National Antimicrobial Guideline (NAG), Ministry of Health Malaysia

ADULT

CARDIOVASCULAR INFECTIONS

In this topic:

3. TREATMENT OF CARDIAC IMPLANTABLE ELECTRONIC DEVICES (CIED) INFECTIONS

1. INFECTIVE ENDOCARDITIS

For additional information, please refer to Ministry of Health CPG for Prevention, Diagnosis and Management of Infective Endocarditis.

1.1 Empirical Treatment (native valve)

Preferred

Ampicillin 12g/day IV (2g q4h)

PLUS

Gentamicin 3mg/kg/day IV q24h, MAY ADD **Cloxacillin 12g/day IV (2g q4h)

Alternative

Antibiotic allergy:

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose

PLUS

Gentamicin 3mg/kg IV q24h

Comments

To adjust antibiotics based on culture and sensitivity. If culture negative, to refer Infectious Disease (ID) physician.

*Refer to Appendix 1 for vancomycin loading dose.

**Cloxacillin: For patients with suspected Staphylococcus aureus infections (such as IVDU or patients with prosthesis) and acute presentation.

Refer to Appendix 3 for antibiotic allergy.

1.2 Empirical Treatment (prosthetic valve)

1.2.1 Empirical Treatment (prosthetic valve);

Early, < 1 year

Preferred

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose

PLUS

Gentamicin 3mg/kg IV q24h

PLUS

**Cefepime 2g IV q8h

PLUS

***Rifampicin 300-450mg PO/IV q12h

Alternative

Comments

*Refer to Appendix 1 for vancomycin loading dose.

**Cefepime is indicated if local epidemiology suggests for Gram-negative rod infections (such as Pseudomonas).

***Rifampicin is only recommended for PVE and it should be started 3-5 days later than vancomycin and gentamicin.

1.2.2 Empirical Treatment (prosthetic valve);

Late, ≥ 1 year

Preferred

Ampicillin 12g/day IV (2g q4h)

PLUS

Gentamicin 3mg/kg IV q24h

PLUS

Cloxacillin 12g/day IV (2g q4h)

Alternative

Antibiotic allergy:

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose

PLUS

Gentamicin 3mg/kg IV q24h

Comments

*Refer to Appendix 1 for vancomycin loading dose.

1.3 Viridans Streptococci & Streptococcus bovis

Refer to organism antimicrobial quick check guide
It is recommended MIC estimation is done for these isolates to facilitate management

1.3.1 Native and Prosthetic Valves - Penicillin-Susceptible Viridans

MIC: ≤ 0.12 μg/mL

Streptococci & Streptococcus bovis

Preferred

Benzylpenicillin 3MU IV q4-6h for 4 weeks (native valves) or 6 weeks (prosthetic valves)

Alternative

Ampicillin 2g IV q4h for 4 weeks (native valves) or 6 weeks (prosthetic valves)

Ceftriaxone 2g IV q24h for 4 weeks (native valves) or 6 weeks (prosthetic valves) (for non-severe hypersensitivity to penicillin)

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for 4 weeks (native valves) or 6 weeks (prosthetic valves) (for severe hypersensitivity to penicillin e.g., anaphylaxis, DRESS etc.)

Comments

For penicillin-susceptible Viridans streptococci, monotherapy with benzylpenicilin, ampicillin or ceftriaxone is adequate.

4 weeks for NVE and 6 weeks for PVE.

*Refer to Appendix 1 for vancomycin loading dose.

Refer to Appendix 3 for antibiotic allergy.

1.3.2 Native and Prosthetic Valves - Penicillin-Relatively Resistant Viridans

MIC: 0.25-2 μg/mL

Streptococci & Streptococcus bovis

Preferred

Benzylpenicillin 4MU IV q4h (total 24 MU/24h) or 24MU IV continuously for 4 weeks (native valves) or 6 weeks (prosthetic valves)

PLUS

*Gentamicin 3mg/kg IV q24h for 2 weeks (native valves and prosthetic valves)

Alternative

Ceftriaxone 2g IV q24h for 4 weeks (native valves) or 6 weeks (prosthetic valves) (for non-severe hypersensitivity to penicillin)

PLUS

*Gentamicin 3mg/kg IV q24h for 2 weeks (native valves and prosthetic valves)

Prosthetic Valve:

**Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for 6 weeks (for severe hypersensitivity to penicillin)

PLUS

*Gentamicin 3mg/kg IV q24h for 2 weeks

Native Valve:

**Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for 4 weeks (for severe hypersensitivity to penicillin)

Comments

*Gentamicin: aim for pre-dose (trough) serum level of < 1 mcg/ml.

**Refer to Appendix 1 for vancomycin loading dose.

Refer to Appendix 3 for antibiotic allergy.

