA Thorax: multiple lung nodules -
irregular, and consolidations, with
surrounding GGO.
• Sputum AFB x1x2: no AFB
• Sputum MTB gene Xpert: not detected
21/2
• AMS rounds - informed that blood C+S
(Aerobe) grew Staph Aureus (pending
sensitivity).
• Currently on IV Rocephine -> planned
to treat as IE and changed antibiotics to
cefazolin (patient risk of overload/ on
HD).
• Duration will be at least 6-8 weeks
depending on source / culture
clearance.
• ECHO:
• Oscillating mass at PMVL (Possible
IE), Prolapse AMVL with severe MR.
• No need TOE in view of culture
positive / mass evidenced on ECHO:
fulfilled criteria for IE (2 major)
• LVEF is 51%

ICU Progress
23/12
• Dr Azlina (ID)
• Treat as IE, no need Genta as this is
native valve.
• Cont Cefazolin for now (patient on
regular HD with risk of overload).
• Need to find other sources of MSSA -
Suggest to get ortho input on
shoulder joint imaging/ aspiration
(ensuring not septic arthirtis in view of
initial complain was bilateral
shoulder pain with persistent
elevated wcc/crp)
• Nephro suggest to change to
Cloxacillin.
23/12
• ECHO:
• Normal left ventricular size with
normal systolic function. Calculated
LVEF is 60% (method: HM Biplane)
• No gross regional wall motion
abnormality seen.
• Thicken and calcific mitral valve
leaflets measuring vegetation 1.8cm x
0.5cm. Severe MR on CFM. Systolic
reversal pulmonary venous inflow
pattern is present.
• Vegetation seen at tricuspid valve
measuring 1.4cm x 0.7cm. Moderate
TR on CFM. Regurgitation jet is
eccentric jet. (TR Vmax: 4.27m/s, TR
max PG: 73mmHg).
24/12
• T/O Ward 8C

8C Progress
26/2
•ID plan
•To refer CTS
•Patient already fulfilled the
indication for urgent surgery.
•Big IE: 1.4-1.8cm
•With high risk to embolise
•Admitted for HF 2nd to Severe
MR/TR (easily to tipped off).
•Counselled patient - keen to
hear first from CVTS team on
further management.
27/2
•USG Left shoulder:
•Findings are of an extensive large
multiloculated collection in the
left axilla, extending to the sub-
coracoid and left upper arm
region.
27/2
•T/O to Cardiothoracic in Sg Buloh.
•IV Cloxacilin 2g 4hourly.
•Duration: Min 6 weeks .
•Up to 3 months if involved spine
(to sort backpain issues with
appropriate imaging to assess
paravertebral collection or
spondylodiscitis).
•Nephro: To allow renal recovery,
aim I/O to slight positive.

CTC Progress
28/2
• Can proceed for
operation but not
now, to settle
issue with
infection first.
5/3
• Left shoulder C+S
pus aspirate was
taken.
• Rt PICC inserted.
12/3
• Spoken to patient
regarding plan for
operation.
• He is not keen
waiting for wife to
come.
• Not keen to
ambulate.
Encouraged to
ambulate.
13/3
• Not For surgical
intervention,
Discharge CVTS.
• Update ID, for ID
to take over.
• Refer psychiatry -
to update back if
patient transfer to
HASA.
14/3
• T/O HASA ward 9A

9A Progress
14/3
• Cont IV Cloxacillin 2g 4hourly
• Ortho to review for shoulder abscess
21/3
• Discharged ortho
• Planned for 6 weeks from culture
clearance tentatively until 24/4/24

Lab Investigation
18/2 20/2 21/2 26/2 6/3 15/3 18/3 21/3 25/3
WBC 26.2 22.6 22.6 20.6 10.14 9.2 10.1 8.8 6.9
Hb 8.7 8.7 8.8 7.2 7.3 7.9 9 9.2 7.4
Plt 284 203 204 284 356 301 259 296 188
CRP 249.2 195.7 107.4 61.5 16.4 30.4 20.1
Urea 38.6 35.7 28.8 25.2 23.6 19.3 20.2 22.6 16.2
K 5.3 4.5 4.4 4.6 5 3.8 4.4 4.6 4
SCr 446 376 336 393 334 311 340 327 202
eGFR 11 14 16 19 16 17 16 16 29
Albumin 25.3 20.4 21.8 21.6 22 25.1 24.8 25.8 25.5
ALP 99 150 268 167 101 137 186 133
ALT 22.3 27.3 32.6 5.9 5.9 8.9 11.8 11.4
NT-proBNP >35000

