National Antimicrobial Guideline (NAG), Ministry of Health Malaysia

ADULT

INFECTIONS IN IMMUNOCOMPROMISED PATIENTS

In this topic:

1. HEMATOLOGY-ONCOLOGY

2. OPPORTUNISTIC INFECTION (OI) IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV)

1. HEMATOLOGY-ONCOLOGY

Any infection in the immunocompromised host is life-threatening and needs immediate attention. Febrile neutropenia is defined as single temperature: ≥ 38.3°C orally or ≥ 38.0°Cover 1 hour; and neutropenia: < 500 neutrophils/mcL or < 1000 neutrophils/mcL and a predicted decline to ≤ 500 neutrophils/mcL over the next 48 hours.
Cultures may be positive in less than 40% of cases. Patients have impaired inflammatory responses and hence may have no localizing signs. The usual sign is fever > 38°C or hypothermia. The common portals of infection include the oral cavity, gastrointestinal tract, perianal region, lungs and IV lines.
Patients may not always mount a temperature response due to the severity of their illness. If a patient is unwell on assessment with a history of receiving systemic anticancer therapies, neutropenic sepsis should be suspected.
Other signs/symptoms that may suggest infection in neutropenic patients (any one of the following):

Signs

Hypothermia < 35.0oC (two readings 1 hour apart)
Unexplained hypotension / tachycardia / abdominal pain
Any unexplained clinical deterioration, even in the absence of fever

Symptoms

Chills/rigors/sweating
Sore throat / cough / urinary symptoms, unexplained skin lesions
Pain at intravenous catheter sites (tunneled or untunnelled)
Unexplained diarrhoea

Note: Focal signs/symptoms of infection may or may not be present

5. Potential pathogens are dependent on the underlying defect. For example;

Neutropenia : Gram-negative organisms, Gram-positive organisms, Fungi
Hypogammaglobulinaemia, post splenectomy/hyposplenic patients : Encapsulated organisms
Defective cellular immunity : Pneumocystis jirovecii, Toxoplasma, Fungi, Viruses, Mycobacteria

Neutropenia : Gram-negative organisms, Gram-positive organisms, Fungi
Hypogammaglobulinaemia, post splenectomy/hyposplenic patients : Encapsulated organisms
Defective cellular immunity : Pneumocystis jirovecii, Toxoplasma, Fungi, Viruses, Mycobacteria

*Flowchart modified from NCCN (Clinical Guideline: Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients)

6. The oncology or haematology team responsible for the patient should be made aware as soon as possible that the patient has been admitted for suspected neutropenic sepsis.

1.1 Suggested Empirical Antibiotic Therapy in Adult Febrile Neutropenic Patients

1.1.2 Low Risk (Outpatient)

Suitable low risk patients include:

no evidence of dehydration or hypotension
no evidence of pneumonia
no COAD
able to access prompt medical attention if deteriorates

Outpatient oral antibiotics may be considered after careful risk assessment and consultation with a hemato-oncologist.

Preferred

Amoxicillin/clavulanate 625mg PO q8h

MAY ADD

*Ciprofloxacin 500mg PO q12h

Alternative

Comments

Treat until patient recovers.

Can consider stopping the antibiotic after reassessing the patient following 2 days afebrile at the discretion of the treating hemato-oncologists – if the patient has stable vital signs, no evidence of ongoing infection, are educated about their condition and stay near to hospital facilities.

*Add ciprofloxacin if patient is previously colonized by Pseudomonas aeruginosa.

1.1.3 High Risk (Inpatient)

Risk assessment for complication of severe infection should be done during triage. Patient is deemed high risk if there is:

prolonged and profound neutropenia with ANC < 0.1x109/L
hypotension
pneumonia
new onset abdominal pain or neurological signs

The administration of the first dose of empirical antibiotic with anti-pseudomonal coverage should be done as soon as possible following triage (within the first hour) after taking blood cultures. The suggested antibiotics are listed below.

Consider IV to PO antibiotic switch in a clinically stable patient who has no gastrointestinal absorption issue.

Preferred

First line therapy:

*Piperacillin/tazobactam 4.5g IV q6h

MAY ADD

**Amikacin 15mg/kg IV q24h

Alternative

Cefepime 2g IV q8h

MAY ADD

**Amikacin 15mg/kg IV q24h

MAY ADD

***Metronidazole 500mg IV q8h

Comments

*Piperacillin/tazobactam: if given as q8h, to be given as extended infusion (over 3-4 hours).

**Amikacin may be added in patient with severe sepsis for broader gram negative coverage. It can be discontinued if microbiological cultures showed isolated organisms sensitive to piperacillin/tazobactam or cefepime and patient is clinically stable.

***Metronidazole may be added in the presence of:

severe mucositis
intra-abdominal infections
peri-anal abscesses
colitis

Preferred

Severe sepsis or

Second line therapy for persistent fever of 4 - 7 days and deterioration of signs:

Meropenem 1g IV q8h

MAY ADD

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

Alternative

Imipenem 500mg q6h or 1g IV q8h (in severe sepsis)

MAY ADD

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

Comments

*Refer to Appendix 1 for vancomycin loading dose.

