Indian Antimicrobial Prescription Guidelines in Critically Ill Immunocompromised Patients

How to cite this article: Kulkarni AP, Sengar M, Chinnaswamy G, Hegde A, Rodrigues C, Soman R, Khilnani GC, Ramasubban S, Desai M, Pandit R, Khasne R, Shetty A, Gilada T, Bhosale S, Kothekar A, Dixit S, Zirpe K, Mehta Y, Pulinilkunnathil JG, Bhagat V, Khan MS, Narkhede AM, Baliga N, Ammapalli S, Bamne S, Turkar S, Bhat KV, Choudhary J, Kumar R, Divatia JV. Indian Journal of Critical Care Medicine 2019;23(Suppl 1): S64-S96.


INTRODUCTION
The number of admissions of immunocompromised patients in the Indian intensive care units (ICUs) is growing.This is because of availability of better treatments for acquired immunodeficiency states, increasing incidence and detection of cancer, with more aggressive therapies aimed at cancer cure, and increased expectations of better ICU outcomes in the cancer patient. 1,2he indications of immunosuppression have expanded, contributing to an increased number of immunocompromised patients.There is a sharp rise in the number of solid organ transplants being performed in India contributing to the increased number of patients with immunosuppression getting admitted to the ICU in immediate postoperative and subsequent follow-up period.In the pediatric population, we can recognize the genetic predisposition of patients to congenital immunodeficiency states.All these patients have greater susceptibility to new infections or reactivation of latent infections. 3Therefore, it is the need of the hour to develop Indian guidelines for prescribing antimicrobial therapy in this population presenting to the ICU.
We feel that the outcomes are likely to be better if these immunocompromised patients with infectious diseases requiring ICU admission are preferably treated at a tertiary care center where all diagnostic facilities along with specialists in microbiology, immunology, infectious disease are likely to be available.We present guidelines in five separate sections: febrile neutropenic patients, patients who have undergone a solid organ transplant, patients with human immunodeficiency virus infections presenting to ICU, congenital asplenia or hyposplenia, and those with congenital primary immunodeficiency syndromes.
These guidelines were developed starting with a collection of Indian and other data which was communicated to members by electronic communication.A meeting of all committee members was held where the data was presented in the form of questions pertaining to the evidence, available evidence from Indian ICUs, and evidence statements and recommendations.A draft of each section was prepared and circulated and finally presented in another committee meeting.The final draft of guidelines was prepared and again communicated to members.The GRADE system was used for the quality of evidence and recommendations (Table 1).

Quality of Evidence
Level of evidence Evidence from ≥ 1 good quality and well conducted randomized control trial(s) or meta-analysis of RCT's.

Strength of Recommendation
Grade Strong recommendation to do (or not to do) where the benefits clearly outweigh the risk (or vice versa) for most, if not all patients.

A
Weak recommendation, where benefits and risk are more closely balanced or are more uncertain.

B PART 1. PATIENT WITH FEBRILE NEUTROPENIA IN THE INTENSIVE CARE UNIT
Febrile neutropenia (FN) is defined as an oral temperature of >38.3°C or two consecutive readings of > 38.0° C for 2 hours and an absolute neutrophil count (ANC) of < 0.5 × 10 9 /L or expected to fall below 0.5 × 10 9 /L. 4 These guidelines are applicable to a critically ill febrile neutropenic patient presenting to the ICU, with any of the following clinical or laboratory parameters of organ failure but not limited to: • Hypotension • Tachypnoea requiring oxygen therapy more than 4 liters/minute to maintain saturation > 90% • Altered mental status (without focal neurological deficit) • Oliguria or rising creatinine

