Treatment

Empiric Pharmacological Therapy

• In uncomplicated cases, antibiotics may be postponed up to 48 hr until results of initial BCs are known
• Empiric antibiotic treatment should be initiated immediately after 3 BCs have been taken in cases complicated by:
  • Sepsis, severe valvular dysfunction, conduction disturbances or embolic events
• Empiric therapy should include use of agents that are effective against streptococci, staphylococci & enterococci
• Subsequent changes in the antibiotic regimen should be based on the results of culture & sensitivity testing

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Pathogen-Specific Pharmacological Therapy

Streptococcal IE

• Penicillin, Amoxicillin or Ceftriaxone
  • These agents when used alone x 4 wk obtain high bacteriologic cure rates
  • 4 wk of monotherapy has the advantage of avoiding the potential ototoxic or nephrotoxic effects of Gentamicin
  • Ceftriaxone has the advantage of once-daily dosing
• (Penicillin, Amoxicillin or Ceftriaxone) plus Gentamicin or Netilmicin for the 1st 2 wk
  • When given in selected patients, gives similar cure rates to 4 wk of monotherapy
  • Once-daily dosing of Gentamicin may be used
• Vancomycin
  • Reserved for patients who are unable to tolerate Penicillin or Ceftriaxone
• Teicoplanin
  • Alternative drug that may be used once daily to treat streptococcal IE in penicillin-allergic patients
  • Inadequate doses can result in treatment failure
  • Steady-state serum is achieved only after 1 wk

• (Penicillin or Amoxicillin) x 4 wk plus Gentamicin x 2 wk should be given
  • Once-daily dosing of Gentamicin may be used
• Vancomycin
  • Reserved for patients who are unable to tolerate Penicillin or Amoxicillin

• Should be treated w/ regimens recommended for enterococcal endocarditis

• All enterococci causing IE should be tested for antimicrobial susceptibility to determine optimal therapy
  • In vitro susceptibility to Penicillin & Vancomycin along w/ high-level resistance to Gentamicin & Streptomycin should be tested
• Successful treatment requires the synergistic action of Penicillin, Ampicillin or Vancomycin w/ either Gentamicin or Streptomycin
• Multi-daily dosing should be used for the aminoglycosides

• Treatment duration for 4-6 wk
• For enterococcal strains susceptible to Penicillin:
  • Bactericidal activity of Ampicillin is 2x that of Penicillin against E faecalis
  • Penicillin may be preferred because higher serum conc of Penicillin will compensate for the difference & because it is important to avoid Ampicillin rash during long-term treatment

• These enterococci are usually resistant to all other aminoglycosides except Streptomycin
• Combination therapy w/ Ampicillin & Ceftriaxone should also be considered

• Should be reserved for patients allergic to Penicillin or in Penicillin-resistant strains
• Glycopeptides need to be combined w/ aminoglycosides since they are not usually bactericidal against enterococci

• Consultation w/ microbiologist/infectious disease specialist is recommended

• Appropriate antibiotic therapy should be started promptly to improve overall prognosis
• S aureus in non-IVDA usually involves the left-sided cardiac valves
• Factor in determining antibiotic treatment is whether the organism is sensitive to Methicillin
• Gentamicin in the following regimens should be administered in multiple daily dosing at 3 mg/kg/day

• <10% of IE strains of S aureus are susceptible to Penicillin
• Penicillin may be used x 4 wk combined w/ Gentamicin for the 1st 3-5 days of therapy

• Antistaphylococcal Penicillin w/ or w/o Gentamicin
  • Antistaphylococcal Penicillin is the treatment of choice
  • Adding Gentamicin for the 1st 3-5 days may protect the infected valve from further damage & may decrease the duration of bacteremia which may result in faster defervescence
• Antistaphylococcal Penicillin + Fusidic acid
  • This combination may be an option for Fusidic acid-sensitive strains
• Cephalosporin (1st Generation) w/ or w/o Gentamicin
  • May be used for the treatment of MSSA endocarditis when patient has non-anaphylactoid Penicillin allergy
• 4 wk of therapy w/ antistaphylococcal Penicillin or cephalosporin may be used for uncomplicated infection
  • Complicated IE eg abscess formation or septic metastatic complications should be treated x 6 wk
• Vancomycin + Gentamicin
  • Reserved for patients allergic to beta-lactams; there are recent reports of suboptimal outcomes w/ Vancomycin therapy for serious S aureus infections
  • Vancomycin + Gentamicin x 3-5 days in MSSA is associated w/ faster clearing of bacteremia