*Vancomycin is not a routine in the initial antibiotic regime. Consider add vancomycin for these patients:

colonized with MRSA
suspected to have catheter-related infection, skin and soft-tissue infection
in septic shock

Stop vancomycin after 48 hours if no evidence of gram positive cocci.

Linezolid is an alternative in those patients with no clinical response to vancomycin and in those with suspected or confirmed VRE, VISA or VRSA.

1.2 De-escalation Strategies

Modification of antibiotic regime if deterioration of clinical status or if there is no clinical improvement over 72-96 hours in a stable patient.
The antibiotics are generally kept for a minimal duration of 5 to 7 days or stopped if afebrile for 2 days in patients who is asymptomatic with negative cultures and improving neutrophil *count. (*refer to comment on low risk out-patient).
In instances where cultures are positive and the patient is improving with targeted therapy, consider discontinuing non-relevant combination therapy. For example: patient with MRSA positive cultures on combination therapy meropenem and vancomycin, to stop meropenem.

1.3 Infection Prevention Strategies

Strict isolation measures.
Patient’s personal hygiene and diet.
Regular surveillance culture.
Hand washing and strict aseptic technique.
Prevention of HCAI (E.g.: BSI, HAP, VAP)

1.4 Antifungal Therapy

It should be initiated earlier in the presence of:

severe mucositis
oral thrush
dysphagia
suspicious skin infiltrates or pulmonary infiltrates
fundal exudates
prolonged steroid use more than 2 weeks

IV amphotericin B remains the empirical therapy of choice for invasive fungal infections. For patients who are intolerant, refractory or those with toxicity to conventional amphotericin B, the lipid formulations of amphotericin B, voriconazole and echinocandins are alternatives for empirical therapy based on local availability and costs.

Voriconazole is an alternative to amphotericin B for pre-emptive and directed therapy for invasive aspergillosis.

In candidiasis, echinocandins, azoles and amphotericin B are antifungals of choice.

Daily Dose of Antifungal Agent

Amphotericin B lipid complex (ABLC): 5mg/kg q24h
Amphotericin B deoxycholate (conventional): 0.7-1.0mg/kg q24h
Liposomal amphotericin B: 3-5mg/kg q24h
Anidulafungin: 200mg loading dose, followed by 100mg q24h
Caspofungin: 70mg loading dose, followed by 50mg q24h
Micafungin: 100mg q24h
Fluconazole: 12mg/kg/day for 1 day, then 6mg/kg q24h
Itraconazole: 200mg q8h for 3 days, followed by 200mg q12h
Posaconazole: (Tablet) 300mg q12h for 1 day, followed by 300mg q24h
Voriconazole: 6mg/kg q12h for 2 doses, followed by 3-4 mg/kg q12h

a) For patients on fluconazole or no antifungal prophylaxis, if

New clinical signs or symptoms suggestive of invasive fungal infections (IFI)*
Fever persists ≥ 7days with no identified fever source

Preferred

Micafungin 100mg IV q24H

Alternative

Anidulafungin 200mg IV single dose, then 100mg IV q24h

Caspofungin 70mg IV single dose, then 50mg IV q24h

Comments

*If sinus and/or chest CT scan findings not suggestive of fungal infection, it is less likely to be aspergillus or mold infections.

b) If signs and symptoms suggestive of invasive fungal infections (IFI)* AND sinus ± chest CT suggestive of fungal infection.

Preferred

Voriconazole 6mg/kg IV q12h for 2 doses, then 4mg/kg IV q12h

Alternative

*Amphotericin B deoxycholate

0.7-1mg/kg IV q24h

*Liposomal Amphotericin B 3-5mg/kg IV q24h

Comments

*For patients on voriconazole or posaconazole as prophylaxis, empirical antifungal of choice will be amphotericin B.

References:

National Comprehensive Cancer Network. Clinical Guidelines: Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients. Updated information January 2020
Policies and Procedures on Infection Prevention and Control. Quality Medical Care Section, Medical Development Division, Ministry of Health Malaysia. 2019, 3rd edition.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Prevention and treatment of cancer-related infections. Version 1.2012. NCCN: Fort Washington, 2012.
Hughes W T, Armstrong D, Bodey G P et al. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002 ; 34 : 730-751
Herbrect R, Denning D W, Patterson T F et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. NEJM 2002 ; 347: 408-415
Walsh TJ, Teppler H, Donowitz G R et al .Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropaenia. NEJM 2004;351(14):1391-1402
Dellinger RP, Levy MM, Carlet JM et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Intensive Care Med 2008, 34 : 17-60
Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database of Systematic Reviews 2008, Issue 4.
Alison GF, Eirc JB, Kent A S et al. IDSA guideline: Clinical Practice guideline for the Use of Antimicrobial Agents in Neutropenic Patients with cancer :2010 update by the Infectious Diseases Society of America . CID 2011; 52: 56-93.
Mica P, Sara B, Abigail F, Liat v and Leonard L. Empirical antibiotics against Gram-positive infections for febrile neutropenia: Systemic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2005; 55: 436-444.
Diana A, Christina O, Catherine C et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European conference on the infections in Leukaemia. Haematologica 2013;98(12) :1826-1835
Paul M, Yahav D, Fraser A, et al. Empirical antibiotic monotherapy for febrile neutropenia: Systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2006;57:176-89.
13. Engelhard D. Akova M, Boeckh MJ et al. Bacterial infection prevention after hematopoietic cell transplantation. Bone marrow Transplant 2009; 44:467-470.
14. Cornely OA, Bohme A, Buchheidt D et al. Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and oncology. Haematologica 2009; 94: 113-22.
15. Zaia J, Baden L, Boeckh MJ et al. viral disease protection after hematopoietic cell transplantation. Bone marrow Transplant 2009; 44:471-482.
16. J.Klatersky, J.de Naurios, K.Rolston et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Annals of Oncology 27 (Supplement 5):v111-v118, 2016. Doi:10.1093/annonc/mdw325