Empiric Antibiotic Therapy in Critically Ill Febrile Neutropenic Patients with Suspected Bloodstream Infection Evidence Statements
• In a critically ill febrile neutropenic patient presenting to the ICU with organ failure, empiric antibiotic therapy should be initiated or escalated to a broad spectrum carbapenem like imipenem or meropenem (UPP, A). • Empiric combination of Imipenem or Meropenem and Colistin/Polymyxin B may be considered in the following patients having a high risk of infection with resistant gram-negative organisms (UPP, A): a. Critically ill patients with underlying acute Leukaemia presenting to the ICU.b.Patients of Leukaemia/Lymphoma on b-lactam/blactamase inhibitor (BL/BLI) ± aminoglycosides, shifted to ICU from the ward.c.Previous exposure to broad-spectrum antibiotics like carbapenem or BL/BLI combination in last 1 month.d.Hypotensive patients requiring vasopressor infusions (refractory septic shock).e. Patient shifted to the ICU on carbapenem therapy.• We strongly caution against the use of an empiric combination of Imipenem or Meropenem and Colistin/Polymyxin B or Colistin/Polymyxin B alone in patients who are not a high risk of infection with carbapenem-resistant gram-negative organisms as defined above (UPP, A). • We recommend against empirical use of Doripenem and Ertapenem (III, A) • Vancomycin/Teicoplanin should be added as empiric therapy in a critically ill febrile neutropenic patient with a. Suspected Indwelling vascular catheter infection b.Skin and soft-tissue infection c.Previous Colonization/infection with methicillinresistant Staphylococcus aureus (MRSA) d.Blood Culture: Gram-positive cocci awaiting identification e. Severe mucositis (III, A) f.Hemodynamic instability (hypotension) in patients admitted from home /OPD (UPP, A) • We caution against empirical use of Vancomycin in another group of patients including patients on broad-spectrum antibiotics admitted to the ward and presenting to ICU with hemodynamic instability unless there is a high incidence of MRSA in the institute (UPP, A)

Evidence Summary
Common isolates in a blood culture in febrile neutropenic patients In India, in febrile neutropenic patients, gram-negative bacteremia is much more common than gram-positive bacteremia (Table 2); in contrast to the western data, where gram-positive isolates are more common. 5,6The spectrum of bacterial isolates from a number of studies in India suggest Enterobacteriaceae (E. coli and Klebsiella species) and Pseudomonas aeruginosa be the most common among gram-negative organisms.Among gram-positive isolates, Staphylococcus aureus and Coagulase-negative staphylococcus (CoNS) are most common isolates.
There are scarce data regarding the choice of empirical antibiotic regimens in critically ill febrile neutropenic presenting to the Indian ICUs.Most of the studies have a heterogeneous patient population-leukemia, lymphoma, solid, etc. Choice of antibiotics depends on the most likely causative microorganism, local antimicrobial sensitivity patterns, mechanism of action of antimicrobials, and site of infection, patient's predisposing condition and treating physician's judgment.Recent data show an increased prevalence of Multidrug-resistant (MDR) organisms.5][16][17] Hence, initial antibiotic choice in a febrile neutropenic patient who is critically ill present-ing to the ICU will be carbapenems like Meropenem or Imipenem.The prevalence of carbapenem-resistant gramnegative organisms is alarming at present.According to the Indian Council of Medical Research (ICMR) data on non-neutropenic population, carbapenem resistance among Enterobacteriaceae is 35 to 50 %, Pseudomonas spp 47% and Acinetobacter spp 62%. 17Based on the epidemiology, current evidence and clinical experience the committee has identified risk factors for carbapenem resistance.Particular subgroups of patients, such as acute leukemia patients presenting to the ICU, a patient already on carbapenem shifted to ICU from the ward, previous antibiotic exposure in the last 1 month and patients on vasopressors are at risk of harboring carbapenemresistant organisms. 18Hence in these groups of patients, initial empiric antibiotic regimen should include colistin/polymyxin B along with Imipenem or Meropenem (Table 3).
Vancomycin is not a standard part of empirical antibiotic therapy for the febrile neutropenic patient.In the western countries with predominant gram-positive bacteremia and high incidence of MRSA, studies have failed to show any benefit with empiric vancomycin in terms of fever or mortality. 19In India, with predominant gramnegative sepsis and low incidence of MRSA (35% as per ICMR data), 17 Vancomycin/Teicoplanin is recommended as part of initial antibiotic regimen only in patients with suspected indwelling catheter infection (rigors following infusion, cellulitis at exit site), skin and soft tissue infection, severe mucositis, culture growing gram-positive cocci pending identification, previous MRSA colonization/ infection and hemodynamic instability admitted from home/OPD. 7