1.3.3 Native and Prosthetic Valves - Penicillin-resistant Viridans

MIC ≥4 µg/ml

Streptococci & Streptococcus bovis

Treat as resistant enterococcal endocarditis - Refer to Section 1.4: Enterococcus

1.3.4 Nutritionally variant streptococci; NVS

(Abiotrophia defective and Granulicatella species, both formerly known as NVS)

Preferred

Ampicillin 2g IV q4h for 6 weeks (native and prosthetic valves)

Benzylpenicillin 4MU IV q4h or 24MU/day as a continuous infusion for 6 weeks(native and prosthetic valves)

PLUS

Gentamicin 1mg/kg IV q8h for 2 weeks (prosthetic valves only)

Alternative

Ceftriaxone 2g IV q24h for 6 weeks (for non-severe hypersensitivity to penicillin; native and prosthetic valves)

PLUS

Gentamicin 1mg/kg IV q8h for 2 weeks

(prosthetic valves only)

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2 g/dose, for 6 weeks (for severe hypersensitivity to penicillin)

PLUS

Gentamicin 1mg/kg IV q8h for 2 weeks(prosthetic valves only)

Comments

Ceftriaxone is preferred if clinically not responding to penicillin.

*Refer to Appendix 1 for vancomycin loading dose.

1.4 Enterococcus

It is recommended that all these isolates are tested for high level resistance (HLR) to gentamicin

1.4.1 Native and Prosthetic Valves Enterococcal Endocarditis

Sensitive to ampicillin and gentamicin

Preferred

Ampicillin 2g IV q4h

PLUS

*Gentamicin 1mg/kg IV q8h

Alternative

Comments

Duration of therapy:

● Symptoms < 3 months and native valve: (4 weeks ampicillin, 2 weeks gentamicin).

● Symptoms > 3 months or prosthetic valves: 6 weeks therapy (6 weeks ampicillin and 2 weeks gentamicin).

*Gentamicin: In order to maximise synergistic effect, administer gentamicin at the same time or temporally close to ampicillin.

Consult ID specialist for enterococcal endocarditis with high level resistance to gentamicin.

1.4.2 Enterococcus - Sensitive to ampicillin and gentamicin

Renal impairment or elderly patients

Preferred

Ampicillin 2g IV q4h for 6 weeks

PLUS

Ceftriaxone 2g IV q12h for 6 weeks

Alternative

Comments

This combination is not active against Enterococcus faecium.

Ceftriaxone should not be used alone for enterococcus infection, as they are intrinsically resistant.

1.4.3 Enterococcus - High level resistance to gentamicin

Sensitive to ampicillin and vancomycin

Preferred

Ampicillin 2g IV q4h for 6 weeks

PLUS

Ceftriaxone 2g IV q12h for 6 weeks

Alternative

Comments

This combination is not active against Enterococcus faecium.

Ceftriaxone should not be used alone for enterococcus infection, as they are intrinsically resistant.

1.4.4 Enterococcus - Resistant to ampicillin and susceptible to aminoglycosides and vancomycin

Preferred

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2 g/dose, for 6 weeks

PLUS

**Gentamicin 1mg/kg IV q8h for 2 weeks

Alternative

Comments

*Refer to Appendix 1 for vancomycin loading dose.

**Gentamicin: aim for pre-dose (trough) serum level of < 1 mcg/ml.

1.5 Staphylococcus aureus

1.5.1 Native valves

Methicillin-Susceptible Staphylococci (MSSA)

Preferred

Left sided endocarditis or complicated right sided endocarditis:

Cloxacillin 2g IV q4h for 4 to 6 weeks

*Right sided endocarditis (tricuspid valve) in uncomplicated endocarditis:

Cloxacillin 2g IV in q4h for 2 to 4 weeks

Alternative

Antibiotic allergy:

Severe hypersensitivity to penicillin:

**Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for 4 to 6 weeks

For non-severe hypersensitivity:

Cefazolin 2g IV q8h for 4 to 6 weeks

Comments

*2 weeks’ regime is sufficient for right sided IE provided the patient fulfils all the following criteria (uncomplicated IE):

● MSSA

● Absence of associated prosthetic valve or left sided valve infection

● Good response to treatment

● Absence of metastatic sites of infection or empyema

● Absence of cardiac and extracardiac complications

● Vegetation < 10 mm

●Absence of severe immuno-suppression (< 200 CD4 cells/ml) with or without Acquired Immune Deficiency Syndrome (AIDS)

**Refer to Appendix 1 for vancomycin loading dose.

1.5.2 Prosthetic Valves

Methicillin-Susceptible Staphylococci (MSSA)