2. OPPORTUNISTIC INFECTION (OI) IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Important cut-offs for CD4 T cells, above which particular AIDS illnesses are improbable. These CD4 counts are only reference values; exceptions are always possible.

No cut-off: Kaposi’s sarcoma, pulmonary tuberculosis, HZV, bacterial pneumonia, lymphoma, HSV

< 250/μl: PCP, oesophageal candidiasis, PML, HIV encephalopathy

< 100/μl: Cerebral toxoplasmosis, cryptococcosis, miliary tuberculosis

< 50/μl: CMV end organ disease, cryptosporidiosis, atypical mycobacteriosis

The treatment regimens are based on drugs available in the Ministry of Health National Formulary and hence in some instances may vary from internationally accepted treatments. Some regimes are chosen as preferred regimes due to cost considerations.

2.1 Pneumocystis jiroveci (carinii) Interstitial Pneumonia (PJP/PCP)

2.1.1 Treatment

Preferred

Trimethoprim/ sulfamethoxazole 15-20mg/kg/day [TMP component] IV/PO in 3-4 divided doses

Alternative

For mild to moderate cases:

(PO2 70-80mmHg)

Clindamycin 600mg IV/PO q8h

PLUS

Primaquine 30mg (base) PO q24h

Dapsone 100mg PO q24h

PLUS

Trimethoprim 15mg/kg/day PO in 3-4 divided doses

For severe cases:

(PO2 < 70mmHg)

Pentamidine 4mg/kg/day IV

(in 1 pint D5% or NS run over 1-2 hours)

Clindamycin 600mg IV q6h or 900mg IV q8h

PLUS

Primaquine 30mg (base) PO q24h

Comment

Duration: 21 days

Patients with severe disease should receive adjunctive corticosteroids as soon as possible (within 72 hours of starting PCP treatment):

Prednisolone dose:

40mg PO q12h for 5 days, then

40mg PO q24h for 5 days, then

20mg PO q24h for 11 days

(Total duration is 21 days)

Trimethoprim/sulfamethoxazole & clindamycin has excellent bioavailability, may consider IV to PO switch after clinical improvement.

Patients given dapsone or primaquine should be tested for G6PD deficiency.

2.1.2 Prophylaxis (primary and secondary)

Indications:

CD4 count < 200 cells/μL
CD4 count 200-250 cells/μL if ART cannot be initiated

Preferred

Trimethoprim/sulfamethoxazole (80/400mg) 1–2 tablets PO q24h

Alternative

*Dapsone 100mg PO q24h

*Aerosolized Pentamidine 300mg monthly via ultrasonic nebulizer

Comment

Discontinuation:

Can consider when CD4 100-200 cells/μL if HIV RNA is suppressed for 3-6 months with ART.

Restarting prophylaxis:

CD4 count falls to < 200 cells/μL or PCP occurs at a CD4 > 200 cells/μL (lifelong prophylaxis should be considered).

Patients receiving Sulfadiazine/ Pyrimethamine or Sulfadoxine/ Pyrimethamine for treatment or suppression of toxoplasmosis do not require additional prophylaxis for PCP.

*Requires DG’s approval.

2.2 Toxoplasma gondii Encephalitis

2.2.1 Acute Infection

Up to 97% patients are Toxo IgG +ve

Preferred

Trimethoprim/sulfamethoxazole 10mg/kg/day (TMP component) IV/PO in 2 divided doses

*Pyrimethamine 200mg PO loading dose followed by Pyrimethamine:

50mg PO q24h (if BW ≤ 60kg)
75mg PO q24h (if BW > 60kg)

PLUS

Folinic acid 10-25mg IV q24h OR 15mg PO q24h

PLUS

*Sulfadiazine 1g PO q6h

Alternative

*Pyrimethamine 200mg PO loading dose followed by Pyrimethamine:

50mg PO q24h (if BW ≤ 60kg)
75mg PO q24h (if BW > 60kg)

PLUS

Folinic acid 10-25mg IV q24h OR

15mg PO q24h

PLUS

Clindamycin 600mg IV/PO q6h

Comments

Duration: At least 6 weeks

Longer duration if clinical and radiologic disease is extensive or response is incomplete in 6 weeks.