Evidence Statements
• We recommend a collection of at least two sets of blood cultures, with a set collected simultaneously from a peripheral site and one from the central line.In the case of a multi-lumen catheter, one set per lumen should be collected.

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• One set includes one aerobic and one anaerobic culture bottle.Blood culture volume should be at least 10 mL/ bottle 7,20 (I, A).

Evidence Summary
The volume of blood is an important variable for detection of bloodstream infection volume of blood.Each ml of blood increased the yield (detection of positive culture) of blood cultures in adults by approximately 3%.Collection of two blood culture sets provide 80 to 90% yield of bloodstream pathogens in critically ill patients.In the pediatric population, smaller volumes of blood are suggested due to lesser total blood volume.The general consensus is not to exceed 1% of a patient's total blood volume.

Empiric Antifungal Therapy in Febrile Neutropenic Patient Evidence Statements
Following patients should be considered for initiation of antifungal therapy when they present to ICU with shock or respiratory distress especially when they have a persistent or recurrent fever or clinical deterioration after > 3 days of broad-spectrum antibiotics (II, A) a. Allogenic hematopoietic stem cell transplantation (HSCT).b.Severe mucositis with diarrhea.c.Prolonged/anticipated duration of neutropenia >10 days.d.Worsening on broad-spectrum antibiotics like BL/ BLI and Carbapenems.e.More than 3 weeks of steroids.f.History of invasive fungal infection.g.2][23][24][25] (II, A). • We do not recommend the routine use of combination antifungal therapy for probable or proven invasive aspergillosis (III, A).

Evidence Summary
Invasive Candida or Aspergillus infections have been demonstrated in the autopsy of patients who died of a neutropenic fever with no clinical evidence of invasive fungal infection (IFI) except for a continuous fever. 26It is estimated that approximately 15 to 45% of patients with prolonged neutropenia have an invasive fungal infection (IFI).IFI is difficult to diagnose both in critically ill patients and patients with febrile neutropenia.Invasive fungal infection is associated with high mortality in both these groups especially if treatment is delayed.High-risk patients who have received intensive cytotoxic chemotherapy are at risk for invasive fungal infection.Yeast (primarily Candida species) and molds typically cause infections, which are manifested by persistent or recurrent fever in patients with prolonged neutropenia, rather than causing initial fever in the course of neutropenia. 27,28Empirical antifungal therapy is instituted for the treatment of ''occult'' fungal infection presenting as persistent neutropenic fever despite 4 to 7 days of empirical antibiotic therapy. 29he echinocandins have demonstrated significant fungicidal activity and treatment success against most of the Candida species in randomized clinical trials.Availability of intravenous formulation, limited drug interactions, favorable safety, and efficacy profile make them the first choice of empirical antifungal in critically ill patients including patients with febrile neutropenia.It is generally agreed upon that individual echinocandins namely caspofungin, micafungin and anidulafungin have similar efficacy and are interchangeable. 30

Recommended Dosage
• Caspofungin: loading dose of 70 mg followed by 50 mg daily.Dosage reduction is recommended for patients with moderate to severe hepatic dysfunction.