SBP & HR
0
20
40
60
80
100
120
140
SBP HR

Temperature
36
36.2
36.4
36.6
36.8
37
37.2
37.4
37.6
Temp
Temp

Culture and Sensitivity
Date Source Microorganism Sensitivity
18/2 Blood MSSA Genta/Oxacillin
21/2 Blood:
1st site
2nd site
3rd site
MSSA
MSSA
MSSA
23/2 Blood:
Red
Blue
Peripheral
NOG
NOG
GPC in cluster
5/3 Pus aspirate
(Lt shoulder)
MSSA
5/3 Respi panel Staph DNA detected
14/3 Blood:
Peripheral
Central
NOG

Meds in ward
Start Stop Indication
IV Ceftriaxone 1g BD 18/2 21/2 CAP
IV Cefazolin 1g BD 21/2 22/2 IE
IV Cloxacillin 2g 4H 23/2 IE
T. Cardiprin 1 tab OD 14/3 IHD
T. Atorvastatin 14/3 IHD
T. Frusemide 40mg OD 14/3 Diuretic
S/C Enoxaparin 40mg OD → 20mg OD 14/3 VTE prophylaxis
T. Pantoprazole 40mg OD 14/3 Stress ulcer prophylaxis
T. Ferrous fumarate 400mg OD 14/3 Hematinics
T. Folic acid 5mg OD 14/3 Hematinics
T. Vitamin B Complex 1 tab OD 14/3 Hematinics
T. Paracetamol 1g QID 14/3 Analgesic
C. Tramadol 50mg BD 17/3 Analgesic

PCI
• Cloxacillin vs Cefazolin in fluid restricted patients
• OPAT
• Ceftriaxone use in hypoalbuminemia
• Enoxaparin dose in renally impaired patients

Objective
• Temp: 38.8°C
• Blood C+S: MSSA
• ECHO findings:
• Thicken and calcific mitral valve leaflets measuring vegetation 1.8cm x
0.5cm
• Vegetation seen at tricuspid valve measuring 1.4cm x 0.7cm

PCI
• Cloxacillin vs Cefazolin in fluid
restricted patients
• OPAT

Assessment
Infective Endocarditis

Diagnosis (2023 Duke-ISCVID IE Criteria)

2023 Duke-
ISCVID IE
Criteria
Patient has 2 major:
1. Positive blood culture
2. Echocardiography
showing vegetation

Empirical antibiotic for MSSA bacteremia
• Cloxacillin/cefazolin administration is associated with lower
mortality rates than other beta-lactams, including
amoxicillin/clavulanic acid or ampicillin/sulbactam.
Paul, M., Zemer-Wassercug, N., Talker, O., Lishtzinsky, Y., Lev, B., Samra, Z., Leibovici, L., & Bishara, J. (2011). Are all beta-lactams similarly effective in the treatment of methicillin-
sensitive Staphylococcus aureus bacteraemia? Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases,
17(10), 1581–1586. https://doi.org/10.1111/j.1469-0691.2010.03425.x

MSSA IE Choice of Antibiotic
IDSA Infective Endocarditis in Adults 2015
Malaysia Clinical Practice
Guidelines For The Prevention,
Diagnosis & Management of
Infective Endocarditis 2017.
2023 ESC Guidelines for the Management of Endocarditis

Concern in ROF patients
• According to Hospital UiTM Antibiotic Reconstitution and Dilution Protocol 2020, the
maximum concentration of IV Cloxacillin infusion is 2mg/mL. A dose of 2g every 4 hours
equals to 6L of fluids daily.
• Dilution of Cloxacillin at 250 mg/mL using sterile water for injection (SWFI) will result in a
hypertonic solution with the osmolality of around 550 mOsmol/L, allowing for intravenous
administration 1. Hence, Cloxacillin may be diluted using 50mL of SWFI which will result in
around 300mL of fluid volume per day.
• Hypertonic solution has been shown to induce pain upon administration2 and patient need
to endure this 6 times per day due to every 4 hours dosing.
• In contrast, IV Cefazolin 1g BD will only results in 100mL of fluid volume per day and
incidence of pain may be greatly due to reduced frequency.
1. Loeuille, G., D’Huart, E., Vigneron, J., Nisse, Y.-E., Beiler, B., Polo, C., Ayari, G., Sacrez, M., Demoré, B., & Charmillon, A. (2022). Stability Studies of 16 Antibiotics for Continuous
Infusion in Intensive Care Units and for Performing Outpatient Parenteral Antimicrobial Therapy. Antibiotics, 11(4), 458. https://doi.org/10.3390/antibiotics11040458.
2. Wang, W. (2015). Tolerability of hypertonic injectables. International Journal of Pharmaceutics, 490(1–2), 308–315. https://doi.org/10.1016/j.ijpharm.2015.05.069