Adjunctive corticosteroids

(E.g.: dexamethasone) should be administered when clinically indicated to treat mass effect associated with focal lesions or associated oedema but should be discontinued as soon as clinically feasible.

To use trimethoprim/sulfamethoxazole if pyrimethamine not available.

In the case of sulfa allergy and pyrimethamine is not available, sulfa desensitization should be attempted in those without a history of severe reaction (E.g.: Stevens-Johnson syndrome).

If clindamycin is used, additional therapy must be added for primary prophylaxis for PCP.

*Requires DG’s approval.

2.2.2 Suppressive/ Maintenance Therapy

Preferred

Trimethoprim/ Sulfamethoxazole

(80/400mg) 2 tablets PO q12h

Alternative

*Dapsone 100mg PO q24h OR

Clindamycin 600mg PO q8h

PLUS

*Pyrimethamine 50mg PO q24h

MAY ADD

Folinic acid 15mg PO q24h

*Sulfadiazine 0.5-1gm PO q6h

PLUS

*Pyrimethamine 25-50mg PO q24h

PLUS

Folinic acid 15mg PO q24h

Comments

Discontinuation:

Consider when CD4 >200 cells/μL if HIV RNA is suppressed for 6 months with ART.

*Requires DG’s approval.

2.2.3 Primary Prophylaxis

Indications:

Toxoplasma IgG +ve with CD4<100

Preferred

Trimethoprim/ Sulfamethoxazole (80/400mg) 2 tablets PO q24h

Alternative

*Dapsone 50mg PO q24h

PLUS

*Pyrimethamine 50mg PO once weekly

PLUS

Folinic acid 30mg PO once weekly

*Dapsone 200mg PO once weekly

PLUS

*Pyrimethamine 75mg PO once weekly

PLUS

Folinic Acid 30mg PO once weekly

Comments

Discontinuation:

CD4 > 200 cells/μL for > 3months

CD4 > 100 cells/μL, if HIV viral load suppressed for 3 to 6 months.

*Requires DG’s approval.

2.3 Mucocutaneous Candidiasis

2.3.1 Oropharyngeal (oral thrush)

Preferred

Fluconazole 100mg PO q24h

Nystatin suspension 500,000 units PO 4 times daily

Alternative

*Itraconazole 200mg PO q24h

Comments

Duration: 7-14 days

Chronic suppressive therapy is usually not recommended.

*Itraconazole: Absorption depends on gut acidity. Take capsule with a full meal. Oral solution should be taken on an empty stomach. Avoid PPIs and H2 blockers.

2.3.2 Oesophageal

Preferred

Fluconazole 200-400mg PO/IV q24h

Alternative

*Itraconazole 200mg PO q24h

Comments

Duration: 14-21 days

Infection with other pathogens (E.g.: CMV, HSV that causes esophagitis) can result in symptoms that mimic esophageal candidiasis, a diagnostic and therapeutic trial of antifungal therapy is usually warranted before endoscopy.

Endoscopy is required with unusual presentations or lack of response to azole within several days.

2.4 Cryptococcal Meningitis or Meningoencephalitis (Cryptococcus neoformans)

2.4.1 Induction Therapy

Preferred

*Amphotericin B deoxycholate 1mg/kg IV q24h

PLUS

Flucytosine 25mg/kg PO q6h

(Duration : 1 week)

Followed by:

Fluconazole 1200mg PO q24h

(Duration : 1 week)

**Liposomal Amphotericin B 10mg/kg (single high dose)

Followed by:

Fluconazole 1200mg IV/PO q24h

PLUS

Flucytosine 25mg/kg PO q6h

(Duration : 2 weeks)

Alternative

*Amphotericin B deoxycholate 0.7-1mg/kg IV q24h

PLUS

Fluconazole 800-1200mg IV/PO q24h (may be given in divided dosing)

(Duration : 2 weeks)

Fluconazole 1200mg IV/PO q24h

PLUS

Flucytosine 25mg/kg PO q6h

(Duration: 2 weeks)

Comments

**Liposomal Amphotericin B may be used instead if available.

For severe/recurrent infection, please refer to ID physician.

2.4.2 Consolidation Therapy

Continued after successful induction therapy; defined as substantial clinical improvement and negative CSF culture after repeat LP.

Preferred

*Fluconazole 400mg - 800mg PO/IV q24h

**Use actual body weight for weight-based dose calculations: 6 mg/kg once daily (maximum dose [not well established]: 800mg to 1600mg).

Alternative

Itraconazole 200mg PO q12h

Comments

Duration: 8 weeks

*The dose can then be reduced to 400mg/day to complete the 8-week consolidation phase if all of the following criteria are met:

(i) The patient received induction therapy with amphotericin B plus flucytosine for 2 weeks.

(ii) CSF cultures obtained after 2 weeks of induction therapy are negative.

(iii) ART has been started.