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Echinocandins have activity against Aspergillus species.However, Echinocandins monotherapy as the first line for treatment of Aspergillus is not studied well.Echinocandins have shown to be effective in salvage therapy however they are not recommended as monotherapy for the primary treatment of IA due to lack of evidence. 29ipid formulations of amphotericin B should be used as first-line treatment if Mucormycosis (Zygomycosis) is suspected.The recommended dose is 3 to 5 mg/kg daily. 32nvasive aspergillosis should be suspected in patients with persistent febrile neutropenia with the development of signs of pneumonia including lung infiltrate.Voriconazole can be used for suspected or proven cases of IPA.The dose of Voriconazole is 400 mg (6 mg/kg) twice daily for two doses, then mg/kg) twice daily.As mentioned above, Echinocandins are recommended for salvage therapy of aspergillosis. 33mphotericin B deoxycholate should be avoided in patients with underlying renal impairment, patients on other nephrotoxic drugs such as cyclosporine or tacrolimus after allogeneic HSCT, or antibiotics, such as aminoglycosides and in patients with previous history of toxicity.
Recommended minimum duration of therapy for candidemia without metastatic complications is 2 weeks after documented clearance of Candida from the bloodstream, provided neutropenia and symptoms attributable to candidemia have resolved. 7nvestigation for confirmation of invasive fungal infection: Poor sensitivity of chest radiograph compared to CT scan for detection of pneumonia in this population should be kept in mind. 34The galactomannan assay is highly specific for Aspergillus species with some cross-reactivity with Histoplasma capsulatum and Penicillium species.The false positive reaction can occur with concomitant use of b-lactam/b-lactamase combinations, such as piperacillintazobactam. 22arr et al have demonstrated 8.2% absolute reduction in mortality rates with the combination of voriconazole and anidulafungin in adult patients with hematologic malignancies (HMs) and hematopoietic stem cell transplantation (HSCT) having probable or proven Invasive aspergillosis (IA).However, this difference was not statistically significant.
Combination antifungal treatments are used with the rationale to maximize treatment by targeting multiple sites or metabolic pathways or different steps in the same pathway hence leading to an additive or synergistic effect.While in vitro studies on combination antifungals showed additive or synergistic effect; in vivo studies have given mixed results.While the combinations of azoles with echinocandins has shown additive or synergistic effects; combinations of polyenes with triazoles have demonstrated the antagonistic effect.Lack of in vitro findings has not been replicated with consistency.These in vivo studies are difficult to interpret due to the lack of validated protocols, variable test designs, and a definite end point.Combination antifungal therapy definitely increases the cost of treatment, has the potential to cause deleterious drug interactions, may add toxic effects and have the possibility of increased risk for resistance.In view of the lack of strong evidence in favor as well as potential harmful effects, routine use of a combination of combination antifungal therapy is not recommended. 35

Empiric Antiviral Therapy in Febrile Neutropenic Patient Evidence Statements
• There is no role of empirical antiviral therapy with febrile neutropenia (III, A)

Evidence Summary
3][44] If they present with hypoxemic respiratory failure, then such patients should be on sulfamethoxazole/trimethoprim.Hypoxemia is the most characteristic abnormality in PCP pneumonia.Chest radiograph might be normal in early disease.

Role for Empiric Antimicrobial Therapy for Tropical Infections like Malaria, Leptospirosis Evidence Statements
• There is no role for empirical antimicrobial therapy against tropical infections like malaria, leptospirosis (III, A) • Documented tropical infections in neutropenic patients in ICU should be treated similarly as they are treated in non-neutropenic patients (UPP, B)