• Vancomycin
  • Treatment of choice in MRSA
  • Treatment duration for 4-6 wk
  • Addition of Gentamicin or Rifampin to Vancomycin is not recommended for native valve IE
• Linezolid or (Co-trimoxazole, Doxycycline or Minocycline w/ or w/o Rifampicin)
  • These agents may be an option in patients who are intolerant of Vancomycin or fail therapy
  • Data on clinical efficacy is limited compared to other agents

• (Antistaphylococcal penicillin + Rifampicin) x 6-8 wk, + Gentamicin for the 1st 2 wk of treatment
  • S aureus IE in PVE patients has a high mortality rate & surgery should be combined w/ antimicrobial therapy
  • Though in vitro & clinical studies are lacking, it is accepted that this 3-drug combination is used to treat MSSA in PVE
  • Cefazolin may be substituted for those w/ non-anaphylactoid-type Penicillin allergy
• Vancomycin + Rifampicin + Gentamicin
  • Used for MRSA & coagulase-negative staphylococci
• Quinolone
  • May be used in combination w/ Vancomycin & Rifampicin when the causative microorganism is resistant to all aminoglycosides

IVDA

• 2 wk antistaphylococcal penicillin + Gentamicin
  • Should be reserved for uncomplicated cases
• 4 wk oral Ciprofloxacin + Rifampicin
  • Can be used in uncomplicated cases when compliance can be monitored
  • Though oral Ciprofloxacin & Rifampicin combination has been shown to be effective in IV drug users, currently, oral treatment for IE cannot be recommended

• Patient should be treated w/ standard 4-6 wk treatment if:
  • After >96 hr patient fails to show clinical or microbiological response to antibiotic therapy, CHF, vegetations >20 mm, acute resp failure, septic metastatic foci outside the lungs, extra-cardiac complications (eg renal failure) or IVDA w/ severe immunosuppression w/ or w/o AIDS

• Treat as in non-addict

• HACEK group may not be identified in BCs for a wk or longer & empiric antibiotics may be necessary while awaiting culture results
• Beta-lactamase-producing strains of HACEK are appearing w/ increased frequency
  • Difficult to perform antimicrobial susceptibility tests on HACEK organisms; therefore, these should now be considered Ampicillin resistant & Ampicillin should not be used for treatment
• Ceftriaxone
  • Single-agent use is justified by its excellent pharmacokinetic profile
  • Effective against both β-lactamase-producing & non-β-lactamase-producing strains of the HACEK group
  • May be administered alone x 4 wk in NVE & x 6 wk in PVE
  • Alternative: Another 3rd or 4th generation cephalosporin
• Ampicillin/Sulbactam
  • Limited published clinical data demonstrating efficacy
• Quinolone
  • In vitro activity against the HACEK group but limited clinical use; therefore, consult w/ infectious disease specialist before using in patients intolerant to β-lactam therapy

• Treatment of these less common causes of IE is still not adequately defined
• In patients w/ difficult-to-treat organisms (as below) & those w/ intracardiac device or foreign bodies, surgery combined w/ antibiotic therapy may be considered

• Most cases of Bartonella sp IE have required antibiotic therapy & valve-replacement surgery for cure

• Few patients have been cured w/ antimicrobial agents alone; most require valve replacement in combination w/ antibiotics

• Clinical response only persists as long as antimicrobial therapy continues; eradication is unlikely & reinfection of prosthetic material occurs after surgical replacement of infected valves

• Most cases occur in IVDA & right-sided pseudomonal IE can usually be treated w/ antibiotic therapy w/ or w/o surgery
• Valve replacement is usually considered mandatory in left-sided pseudomonal IE since medical therapy is rarely effective alone

• Susceptibility of these organisms can be unpredictable; therefore, treatment should be based on susceptibility testing