**Consider weight-based dosing for Class 1, 2, or 3 obesity (BMI ≥30 kg/m2) patients.

2.4.3 Maintenance Therapy

Continued after consolidation therapy

Preferred

Fluconazole 200mg PO q24h

Alternative

Itraconazole 200mg PO q24h for patients intolerant or failed fluconazole (however, less effective and higher relapse rate)

Comments

Discontinuation:

Completed initial (induction, consolidation) therapy

AND

At least 1 year on maintenance therapy

AND

Remains asymptomatic from cryptococcal infection

AND

CD4 count ≥ 100 cells/µL and suppressed HIV RNA in response to effective ART for ≥ 6 months

2.4.4 Secondary prophylaxis

Preferred

Fluconazole 200mg PO q24h

Alternative

Comments

Restarting secondary prophylaxis:

CD4 count < 100 cells/μL

2.5 Cryptococcosis (Localized Non-meningeal Disease)

2.5.1 Mild-moderate pulmonary infection or extra-pulmonary non-CNS disease OR Asymptomatic with positive lung/blood culture or positive antigen test (no CNS disease)

Preferred

Fluconazole 400mg-800mg PO q24h for 10 weeks.

**Use actual body weight for weight-based dose calculations: 6mg/kg once daily (maximum dose [not well established]: 800mg to 1600mg).

Then, maintenance (secondary prophylaxis): Fluconazole 200mg q24h.

Alternative

*Itraconazole 200mg PO given q8h for 3 days.

Then, consolidation: Itraconazole 200mg PO given q12h for 8 weeks.

Then, maintenance (secondary prophylaxis): Itraconazole 200mg q24h.

Comments

Discontinuation of maintenance:

At least 1 year of treatment

AND

CD4 count ≥ 100 cells/µL and suppressed HIV RNA in response to effective ART for ≥ 6 months.

In the case of treatment failure, all patients initially treated with fluconazole should have their therapy changed to amphotericin B until clinical response is achieved.

*Itraconazole:

Absorption depends on gut acidity. Take capsule with a full meal. Oral solution should be taken on an empty stomach.

**Consider weight-based dosing for Class 1, 2, or 3 obesity (BMI ≥30 kg/m2) patients.

2.5.2 Severe Pulmonary or Extra-pulmonary Non-CNS Disease

Treat as per cryptococcal meningitis.

2.6 Histoplasmosis (Histoplasma capsulatum)

2.6.1 Moderate to Severe Disseminated Disease

Preferred

Induction therapy:

*Amphotericin B deoxycholate 0.7-1.0mg/kg IV q24h for at least 2 weeks

Liposomal amphotericin B at 3 mg/kg IV daily (for 2 weeks or until clinically improved)

Followed by,

Maintenance therapy:

Itraconazole 200mg PO q8h for 3 days, then 200mg q12h for at least 12 months

Alternative

Comments

*Liposomal amphotericin B may be used instead if available.

All triazole antifungals have the potential to interact with certain ARV agents and other anti-infective agents.

Therapeutic drug monitoring is recommended for azoles therapy.

2.6.2 Meningitis

Preferred

Induction therapy:

*Amphotericin B deoxycholate 0.7-1.0mg/kg IV q24h for at least 2 weeks

Liposomal amphotericin B at 5 mg/kg IV daily (for 2 weeks or until clinically improved)

Followed by,

Maintenance therapy:

Itraconazole 200mg PO q8h for at least 12 months and until resolution of CSF abnormalities

Alternative

Comments

*Liposomal amphotericin B may be used instead if available.

All triazole antifungals have the potential to interact with certain ARV agents and other anti-infective agents.

Therapeutic drug monitoring is recommended for azoles therapy.

2.6.3 Mild Disseminated Disease

Blood culture positive but patient is asymptomatic.

Preferred

Induction & maintenance therapy:

*Itraconazole 200mg PO q8h for 3 days, then 200mg PO q12h

Alternative

For patients intolerant to itraconazole:

Fluconazole 800mg PO q24h

Voriconazole 400mg PO q12h on Day 1, then 200mg PO q12h

Comments

Duration: At least 12 months

*Itraconazole: Absorption depends on gut acidity. Take capsule with a full meal. Oral solution should be taken on an empty stomach. Avoid PPIs and H2 blockers.

2.6.4 Chronic Suppressive therapy (Secondary prophylaxis)

Indication:

Severe disseminated or CNS infection after completion of at least 12 months of treatment.
Relapsed despite appropriate initial therapy.

Preferred

*Itraconazole 200mg PO q24h

Alternative

Fluconazole 400mg PO q24h

Comments

Discontinuation:

Received azole for > 1 year

AND

Negative fungal blood cultures

AND

CD4 count > 150 cells/μL for ≥ 6 months on ART

Restarting secondary prophylaxis:

CD4 count < 150 cells/μL

*Itraconazole: Absorption depends on gut acidity. Take capsule with a full meal. Oral solution should be taken on an empty stomach. Avoid PPIs and H2 blockers.

2.7 Penicilliosis (Penicillium/Talaromyces marneffei)

2.7.1 Acute Infection

Preferred

Moderate to severe disease

Induction therapy:

*Amphotericin B deoxycholate 0.7-1.0mg/kg/day IV

Liposomal amphotericin B 3-5mg/kg/day IV for 2 weeks

Must be followed by consolidation therapy.