Evidence Summary
There are occasional reports of malaria in patients on chemotherapy with a solid tumor and hematolymphoid malignancies with febrile neutropenia.In a series of 99 patients of acute leukemia on chemotherapy with febrile neutropenia, malaria was responsible for fever in only 4% of patients. 45ebrile neutropenia patient presenting to ICU often have thrombocytopenia due to the disease itself, chemotherapy or sepsis.Presence of fever and thrombocytopenia itself should not warrant empirical anti-malarial therapy even in a malaria-endemic country like India.
A high index of suspicion is warranted in a resident or traveler of malaria endemic area who presents with the classic triad of symptoms (fever, chills, and sweating).If malaria is suspected, peripheral smear for malaria parasite and rapid malaria antigen [e.g.Histidine-rich protein II (HRP-II) antigen of Plasmodium falciparum and common Plasmodium lactate dehydrogenase (pLDH) of Plasmodium species] should be performed early, and antimalarial therapy should be initiated in positive cases.With rapidity (diagnosis in less than an hour) and good negative predictive value of (98.2%) malaria antigen test, antimalarial therapy is restricted only to positive cases. 46here is lack of enough evidence documenting the etiological role of other tropical infections like Leptospirosis in a subset of patients with febrile neutropenia; hence we believe that until enough evidence is available, suspected or documented tropical infections in neutropenic patients in ICU should be treated similarly as they are treated in non-neutropenic patients.

Role of Surveillance Cultures Evidence Statement
• We strongly recommend against repeated surveillance cultures as these do not help to guide antibiotic therapy (III, A)

Evidence Summary
As most of the infections in neutropenic patients occur due to organisms in the respiratory or gastrointestinal tract, therefore surveillance culture seems to be a reasonable strategy in deciding the empiric antibiotic therapy in febrile neutropenia.The studies published in the 1980s and '90s supported the practice of surveillance culture.However, there has been a very poor correlation between blood and fecal isolates in most of the studies. 47,48idespread antimicrobial treatment may inhibit the growth or distort the proportion of different species found in fecal cultures.A recent study conducted in pediatric allogeneic HSCT patients has demonstrated a positive predictive value of 0.9% to bacterial surveillance cultures, with a sensitivity of 33.3% and a specificity of 47.4%.Surveillance cultures were not cost effective.The sampling and analyses require lots of laboratory and nursing resources. 49Another study in adults who got admitted for HSCT concluded that surveillance blood cultures in patients who have undergone HSCT do not identify bloodstream infections.The number of positive blood cultures was not helpful in determining which patients had an infection.

Evidence Summary
Control of source in the form of drainage of an abscess, debridement of infected necrotic tissue and removal of a potentially infected device is of paramount importance.Foci of infection readily amenable to source control include but not limited to intra-abdominal abscesses, gastrointestinal perforation, ischaemic bowel or volvulus, cholangitis, cholecystitis, pyelonephritis associated with obstruction or abscess, necrotizing soft tissue infection, empyema, septic arthritis, and implanted device infections.There is general agreement that source control should be done at the earliest to reduce microbiological burden, and mere antibiotics and resuscitation would not achieve cure unless adequate source control is done.If Vascular catheters are suspected, its prompt removal should be considered.It is important to note that the classical clinical signs of infection (rubor, calor, dolor, etc) be absent due to low neutrophil counts. 51atients with S. aureus catheter-related bloodstream infection (CRBSI) have a significantly higher risk of hematogenous complications with the retained foreign body, especially in immunocompromised patients.Retention of the catheter has shown to worsen the outcome of candidaemia. 52

Recommendations
• Antimicrobial de-escalation should be implemented in the following situations: (III, A) a. Once and if a pathogen is identified, we recommend de-escalation to an antibiotic that the organism is susceptible to.b.We recommend treating with appropriate agents based on the site and pathogen until the patient is afebrile for at least 48 hours and there is evidence of marrow recovery (neutrophil count ≥ 500 cells/ mm 3 ).c.In patients without microbiologically documented infection we recommend continuing empirical antimicrobials until the patient is afebrile for at least 48 hours and there is evidence of marrow recovery (neutrophil count ≥ 500 cells/mm 3 )

Evidence Summary
Data on de-escalation strategies in neutropenic patients after identification of a clinically relevant pathogen is scant, and there is no data on de-escalation when no pathogen has been identified.Although antibiotics are required to treat an occult infection during neutropenia, marrow recovery is necessary to protect the patient. 18

Useful Practice Points
Antibiotics like Fosfomycin, tigecycline and minocycline may be considered in infection with multidrug-resistant bacteria in the presence of in vitro susceptibility after considering the in vivo penetration at the source of sepsis.