Preferred

Cloxacillin 2g IV in q4h for ≥ 6 weeks

PLUS

Gentamicin 1mg/kg IM/IV q8h for 2 weeks

PLUS

*Rifampicin 300-450mg PO q12h for ≥ 6 weeks

Alternative

Regimen for β-lactam allergic patients, replace cloxacillin with the following:

Severe hypersensitivity to penicillin:

**Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for at least 6 weeks

PLUS

Gentamicin 1mg/kg IM/IV q8h for 2 weeks

PLUS

*Rifampicn 300-450mg PO q12h for ≥ 6 weeks

For non-severe hypersensitivity:

Cefazolin 2g IV q8h for at least 6 weeks

PLUS

Gentamicin 1mg/kg IM/IV q8h for 2 weeks

PLUS

*Rifampicn 300-450mg PO q12h for ≥ 6 weeks

Comments

*Rifampicin: To avoid the development of resistance, it should be started after 3-5 days of effective initial cloxacillin therapy and/or once the bacteraemia has been cleared.

**Refer to Appendix 1 for vancomycin loading dose.

1.5.3 Native Valves

Methicillin-Resistant Staphylococci (MRSA)

Preferred

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for 4 to 6 weeks

Alternative

**Daptomycin 10mg/kg IV q24h for 4 to 6 weeks

Comments

*Refer to Appendix 1 for vancomycin loading dose.

**Daptomycin: Daptomycin might be more effective in IE caused by MRSA with higher MIC (above 1 mg/L) to vancomycin based on case-control studies. However, risk for MIC creep against daptomycin may be present in those exposed to vancomycin.

1.5.4 Prosthetic Valves

Methicillin-Resistant Staphylococci (MRSA)

Preferred

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose, for ≥ 6 weeks

PLUS

Gentamicin 1mg/kg IV q8h for 2 weeks

PLUS

**Rifampicin 300-450mg PO q12h for ≥ 6 weeks*

Alternative

Comments

**Refer to Appendix 1 for vancomycin loading dose.

**Rifampicin: To avoid the development of resistance, it should be started after 3-5 days of effective initial vancomycin therapy and/or once the bacteraemia has been cleared.

1.6 HACEK Microorganisms (Haemophilus parainfluenzae, Aggregatibacter species, Cardiobacterium species, Eikenella corrodens, and Kingella species)

1.6.1 Native and Prosthetic valves

Preferred

Ceftriaxone 2g IV q24h for 4 weeks (native valve) or 6 weeks (prosthetic valve)

Alternative

Ampicillin/sulbactam 3g IV q6h for 4 weeks (native valve) or 6 weeks (prosthetic valve)

Ciprofloxacin 400mg IV or 500mg PO q12h for 4 weeks (native valve) or 6 weeks (prosthetic valve)

Comments

HACEK-group bacilli produce beta lactamases; definitive treatment should be adjusted based on the cultures.

1.7 Therapy for Candida Endocarditis (Native and Prosthetic valve)

1.7.1 Candida Endocarditis (native and prosthetic valve)

Preferred

Initial therapy:

Amphotericin B deoxycholate 0.6-1mg/ kg IV q24h for at least 6 weeks after surgery

Liposomal amphotericin B 3-5mg/kg IV q24h for at least 6 weeks after surgery

MAY ADD

*Flucytosine 25mg/kg PO q6h for at least 6 weeks after surgery

Step down therapy:

Fluconazole 400-800mg (6-12mg/kg) PO q24h for susceptible microorganism in stable patients with negative blood cultures (clearance of Candida from blood stream)

Alternative

Initial therapy:

High dose of echinocandins are recommended. Options include:

● IV caspofungin 150mg daily OR

● IV micafungin 150mg daily OR

● IV anidulafungin 200mg daily

Comments

Valve replacement surgery is mandatory.

Continue therapy for 6 weeks after surgical replacement or longer in patient with perivalvular abscess.

If prosthetic valve cannot be replaced, lifelong suppressive therapy with fluconazole 400mg (6mg/kg) daily is recommended.

The duration of therapy will depend on patient response and surgical intervention.

Patients with Candida IE should be referred to ID physician.

*Flucytosine: For synergistic effect. Causes dose-related marrow toxicity. Avoid using in patients with renal failure.

1.8 Therapy for Culture-Negative Endocarditis

Consultation with ID specialist is needed

1.8.1 Brucella spp.

Preferred

Doxycycline 100mg PO q12h

PLUS

Rifampicin 300-600mg PO q24h

PLUS

Streptomycin 15mg/kg IM q24h

(For first 2-4 weeks only)

Gentamicin 5mg/kg IV q24h

(For first 2-4 weeks only)

Alternative

Comments

Duration: 3-6 months depending on clinical response.