Consolidation therapy:

**Itraconazole 200mg PO q12h for 10 weeks

Must be followed by maintenance therapy.

Alternative

Induction therapy:

Voriconazole 6mg/kg IV q12h on Day 1, then 4mg/kg IV q12h for at least 3 days

Voriconazole 600mg PO q12h on Day 1, then 400mg q12h for 2 weeks if IV therapy not available

Must be followed by consolidation therapy.

Consolidation therapy:

**Itraconazole 200mg PO q12h for 10 weeks

Must be followed by maintenance therapy.

Comments

All triazole antifungals have the potential to interact with certain ARV agents and other anti-infective agents.

**Itraconazole: Absorption depends on gut acidity. Take capsule with a full meal. Oral solution should be taken on an empty stomach. Avoid PPIs and H2 blockers.

Therapeutic drug monitoring is recommended for azoles therapy.

Preferred

Mild disease

**Only skin involvement; no fungaemia

**Itraconazole 200mg PO q12h for at least 8-12 weeks

Loading dose: 200mg q8h for 3 days and then reduce to q12 therapy

Must be followed by maintenance therapy.

Alternative

Voriconazole 400mg PO q12h on Day 1 followed by 200mg q12h for 12 weeks.

Must be followed by maintenance therapy.

Comments

All triazole antifungals have the potential to interact with certain ARV agents and other anti-infective agents.

**Itraconazole: Absorption depends on gut acidity. Take capsule with a full meal. Oral solution should be taken on an empty stomach. Avoid PPIs and H2 blockers.

Therapeutic drug monitoring is recommended for azoles therapy.

2.7.2 Maintenance Therapy/ Secondary Prophylaxis

Preferred

**Itraconazole 200mg PO q24h

Alternative

Voriconazole 200mg PO q12h

Comments

Discontinuation:

CD4 count > 100 cells/μL for ≥ 6 months on ART

2.8 Mycobacterium Tuberculosis Infection and Diseases

Refer to Ministry of Health CPG on Management of Tuberculosis 4th Edition (2021).

2.9 Mycobacterium avium Complex (MAC) Disease

2.9.1 Treatment

Preferred

Clarithromycin 500mg PO q12h

PLUS

Ethambutol 15mg/kg PO q24h

PLUS

***Rifampicin 10mg/kg PO q24h

**MAY ADD

4th drug:

Amikacin 10-15mg/kg IV q24h

Streptomycin 15mg/kg IM q24h

Levofloxacin 500mg PO q24h

Ciprofloxacin 500-750mg PO q12h

Moxifloxacin 400mg PO q24h

Alternative

*Azithromycin 500mg PO q24h

PLUS

Ethambutol 15mg/kg PO q24h

PLUS

***Rifampicin 10mg/kg PO q24h

**MAY ADD

4th drug:

Amikacin 10-15mg/kg IV q24h

Streptomycin 15mg/kg IM q24h

Levofloxacin 500mg PO q24h

Ciprofloxacin 500-750mg PO q12h

Moxifloxacin 400mg PO q24h

Comments

Duration: At least 12 months

*Azithromycin: use if drug interaction or intolerance precludes the use of clarithromycin.

**Addition of 4th drug should be considered for patients with disseminated disease, require IV/IM.

***Concomitant tuberculosis needs to be ruled out if monotherapy rifampicin is used.

Treatment of choice shall be tailored according to culture and susceptibility testing results.

Discontinuation:

Consider if patient is on ART and viral load is suppressed, CD4 > 100 cells/μL > 6 months, asymptomatic of MAC, and has completed > 12 months of therapy.

2.9.2 Maintenance Treatment/ Secondary Prophylaxis

Same as the treatment regimen.

Restarting secondary prophylaxis:

CD4 < 100 cells/μL again

2.9.3 Primary Prophylaxis

Indications:

CD4 < 50 cells/μL
Ruled out active MAC and TB

Preferred

Azithromycin 1250mg PO once weekly

Alternative

Clarithromycin 500mg PO q12h

Comments

Discontinuation:

Consider if patient is on ART

AND

Viral load is suppressed, CD4 > 100 cells/μL > 3 months

2.10 Cytomegalovirus (CMV) Disease

2.10.1 CMV Retinitis

For treatment of:

Immediate Sight-Threatening Lesions - Adjacent to the Optic nerve or Fovea
Small Peripheral Lesions

Refer to Ocular infection section.

2.10.2 Extraocular CMV diseases (Treatment)

Oesophagitis, colitis, interstitial pneumonitis, neurological disease.

Preferred

Ganciclovir 5mg/kg IV q12h, may consider switch to valganciclovir 900mg PO q12h once patient tolerate orally (In CMV oesophagitis and colitis only).

Followed by maintenance therapy.

Alternative

*Foscarnet 60mg/kg IV q8h or 90mg/kg IV q12h

Followed by maintenance therapy.

Comments

Duration: 21-42 days or until signs and symptoms have been resolved.

Immune recovery is essential for successful treatment. Start ART within 2 weeks if possible.

*For patients with treatment limiting toxicities to ganciclovir or with ganciclovir resistant. Requires DG’s approval.