Fosfomycin Tigecycline Minocycline
Good activity It is advisable to have a syndrome-based approach (e.g., Nonspecific febrile illness, pneumonia, urinary tract, central nervous system) at first and then narrow the differential diagnoses of possible organisms that could cause the clinical presentation(s).
Microbiological diagnosis is crucial in this patient group.In the context of extensive differential diagnoses, the value of early and specific diagnostics with the use of invasive procedures if necessary (bronchoscopy, tissue biopsy, or aspiration of collections) to obtain specimens cannot be underestimated.After transplantation, serologic techniques are of limited use because transplant recipients may not mount timely serologic responses.Thus, antigen detection or molecular nucleic acid detection assays are preferred over serologic testing.The timeline of post-transplant infections reflects the post-transplantation relationship between the recipient's epidemiologic exposures and immunosuppressive strategy employed (Table 1).It is used to establish a differential diagnosis for infectious syndromes at various stages after transplantation.Infections occurring outside the usual period or of unusual severity suggest excessive immunosuppression or epidemiologic hazard.Most centers use a variation of standard 'triple immunosuppression' (prednisone, calcineurin inhibitor, antimetabolite such as mycophenolate mofetil).

Evidence Statements
• Infections in the first month (0-30 days) of post SOT period should be treated similarly to the treatment of a non-immunocompromised postoperative patient (I, A).Approach to initial diagnostic workup and empiric therapy in post SOT recipients (30-180 days).
• We recommend early BAL in patients with suspected pneumonia coming to ICU (I, A).We recommend that the BAL fluid should be tested for (I, A).Total and differential cell counts Microbiology q Cultures: Aerobic culture for bacteria, mycobacterial growth indicator tube (MGIT) for mycobacterium tuberculosis, fungal culture q Stains and immunohistochemistry Gram stain: Bacterial KOH preparation/Calcofluor white: Fungal Auramine-rhodamine, auramine-o, or ziehl-neelson: Mycobacterial Modified acid-fast stain (kinyoun): Nocardia Silver methenamine: Pneumocystis carinii pneumonia, fungal q Galactomannan assay: Negative predictive value < 0.5, positive predictive value > 3 q Polymerase chain reaction (PCR) Mycobacterium tuberculosis: Cartridge Based Nucleic Acid Amplification Test (CB-NAAT or GeneXpert) Multiplex PCR assay q Quantitative or semiquantitative cultures particularly for pneumonia.Following organisms are diagnostic of infections.If organisms are identified it is less likely to be the contaminants/colonizers and should be treated.
• Pneumocystis carinii Hospitalization in an acute care hospital ≥ 2 days within the prior 90 days (UPP, B) • We recommend voriconazole in the dose of 6 mg/kg bd for 1-day f/b 3mg/kg bd (I, A) • As a salvage therapy, we recommend Caspofungin (dose 70 mg IV followed by 50 mg iv daily) (I, A) • We recommend therapeutic drug level monitoring of the voriconazole when using these agents for the treatment of Invasive Aspergillosis (I, A).