1. Aminoglycosides

• Adverse Reactions:
  • Ototoxic effects (can cause irreversible ototoxicity resulting in hearing loss, dizziness, vertigo); Renal effects (reversible nephrotoxicity, acute renal failure has been reported usually when other nephrotoxic drugs have also been administered); Neuromuscular effects (neuromuscular blockade resulting in resp depression & muscular paralysis); Hypersensitivity reactions
• Special Instructions:
  • Ototoxicity & nephrotoxicity are most likely in geriatric, dehydrated patients, those w/ renal impairment, in patients who are receiving high doses or for long periods or who are also receiving or have received other ototoxic/nephrotoxic drugs
    • Consider monitoring of serum conc &/or peak serum conc/MIC ratio in these patients
  • Use w/ caution in patients w/ conditions associated w/ muscle weakness (eg myasthenia gravis, Parkinson’s disease), patients w/ preexisting renal dysfunction, vestibular or cochlear impairment

• Dosage Guidelines:

• 3 mg/kg/day IM/IV 8 hrly
• Max dose: 5 mg/kg/day divided 6-8 hrly

• 7.5 mg/kg/day IV divided 8 hrly
• Reduce to ≤6 mg/kg/day IV as soon as clinically indicated usually w/ in 48 hr

• 1-2 g/day IM/IV in divided doses

• P aeruginosa: 8 mg/kg/day IM/IV 24 hrly

2. Antibacterial Combinations

• Adverse Reactions:
  • GI effects (N/V, anorexia, diarrhea, rarely antibiotic- associated diarrhea/colitis, glossitis); Dermatologic effects (rash, pruritus, photosensitivity); Hypersensitivity reactions can range from mild (eg rash) to severe/life-threatening (eg Stevens-Johnson syndrome); Urogenital effect (crystallization in the urine)
  • Rarely hematologic effects which may be more common if given for long periods or w/ high doses; rarely hepatic effects, renal effects; aseptic meningitis has occurred
• Special Instructions:
  • Maintain adequate fluid intake
  • Contraindicated in patients allergic to sulfonamides
  • Use w/ extreme caution or not at all in patients w/ hematological disorders esp megaloblastic anemia due to folic acid deficiency
  • Use w/ caution in patients w/ renal impairment or severe hepatic dysfunction & w/ caution in patients w/ folate deficiency (may consider administration of Folinic acid)

• Dosage Guidelines:

• 800 mg SMZ/160 mg TM PO 12 hrly
• 8-10 mg TM/kg/day IV divided 6 hrly

3. Cephalosporins

• Adverse Reactions:
  • Hypersensitivity reactions (urticaria, pruritus, rash, severe reactions eg anaphylaxis can occur); GI effects (diarrhea, N/V, rarely antibiotic-associated diarrhea/colitis); Other (Candidal infections)
  • High doses may be associated w/ CNS effects (encephalopathy, convulsions); rarely hematologic effects; hepatic & renal effects have occurred
  • Prolonged prothrombin time (PT), prolonged activated partial thromboplastin time (APTT), &/or hypoprothrombinemia (w/ or w/o bleeding) have been reported & occur most frequently w/ NMTT side chain-containing cephalosporins
• Special Instructions:
  • May be taken w/ food to decrease gastric distress
  • Use w/ caution in patients allergic to Penicillin, there may be 10% chance of cross sensitivity
  • Use w/ caution in patients w/ renal impairmen
• Dosage Guidelines:

• 250-500 mg PO 6 hrly or 750 mg PO 12 hrly

• 1-3 g/day IM/IV divided 6-8 hrly
• Max dose: 6 g/day

• 2-4 g/day IV divided 6 hrly
• Max dose: 8 g/day

• 2 g IV/IM 8 hrly
• Max dose: 12 g/day

• 1-2 g IV/IM 12 hrly
• Max dose: 12 g/day

• 1-2 g IV 8-12 hrly
• Max dose: 12 g/day

• 1-2 g IV/IM 8 hrly
• Max dose: 6 g/day

• 0.5-2 g IV/IM divided 6-12 hrly
• Max dose: 4 g/day

• 1-2 g IV/IM 24 hrly or divided 12 hrly
• Max dose: 4 g/day

• 2 g IV 8-12 hrly

4. Macrolide

• Adverse Reactions:
  • GI effects (N/V, abdominal discomfort, diarrhea & other GI disturbances, antibiotic-associated diarrhea/colitis); Other effect (Candidal infections)
  • Hypersensitivity reactions are uncommon (urticaria, pruritus, rash, rarely anaphylaxis); Rarely cardiotoxicity, hepatotoxicity; Dose-related tinnitus/hearing loss have occurred w/ some macrolides
• Special Instructions:
  • May take w/ food to decrease gastric distress
  • Use w/ caution in patients w/ hepatic dysfunction
• Dosage Guidelines:

• Alternative to penicillin for prophylaxis of bacterial endocarditis: 500 mg PO 12 hrly

5. Penicillins

• Adverse Reactions:
  • Hypersensitivity reactions (rash, urticaria, pruritus, severe reactions eg anaphylaxis can occur); GI effects (diarrhea, N/V, rarely antibiotic-associated diarrhea/colitis); Other effect (Candidal infections)
  • Rarely hematologic effects; renal & hepatic effects have occurred; high doses may be associated w/ CNS effects (encephalopathy, convulsions)
• Special Instructions:
  • Avoid in patients w/ Penicillin allergy
  • Use w/ caution in patients w/ renal impairment
• Dosage Guidelines:

• 1.2 g IM/IV 4 hrly

• 500 mg IM/slow IV 8 hrly
• High dose: 1 g slow IV/IV infusion 6 hrly

• 1.2 g IV 8 hrly

• 500 mg IM/IV 4-6 hrly

• 1.5-3 g IV 6-8 hrly
• Max dose: Sulbactam 4 g/day

• 500 mg IM/IV 4-6 hrly
• Max dose: 8 g/day

• 250-500 mg IM/slow IV/IV infusion 6 hrly
• Max dose: Up to 12 g/day divided 4 hrly

• 500 mg-1 g IM/slow IV/IV infusion 4-6 hrly

6. Other Beta-Lactam

• Adverse Reactions:
  • GI effects (diarrhea, N/V, antibiotic-associated diarrhea/colitis, tongue/tooth discoloration, altered taste); Hypersensitivity reactions ranging from mild (eg rash) to severe (eg anaphylaxis) can occur; Other (Candidal infections)
  • CNS effects (mental disturbances, confusion; Imipenem/cilastatin: Seizures & convulsions have been reported esp in patients w/ a history of CNS lesions &/or renal dysfunction); Rarely severe dermatologic reactions (eg exfoliative dermatitis, Stevens-Johnson syndrome, etc); rarely hepatic effects
• Special Instructions:
  • Use w/ caution in patients allergic to penicillins, cephalosporins or other beta-lactams
  • Use w/ caution in patients w/ CNS disorders (eg epilepsy), renal impairment
• Dosage Guidelines:

• 1-2 g/day IV divided 6-8 hrly
• Max dose: 4 g/day or 50 mg/kg/day

7. Quinolones

• Adverse Reactions:
  • GI effects (N/V, diarrhea, abdominal pain, dyspepsia, diarrhea, rarely antibiotic-associated diarrhea/colitis); CNS effects (headache, dizziness, sleep disorders, restlessness, drowsiness); Dermatologic effects (rash, pruritus, photosensitivity); Hypersensitivity reactions can range from mild (eg rash) to severe/life-threatening (eg Stevens-Johnson syndrome)
  • Rarely hematologic effects, hepatic & renal effects
  • Some quinolones have the potential to prolong the QT interval
• Special Instructions:
  • Administer at least 2 hr before or 3 hr after Al- or Mg-containing antacids, dietary supplements containing Zn or Fe or buffered ddl preparations
  • Avoid exposure to strong sunlight or tanning beds
  • Use w/ caution in patients w/ epilepsy or history of CNS disorders, in patients w/ impaired renal or hepatic function & in those w/ G6PD deficiency
• Dosage Guidelines:

• 500 mg PO 12 hrly or
• 400 mg IV 12 hrly

• 400 mg IV 12 hrly

8. Tetracycline

• Adverse Reactions:
  • GI effects (N/V, diarrhea, antibiotic-associated diarrhea/colitis has occurred, dysphagia, esophageal ulceration has occurred when taken w/ an insufficient amount of liqd); Dermatologic effect (photosensitivity); Other effects (Candidal infections, discoloration of teeth, interference w/ bone growth in young infants/pregnant women)
  • Rarely renal dysfunction, hepatotoxicity, hematologic effects, intracranial pressure w/ headache & visual disturbances; hypersensitivity reactions have occurred
• Special Instructions:
  • Avoid long exposure to sunlight or tanning beds
    • Take w/ plenty of fluid while sitting or standing & well before retiring to bed
  • Avoid in children ≤8 yr & pregnant women; avoid in patients w/ SLE
  • Use w/ caution in renal or hepatic impairment
• Dosage Guidelines:

• Loading dose: 200 mg PO/IV 24 hrly or divided 12 hrly
• Maintenance dose: 100 mg PO/IV 24 hrly

9. Other Antibiotics

• Adverse Reactions:
  • GI effects (diarrhea, N/V, constipation); Hematologic effect (anemia)
  • Less common: CV effects (peripheral edema, chest pain, hypertension, hypotension); CNS effects (insomnia, headache); Dermatologic effects (rash, pruritus); Endocrine effects (hypokalemia, hyperkalemia); GUT effect [urinary tract infection (UTI)]; Musculoskeletal effects [increased creatine phosphokinase (CPK), limb pain, back pain, weakness]; Resp effects (pharyngolaryngeal pain, pleural effusion, cough, pneumonia, dyspnea); Misc effects (osteomyelitis, bacteremia, diaphoresis, sepsis, fungal infections, renal failure, inj site reaction)
• Special Instructions:
  • Monitor CPK levels once wkly or more frequently in high-risk patients
  • Monitor for signs & symptoms of neuropathy
• Dosage Guidelines:

• 6 mg/kg IV 24 hrly

• Adverse Reactions:
  • GI effect (mild GI upset); Hepatic effects (jaundice & changes in liver function which return to normal once drug is discontinued)
• Special Instructions:
  • Use w/ caution in patients w/ liver dysfunction & monitoring of hepatic function in these patients is recommended if on high or prolonged doses
• Dosage Guidelines:

• Na fusidate:
  • 500 mg slow IV 24 hrly
  • 500 mg PO 8 hrly
  • Max dose: 2 g/day

• Adverse Reactions:
  • Fever, chills, skin rash, pruritus; occasionally, anaphylaxis or bronchospasm have been reported; generally better tolerated than Vancomycin
  • Other hypersensitivity reactions can occur (eg Stevens- Johnson syndrome); GI effect (GI disturbances); CNS effects (dizziness, headache); hematologic effects; hepatic effects; renal effect (renal impairment, but less often than w/ Vancomycin); ototoxic effects have occurred but less frequently than w/ Vancomycin
• Special Instructions:
  • Use w/ caution in patients w/ preexisting renal dysfunction & monitor renal & auditory function if on prolonged therapy
  • Periodic monitoring of CBC & LFTs are advised
• Dosage Guidelines:

• Loading dose: 400 mg IV 12 hrly for 1st 3 doses
• Maintenance dose: 400 mg IV 24 hrly

• Adverse Reactions:
  • “Red neck syndrome” which is usually related to too rapid infusion: Flushing, erythema, rash over face & upper torso, sometimes hypotension & shock-like symptoms also occur
  • Hypersensitivity reactions (can range from mild to severe eg anaphylactoid reactions, Stevens-Johnson syndrome); Hematologic effects have occurred; Renal effects (nephrotoxicity may occur esp at high doses or in patients w/ predisposing factors); Ototoxic effects (ototoxicity, which is more likely w/ high plasma conc or in renal impairment, may be irreversible; tinnitus may precede hearing loss & can be used as a sign to discontinue treatment)
• Special Instructions:
  • Avoid in patients w/ a history of impaired hearing
  • Use w/ caution in patients w/ impaired renal function & in the elderly
  • Monitoring of serum conc may be done to help avoid renal & otic toxicity, monitoring of CBC & renal function during treatment is suggested along w/ monitoring of auditory function
• Dosage Guidelines:

• 500 mg IV 6 hrly or
• 1 g IV 12 hrly
• Max dose: 2 g/day

• Adverse Reactions:
  • GI effects (diarrhea, severe antibiotic-related pseudomembranous colitis, N/V, abdominal pain, metallic taste); Hypersensitivity reactions (rash, urticaria, rarely anaphylaxis); Severe dermatologic effects have occurred (erythema multiforme, exfoliative & vesiculobullous dermatitis); cardiac, hematologic & hepatic effects have occurred; Other effect (polyarthritis)
• Special Instructions:
  • Use w/ caution in patients w/ GI disease esp w/ history of colitis, in atopic patients & in patients w/ renal or hepatic impairment
  • Discontinue if diarrhea occurs
• Dosage Guidelines:

• Alternative to penicillin for prophylaxis of endocarditis: 150 mg PO 6 hrly or 600 mg PO/IV 1 hr before procedure

• Adverse Reactions:
  • GI effects (diarrhea, N/V, metallic taste, constipation, antibiotic-associated diarrhea/colitis can occur); CNS effects (headache, insomnia, dizziness); Hepatic effect (abnormal LFTs); Hematologic effects (reversible myelosuppression including leukopenia, anemia, pancytopenia, thrombocytopenia has occurred); Other (moniliasis infection)
• Special Instructions:
  • Use w/ caution in patients w/ preexisting myelosuppression & in patients w/ severe renal dysfunction
  • Recommend monitoring of blood counts wkly
• Dosage Guidelines:

• 600 mg PO 12 hrly
• 600 mg IV 12 hrly

• Adverse Reactions:
  • Generally well tolerated; GI effects (N/V, anorexia, diarrhea, GI distress, antibiotic-associated diarrhea/colitis has occurred); Discoloration of urine & body fluids
  • Rarely hepatic effects (transient abnormalities in liver function, hepatitis rarely occurs); Hematologic effects have occurred; Renal effects have been reported w/ intermittent therapy; CNS effects (headache, drowsiness, ataxia, etc)
• Special Instructions:
  • Rifampicin accelerates the metabolism of drugs metabolized by the CYP450
  • Use w/ caution in patients w/ preexisting liver dysfunction, monitor liver function during therapy in these patients
• Dosage Guidelines:

• 600 mg PO 12 hrly
• 600 mg IV 12 hrly

• Adverse Reactions:
  • GI effects (N/V, diarrhea, antibiotic-associated diarrhea/colitis); CNS effect (headache); Hypersensitivity reactions (pruritus, rash, rarely anaphylaxis); Hematologic effects (anemia, eosinophilia, leukopenia, neutropenia); Musculoskeletal effects (myalgia, arthralgia have occurred & may improve w/ decreasing dose frequency); Hepatic effects have occurred
• Special Instructions:
  • Contraindicated in severe hepatic impairment
  • Use w/ caution in patients w/ hepatic dysfunction
  • May cause prolongation of QT interval, use w/ caution in patients w/ cardiac arrhythmia
• Dosage Guidelines:

• 7.5 mg/kg IV 8 hrly

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Surgery

• NVE patients w/ acute aortic or mitral regurgitation & CHF
• Evidence of perivalvular extension
• Persistent infection after 7-10 days of adequate antimicrobial therapy
• Relapsing infection ie recurrence of bacteremia following a complete antibiotic course & subsequently negative BCs w/ no known source of infection
• Infection w/ microorganisms that have poor response to antibiotic therapy (eg fungi, Brucella sp, Coxiella sp, Staphylococcus lugdunensis, Enterococcus sp w/ high-level resistance to Gentamicin, gram-negative organisms)
  • Left-sided IE caused by S aureus, fungal, or highly resistant organisms
• NVE patients w/ mobile vegetation >10 mm before or during the 1st wk of antibiotic therapy
• Recurrent emboli despite appropriate antibiotic therapy
• Obstructive or persistent vegetations
• Early PVE
• Hemodynamically significant prosthetic valve
• IE complicated by annular or aortic abscess, destructive penetrating lesion, or heart block

All dosage recommendations are for non-pregnant & non-breastfeeding women, non-elderly adults w/ normal renal & hepatic function unless otherwise stated.

Not all products are available or approved for above use in all countries. 

Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information.

Click the link below for specific prescribing information of products available in respective countries.

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