2.10.3 Extraocular CMV diseases (Maintenance Treatment / Secondary prophylaxis)

CD4 <100 cells/μL

Preferred

Ganciclovir 5mg/kg IV q24h 5–7 times weekly

Alternative

Valganciclovir 900mg PO q24h

Comments

Discontinuation:

Consider if patient is on ART and viral load well suppressed, CD4 > 100 cells/μL > 3 months and after 3-6 months of CMV treatment.

Maintenance therapy is generally not necessary; ART offers best hope for prevention of relapses.

2.11 Herpes simplex Virus (HSV) Infections

Refer to Sexually Transmitted Infection section.

2.12 Varicella-zoster Virus (VZV) Infections

Refer to Skin and Soft Tissue Infection (SSTI) section.

2.13 Bacterial Enteric Infections

2.13.1 Salmonellosis

Salmonella non-typhi

Preferred

Ciprofloxacin 500-750mg PO or 400mg IV q12h

Ceftriaxone 2g IV q24h

Alternative

Ampicillin 2g IV q4-6h

Trimethoprim/sulfamethoxazole (80/400mg) 2 tablets PO or 2 ampoules IV q12h

Comments

Susceptibility profile may help guide final choice.

Duration:

CD4 ≥ 200: 7-14 days.
CD4 ≥ 200 and with bacteraemia: 14 days is appropriate provided documented clearance of bacteraemia.
CD4 < 200 and with bacteraemia: 6 weeks.

Longer course with debridement and drainage needed for persistent bacteraemia or metastatic disease.

2.14 Rhodococcus Infections (Rhodococcus equi, formerly corynebacterium equi)

2.14.1 Induction Treatment

Preferred

Azithromycin 500mg STAT and then 250mg IV/PO q24h

Ciprofloxacin 500-750mg PO q12h or 400mg IV q8-12h or levofloxacin 500-750mg IV/PO q24h

PLUS

Rifampicin 600mg PO q24h

Alternative

Azithromycin 500mg STAT and then 250mg IV/PO q24h

Ciprofloxacin 500-750mg PO q12h or 400mg IV q8-12h or levofloxacin 500-750mg IV/PO q24h

Rifampicin 600mg PO q24h

PLUS

Imipenem/Cilastatin 500mg IV q6h

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

Comments

Duration:

Immunocompromised – at least 2 months

Duration will depend on the extent of the diseases.

Adjust antibiotics according to susceptibility data.

Use at least two or more susceptible agents.

Concomitant tuberculosis needs to be ruled out with use of rifampicin monotherapy.

For CNS involvement, to consider antibiotics with good CNS penetration.

2.14.2 Maintenance Treatment / Secondary Prophylaxis

Preferred

Azithromycin 250mg PO q24h

PLUS

Ciprofloxacin 500-750mg PO q12h

Levofloxacin 500-750mg PO q24h

Alternative

*Rifampicin 600mg PO q24h

PLUS

Azithromycin 250mg PO q24h

Ciprofloxacin 500-750mg PO q12h

Levofloxacin 500-750mg PO q24h

Comments

Duration: Until CD4 > 200 cells/μL

Choice to be based on susceptibility test.

Concomitant tuberculosis needs to be ruled out with use of rifampicin monotherapy.

2.15 Progressive Multifocal Leukoencephalopathy (PML)

Polyoma virus JC virus (JCV)

No effective therapy exists.

With ART, some patients improve and others stabilize. Few may deteriorate due to immune reconstitution.

2.16 Isospora belli Infection

2.16.1 Initial Therapy

Preferred

Trimethoprim/sulfamethoxazole 160/800mg IV/PO q6h

Alternative

*Pyrimethamine 50-75mg PO q24h

PLUS

Folinic acid 15mg PO q24h

Ciprofloxacin 500mg PO q12h

Comments

Duration: 10 days

For patients whose symptoms persist after 10 days, the treatment duration can be extended to 3-4 weeks.

*Requires DG’s approval.

Discontinuation:

CD4 count > 200 cells/μL for ≥ 6 months on ART.

2.16.2 Secondary Prophylaxis

Preferred

Trimethoprim/sulfamethoxazole 160/800mg PO q24h

Alternative

*Pyrimethamine 25mg PO q24h

PLUS

Folinic acid 15mg PO q24h (if sulfa-intolerant)

Ciprofloxacin 500mg PO three times a week

Comments

Duration: 10 days

For patients whose symptoms persist after 10 days, the treatment duration can be extended to 3-4 weeks.

*Requires DG’s approval.

Discontinuation:

CD4 count > 200 cells/μL for ≥ 6 months on ART.

2.17 Cryptosporidiosis

Cryptosporidium sp.

Symptomatic treatment of diarrhoea.

Effective ART (to increase CD4 > 100 cells/μL) can result in complete, sustained clinical, microbiological and histologic resolution.

2.18 Microsporidiosis

Microsporidium sp.

Preferred

Albendazole 400mg PO q12h for 2-4 weeks

PLUS

Symptomatic treatment of diarrhoea (the best treatment option is ART and fluid support)

Alternative

Comments

Effective ART (to increase CD4 > 100 cells/μL) can result in complete, sustained clinical, microbiological and histologic resolution.