Evidence Summary
During the first month after SOT, opportunistic infections are generally absent as the full effect of immunosuppression has not yet been established.In this period donorderived or recipient-derived viremia, candidemia or technical complications related to surgery are common. 1ost infections are caused by gram-negative bacterial (GNB).Bacterial infections are either nosocomial or healthcare-associated (27.4% and 49.8% respectively); the remaining 22.9% are community-acquired. 2The urinary tract infection (UTI) is the most common primary source of GNB infections in 55.2% of SOT recipients.Gastrointestinal infections are the second most common infections (15.2%).Other infections include infections of the respiratory tract (3.6%), intravascular catheters (3.6%) and skin and soft tissue (2.7%) are also seen in SOT recipients in decreasing order of occurrence.E. coli has been found to be the most common GNB (36.8%), followed by K. pneumoniae (14.3%),P. aeruginosa (13.0%),Enterobacter cloacae

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Indian data shows that UTI is the most common infection. 3In 169 renal allograft recipients, they observed that 23.6% of the SOT recipients develop UTI during first 4 weeks and E. coli is the most common causative agent (12.6%).CMV is the most common (prevalence of CMV 21.8%) between 4 weeks to 3 months after renal transplantation and can cause allograft loss.Tuberculosis reactivated commonly between 3 months to 1-year post-transplant (prevalence of tuberculosis being 10.6%).Pneumocystis carinii and Aspergillus are serious hazards which usually occur after 1 year.Aspergillus infection is the leading fungal infection (10.0%). 3Another retrospective study in of 144 renal transplant patients also found that UTI was the most common infection (34.5%), followed by viral (31.2%), sepsis (15.2%), mycobacterial (9.7%) and fungal (6.2%).Parasitic infections (giardiasis and Strongyloides hyper infection syndrome) occurred in 2 (1.4%) patients.CMV accounted for 14.5% and BK virus (Polyomavirus hominis1) for 5.5% of total infections. 4One prospective observational study in 45 renal transplant recipients reported a similar finding.In the same study, other infections like tuberculosis (n = 8), CMV (n = 6), candidiasis (n = 7), hepatitis (n = 11), cryptosporidiosis and pneumocystis (n = 10) and in 7 patients simultaneous infections with two organisms were seen.E. coli (33.3%) was the most common organism grown in culture followed by Klebsiella (20%), Acinetobacter (20%), Proteus (6.67%), and others such as Staphylococcus or Pseudomonas (6.67%).The incidence of MDR was found to be 31.8%. 5 study on bacterial infections in SOT recipients in liver transplant recipients observed that overall incidence of infections during the first-month post-transplant was 80.2% and the incidence of bacterial pneumonia in the first six months was 21.3% (101/475).A prospective study of 475 liver transplant recipients found that the frequent pneumonia isolates were Enterobacteriaceae, Acinetobacter baumannii, P. aeruginosa and Staphylococcus aureus.Gramnegative bacilli accounted for 69.6% of all pneumonia pathogens out of which MDR rate was 58.9%. 6e prospective multicenter study involving 35 centers reported the incidence of pneumonia after SOT as 10.1 episodes/1000 recipients/year and bacteria (87.1%), virus (29%), and fungi (6.4%) were the common causative agents.A multidrug-resistant bacterium is isolated in 18.2%, 40%, and 100% of patients with CAP, HCAP, and HAP (p = 0.007), respectively.Overall, 11.1% of patients admitted to the intensive care unit, 3.7% developed graft rejection, and graft function deteriorated in 18.5%.In-hospital mortality was 1.9 %. 7 In renal transplant recipients, bacterial infections are the most common cause of pneumonia.A retrospective study of 406 renal transplant recipients observed that incidence of healthcare-associated pneumonia is 56% and bacterial infections are the most common cause (31% of the patients), especially haemophilus influenzae, stenotrophomonas maltophilia, and pseudomonas aeruginosa. 