Cefazolin Advantage
• This systematic review found that the use of cefazolin in both in-patients and outpatients is
associated with low risks of nephrotoxicity, hepatotoxicity, and discontinuation due ADRs
compared to antistaphylococcal penicillins.
• Some of the major benefits of cefazolin are its association with significant reductions in
nephrotoxicity and hepatotoxicity, lower likelihoods of phlebitis and hypersensitivity
reactions, and discontinuation due to side effects.
• Subgroup analysis showed that the reduced nephrotoxicity with cefazolin was significant in
comparisons with both nafcillin and oxacillin.
• The statistically significant differences for hepatotoxicity persisted with subgroup analysis of
cefazolin compared to either nafcillin or oxacillin.
Eljaaly, K., Alshehri, S., & Erstad, B. L. (2018). Systematic Review and Meta-analysis of the Safety of Antistaphylococcal Penicillins Compared to Cefazolin. Antimicrobial Agents and
Chemotherapy, 62(4), e01816-17. https://doi.org/10.1128/AAC.01816-17

Outpatient Parenteral Antibiotic Therapy
(OPAT)
• Outpatient parenteral or oral antibiotic treatment should be considered in patients with left-
sided IE caused by Streptococcus spp., E. faecalis, S. aureus, or CoNS who were receiving
appropriate i.v. antibiotic treatment for at least 10 days (or at least 7 days after cardiac
surgery), are clinically stable, and who do not show signs of abscess formation or valve
abnormalities requiring surgery on TOE1.
• The major benefits of OPAT are the reduction or avoidance of hospital stays, the reduction in
nosocomial infections and hospital-related conditions, significant cost savings, and
improved quality of life for the patient2-3.
• OPAT was useful in reducing bed occupancy rate and hospital associated infection. Patients
also are happy with the service4.
1. Pries-Heje, M. M., Wiingaard, C., Ihlemann, N., Gill, S. U., Bruun, N. E., Elming, H., Povlsen, J. A., Madsen, T., Jensen, K. T., Fursted, K., Schultz, M., Østergaard, L., Christensen, J. J.,
Christiansen, U., Rosenvinge, F., Helweg-Larsen, J., Fosbøl, E. L., Køber, L., Torp-Pedersen, C., … Bundgaard, H. (2022). Five-Year Outcomes of the Partial Oral Treatment of
Endocarditis (POET) Trial. New England Journal of Medicine, 386(6), 601–602. https://doi.org/10.1056/NEJMc2114046.
2. Norris, A. H., Shrestha, N. K., Allison, G. M., Keller, S. C., Bhavan, K. P., Zurlo, J. J., Hersh, A. L., Gorski, L. A., Bosso, J. A., Rathore, M. H., Arrieta, A., Petrak, R. M., Shah, A., Brown, R.
B., Knight, S. L., & Umscheid, C. A. (2019). 2018 Infectious Diseases Society of America Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial
Therapya. Clinical Infectious Diseases, 68(1), e1–e35. https://doi.org/10.1093/cid/ciy745.
3. Gilchrist, M., & Seaton, R. A. (2015). Outpatient parenteral antimicrobial therapy and antimicrobial stewardship: Challenges and checklists. Journal of Antimicrobial Chemotherapy,
70(4), 965–970. https://doi.org/10.1093/jac/dku517.
4. Tan, G. J., & Ponnampalavanar, S. (2023). Out-patient antimicrobial therapy unit in Universiti Malaya: the experience of a single tertiary centre in the klang valley. International Journal
of Infectious Diseases, 130, S70. https://doi.org/10.1016/j.ijid.2023.04.175.

Antibiotic-Induced Neutropenia in OPAT
Lam, P. W., Leis, J. A., & Daneman, N. (2023). Antibiotic-Induced Neutropenia in Patients Receiving Outpatient Parenteral Antibiotic Therapy: A Retrospective Cohort Study.
Antimicrobial Agents and Chemotherapy, 67(3), e01596-22. https://doi.org/10.1128/aac.01596-22
Of the 45 cases where a sole cause was
identified, the three most common
intravenous antibiotic culprits were
vancomycin (21/541; 3.9%), ceftriaxone
(10/490; 2.0%), and cloxacillin (2/103;
1.9%).