2.19 Syphilis (Treponema pallidum Infection)

Refer to Sexually Transmitted Infections section.

2.20 Bartonellosis

2.20.1 Bacillary Angiomatosis, Peliosis Hepatis, Bacteraemia, and Osteomyelitis

Preferred

Doxycycline 100mg PO q12h

Erythromycin 500mg PO/IV q6h

Alternative

Azithromycin 500mg PO q24h

Clarithromycin 500mg PO q12h

Comments

Duration: At least 3 months

If relapse occurs after initial (> 3 month) course of therapy, long-term suppression with doxycycline or a macrolide is recommended as long as CD4 <200 cells/μL.

2.20.2 Other Severe Infections (or CNS involvement)

Preferred

Doxycycline 100mg PO/IV q12h

Erythromycin 500mg PO/IV q6h

MAY ADD

Rifampicin 300mg PO/IV q12h

Alternative

Comments

Duration: At least 3 months

If relapse occurs after initial (> 3 month) course of therapy, long-term suppression with doxycycline or a macrolide is recommended as long as CD4 <200 cells/μL.

2.20.3 Confirmed Bartonella endocarditis

Refer to Cardiovascular infections section.

References:

The BMJ Best Practices: HIV-related opportunistic infections. https://bestpractice.bmj.com/topics/en-us/899.
The Sanford Guide to Antimicrobial Therapy (updated 14/7/2023)
European AIDS Clinical Society (EACS) Guidelines version 11.1, October 2022
Pneumocystis jirovecii pneumonia (PJP) in adults with HIV infection. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; accessed 20th July 2023. https://www.tg.org.au
Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association, and Infectious Diseases Society of America. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/histoplasmosis?view=full (Accessed on July 20, 2023).
Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA, Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807. Epub 2007 Aug 27.
Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO.
Murray M, Hine P. Treating progressive disseminated histoplasmosis in people living with HIV. Cochrane Database Syst Rev. 2020 Apr 28;4(4):CD013594. doi: 10.1002/14651858.CD013594. PMID: 32343003; PMCID: PMC7192368.
Perez, F.; Caceres, D.H.; Ford, N.; Ravasi, G.; Gomez, B.L.; Pasqualotto, A.C.; Hine, P.; Adenis, A.A.; Nacher, M.; Chiller, T.; et al. Summary of Guidelines for Managing Histoplasmosis among People Living with HIV. J. Fungi 2021, 7, 134. https://doi.org/10.3390/jof7020134
Supparatpinyo K, Schlamm HT. Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients. Am J Trop Med Hyg. 2007;77(2):350-353. Available at: https://www.ncbi.nlm.nih.gov/pubmed/1769041
Connolly MP, Goodwin E, Schey C, Zummo J. Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis. Pathog Glob Health. 2017 Feb;111(1):31-44. doi: 10.1080/20477724.2016.1273597. Epub 2017 Jan 16. PMID: 28090819; PMCID: PMC5375610.
Lin WV, Kruse RL, Yang K, Musher DM. Diagnosis and management of pulmonary infection due to Rhodococcus equi. Clin Microbiol Infect. 2019 Mar;25(3):310-315. doi: 10.1016/j.cmi.2018.04.033. Epub 2018 May 16. PMID: 29777923.
British HIV Association guidelines on the management of opportunistic infection in people living with HIV: The clinical management of non-tuberculous mycobacteria 2023.
Daley et al. Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. CID 2020:71 (15 August 2023).
WHO Guidelines for the Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children, June 2022. (Supplement to the 2016 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection)
Jill P Adler-Moore and others, Comparison between liposomal formulations of amphotericin B, Medical Mycology, Volume 54, Issue 3, March 2016, Pages 223–231, https://doi.org/10.1093/mmy/myv111
A systematic review and meta-analysis of the relative efficacy and safety of treatment regimens for HIV-associated cerebral toxoplasmosis: is trimethoprim-sulfamethoxazole a real option? Hernandez AV, Thota P, Pellegrino D, Pasupuleti V, Benites-Zapata VA, Deshpande A, Penalva de Oliveira AC, Vidal JE. HIV Med. 2017;18(2):115. Epub 2016 Jun 28.
Rhodococcus equi infection. Yamshchikov AV, Schuetz A, Lyon GM. Lancet Infect Dis. 2010 May;10(5):350-9.
Shoham, Shmuel. "Cryptococcal Meningitis." Johns Hopkins ABX Guide, The Johns Hopkins University, 2019. Johns Hopkins Guides, www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540146/all/Cryptococcal_Meningitis
Sterling, Timothy R. "Mycobacterium Avium Complex (MAC), Disseminated." Johns Hopkins ABX Guide, The Johns Hopkins University, 2022. Johns Hopkins Guides, www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540363/all/Mycobacterium_avium_complex__MAC___disseminated.
Shoham, Shmuel. "Pneumocystis Jirovecii Pneumonia." Johns Hopkins ABX Guide, The Johns Hopkins University, 2019. Johns Hopkins Guides, www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540439/all/Pneumocystis_jirovecii_pneumonia.

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