1.8.2 Coxiella burnetii (agent of Q fever)

Preferred

Doxycycline 100mg PO q12h

PLUS

Hydroxychloroquine 600mg PO q24h or 200mg PO q8h

Alternative

Comments

Duration: 18-24 months depending on clinical and serological response.

1.8.3 Bartonella spp.

Preferred

Doxycycline 100mg PO q12h for 6 weeks

PLUS

Gentamicin 3mg/kg IV q24h for 2 weeks

Alternative

Comments

Footnotes for antibiotic treatment of endocarditis:

Vancomycin: aim for AUC24/MIC of 400–600 (preferred, if stable renal functions), or serum trough level of 15–20mg/L (10–14 µmol/L) for both adults and paediatrics. Vancomycin dose should be adjusted in patients with renal impairment. Refer to Appendix 2 (Antibiotic Dosage in Adult with Impaired Renal Function) for dosing of adult patients with renal impairment, obese patients and monitoring recommendations.
Gentamicin for gram positive synergy dosing: use adjusted body weight for obese patients. Monitor gentamicin levels at least weekly. For conventional dosing (1mg/kg/dose q8h), aim for gentamicin peak level (taken 30 mins after completion of a 30-minute infusion OR one hour after bolus injection) of 6–10 µmol/L (3-5 mcg/mL) and trough level (within 30 mins before the next dose) of < 2 µmol/L (< 1 mcg/mL). For gentamicin 3mg/kg q24h dosing, monitor trough levels only. Refer to Appendix 1 (Clinical Pharmacokinetic Guidelines (Aminoglycosides & Vancomycin).
There should be a high tendency for stopping gentamicin in patients with deteriorating renal function or other signs of toxicity.
If there is high level of gentamicin resistance, ampicillin or vancomycin will need to be continued for ≥ 6 weeks. Referral to an ID physician is recommended if high level gentamicin resistance is present.
Rifampicin should always be used in combination with another effective antistaphylococcal drug (ideally two active agents, i.e. cloxacillin) to minimize risk of resistance. Rifampicin increases hepatic clearance of warfarin and other drugs.
In selected patients of native valve endocarditis with a stable clinical course, it may be possible to switch from IV to oral antibiotics after careful assessment by both cardiologist and ID physician. If feasible, outpatient parenteral antimicrobial therapy (OPAT) can also be considered in this subset of patients.

2. CATHETER RELATED INFECTIONS

2.1 Non- tunneled central venous catheter (subclavian, internal jugular, femoral)

Peripherally inserted central catheter

Preferred

Cloxacillin 2g IV q4-6 h

Cefazolin 2g IV q8h

MAY ADD

Ceftazidime 2g IV q8h

(For gram negative coverage if critically ill, OR patients with femoral lines)

Alternative

If patient has risk factor for MRSA :

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose

If local epidemiology shows high ESBL prevalence AND if patient severely ill (E.g.: hypotension, multiorgan failure):

Meropenem 2g IV q8h

Imipenem 1g IV q8h

Comments

BOTH peripheral blood C&S and cultures from the central line must be obtained if CRBSI is suspected.

Change antibiotic to targeted therapy once cultures available.

Antibiotic of choice depends on local epidemiology of CRBSI and guided by antibiogram results.

Catheter removal is recommended.

Duration of antibiotics depends on organisms, catheter removal, and presence of complications. Suggest ID consultation.

**Refer to Appendix 1 for vancomycin loading dose.

2.2 Tunnel type indwelling venous catheters and ports (Broviac, Hickman)

Haemodialysis catheter

Preferred

Cloxacillin 2g IV q4-6h

Cefazolin 2g IV q8h

PLUS

Ceftazidime 2g IV q8h

Alternative

If patient has risk factor for MRSA:

*Vancomycin 15-20mg/kg (actual body weight) IV q8-12h; not to exceed 2g/dose

PLUS

Ceftazidime 2g IV q8h

Comments

Adjust dose according to renal function.

Catheter removal is recommended in the following:

● Septic shock

● Septic phlebitis

● Endocarditis, or metastatic infections

● Persistent positive culture > 72 hours

● Pathogens: S.aureus, P.aeruginosa, fungi, mycobacteria

● Tunnel infections

● Port abscess

Duration of antibiotics depends on organisms, catheter removal, and presence of complications. Suggest ID consultation.

*Refer to Appendix 1 for vancomycin loading dose.

3. TREATMENT OF CARDIAC IMPLANTABLE ELECTRONIC DEVICES (CIED) INFECTIONS

3.1 Cardiac Implantable Electronic Devices (CIED) Infections

(E.g.: pacemaker infection)

Refer to Ministry of Health Malaysia’s CPG for the Prevention, Diagnosis & Management of Infective Endocarditis 2017 Section 7.4.

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