Plan
PCI Recommendation Outcome
Cefazolin was change to
Cloxacillin
Cefazolin is a safer alternative
with reduced fluid requirement
Cloxacillin was continued

PCI • Ceftriaxone use in
hypoalbuminemia

Assessment
Range 18/2 20/2 21/2
IV Ceftriaxone 2g STAT & 1g BD x x x
SCr 64-122 umol/L 446 376 336
eGFR 11 14 16
Albumin 35-50 g/L 25.3 20.4 21.8

Ceftriaxone in hypoalbuminaemia
• Ceftriaxone's pharmacokinetic profile displays high protein binding (83%–96%)1.
• Higher free-drug concentrations may lead to an increase in volume of distribution and drug
clearance, which could result in suboptimal time of concentrations above the minimum
inhibitory concentration (MIC) and, thus, increased risk for treatment failure1.
• Significantly increased Vd and CL in patients with hypoalbuminaemia, leading to failure to
attain the pharmacodynamic targets for therapy in some of the patients2.
• Critically ill patients may be subject to higher incidence of treatment failure in the presence
of hypoalbuminemia. More aggressive dosing strategies or selection of alternative agents,
when possible, may be preferred in this population1.
1. Stoeckel, K., McNamara, P. J., Brandt, R., Plozza-Nottebrock, H., & Ziegler, W. H. (1981). Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics. Clinical
Pharmacology and Therapeutics, 29(5), 650–657. https://doi.org/10.1038/clpt.1981.90.
2. Joynt, G. M., Lipman, J., Gomersall, C. D., Young, R. J., Wong, E. L., & Gin, T. (2001). The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. The Journal of
Antimicrobial Chemotherapy, 47(4), 421–429. https://doi.org/10.1093/jac/47.4.421.

Ceftriaxone clearance in renal impairment
• Shorter dosing interval or with administration by infusion, would be required to ensure
adequate ceftriaxone concentrations over the full dosing interval in patients with severe
sepsis and normal renal function1.
• Ceftriaxone CL in critically ill patients is primarily dependent on renal CL,2 and the increased
Vss and decreased CL result in a markedly prolonged t½.
• This finding is clinically important as renal dysfunction may result in unsuspected
accumulation in critically ill patients1.
• The determination of creatinine clearance, preferably by direct measurement, and not simply
observation of blood creatinine concentrations is needed. A dose reduction of one-third in
patients with ≥50% reduction in creatinine CL, and a reduction of two-thirds in patients who
are anuric has been suggested2.
1. Joynt, G. M., Lipman, J., Gomersall, C. D., Young, R. J., Wong, E. L., & Gin, T. (2001). The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. The Journal of
Antimicrobial Chemotherapy, 47(4), 421–429. https://doi.org/10.1093/jac/47.4.421.
2. Heinemeyer, G., Link, J., Weber, W., Meschede, V., & Roots, I. (1990). Clearance of ceftriaxone in critical care patients with acute renal failure. Intensive Care Medicine, 16(7), 448–
453. https://doi.org/10.1007/BF01711224.

Plan
Ceftriaxone dose in
hypoalbuminaemia.
Use a more frequent dosing. Ceftriaxone is change from 2g OD
to 1g BD.

PCI • Enoxaparin dose in renally
impaired patient

Assessment
Range 18/2 20/2 21/2 14/3 15/3
S/C Enoxaparin 40mg OD x x x x
S/C Enoxaparin 20mg OD x
SCr 64-122
umol/L
446 376 336 358 311
eGFR 11 14 16 15 17

Assessment:
Enoxaparin dose recommendation
• Thromboprophylaxis dose recommendation for CrCl of <30 mL/minute is 20mg OD.
• Resulted in a 5.6% incidence of VTE, which is similar to the previously published acceptable
incidence of VTE in patients with normal renal function receiving enoxaparin 40 mg SC daily.
• The incidence of major bleeding events was 10%, which is lower than that previously
published in the literature.
Karaoui, L. R., Tawil, S., Salameh, P., & Chamoun, N. (2019). Enoxaparin 20 mg for thromboprophylaxis in severe renal impairment. The Journal of International Medical Research, 47(1),
225–234. https://doi.org/10.1177/0300060518799896

Plan
S/C Enoxaparin dose is 40mg OD
for VTE prophylaxis
To reduce to 20mg OD to reduce
risk of major bleeding
S/C Enoxaparin dose reduced to
20mg OD

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