8Another prospective study of 610 kidney transplant recipients also observed 60 episodes of pneumonia in 54 patients (8.8%), of which 23 had a nosocomial origin (38%) and 37 were community-acquired infections(62%).Bacterial infection is the most frequent etiology (44%), followed by fungal in 4 (7%) and viral in 2 (3.5%).The most commonly isolated microorganism in nosocomial pneumonia is P. aeruginosa (26%, among which 50% were multidrug resistant).In 34% episodes, no microorganism is isolated.The most common pathogen among community-acquired pneumonias is S. pneumoniae (11%).In 54% of cases, there is no microbiologic confirmation of disease.The overall accuracy of bronchoalveolar lavage is 72%.When 21 patients with pneumonia (35%) were admitted to the ICU; of these, 14 had a nosocomial infection (60%) and 9 (15%) died due to the infection (p = 0.001). 9ata on heart transplant recipients has also shown that pneumonia is the most common complication.A prospective review of 307 heart transplant recipients found 21.1 cases of pneumonia per 100 heart transplantations.75% of the cases occurred in the first 3 months, 82 causal agents are identified, of which 60% were opportunistic, 25% are nosocomial, and 15% were community-acquired.The most frequent isolates were CMV,20 aspergillus species, 13 and pneumocystis carinii. 11Hemoptysis occurred more frequently in aspergillus pneumonias than in other pneumonias (54% vs. 6%, respectively; p < .05);aspergillus pneumonia is the only type of pneumonia during which cavitated nodules were noted on thoracic radiographs.The overall mortality rate was found to be 30.8%. 10 Lenner et al reported 47 of 159 heart transplant recipients (29.9%) had 81 pulmonary complications.1including Pneumonia (n = 27), and bronchitis (n = 15). 11 retrospective review of 34 heart transplant recipients (31.3%) who developed pulmonary complications, within first 6 months post-transplant showed Hospital-acquired bacterial pneumonia in 5 patients, fungal pneumonia in 3 patients, a post-transplant lymphoproliferative disease in 1 patient, and community-acquired pneumonia in 1 patient.Pneumonia-related mortality rate was 14.7% due to early-onset nosocomial pneumonias where bacterial and opportunistic microorganisms organisms were more commonly seen. 12OT recipients are at risk of developing bacterial infections like nocardia. 13The risk of developing nocardiosis after SOT varies with the type of organ transplanted, e.g.lung transplant.In a review of 5126 organ transplant recipients has demonstrated that highest nocardial infection rate was seen among lung transplant recipients (3.5%). 14ue to frequent exposure to antibiotics and repeated hospitalizations; SOT patients are at risk of developing intra-abdominal infections (IAI).IAI is commonly seen as a complication in post-liver, pancreas, multi-visceral transplants.Superinfection with MDR pathogens occurs frequently causing tertiary peritonitis. 15Clostridium difficile-associated disease (CDAD) is the most common cause of nosocomial diarrhea.One cohort study involving 4472 SOT patients observed that 42 episodes of CDAD were diagnosed in 36 patients (0.94%).Median onset of infection was 31.5 days (range 6-741).It occurred during the first month after transplantation in half the cases and overall the prognosis was good. 16OT recipients are at risk to develop viral infections leading to various nonspecific viral syndromes.Common viruses seen are CMV, EBV, and other viruses like herpesvirus, 8 Zika virus, RNA respiratory viruses, adenovirus, norovirus, and polyomaviruses. 17Among viruses CMV virus disease which occurs during the first 3 months.With the introduction of CMV prophylaxis, this onset has been delayed.The seroprevalence rate of CMV ranges from 30-97%. 18he incidence of PCP in SOT recipients is variable.In a retrospective study of 1192 renal transplant patients, it was reported to be 0.6 to 9%.They obsereved that the incidence of PCP with a moderate Cyclosporine based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors. 19n another retrospevtive study of 601 renal transplant recipients, PCP incidence was 2.2%. 20In liver transplant recipients (154 adult patients) PCP occurred in 5.2% and the authors observed that patients who developed PCP had more episodes of rejection (p < 0.05), received more OKT3 (p < 0.05), a prednisone (p < 0.05) than controls. 21nother retrospective study of 43 adult OLT recipients showed that the incidence of PCP was 0.9%.Most of the patients developed PCP at around 1 year of post-OLT, and the risk of PCP was closely related to strong immunosuppressive regimen.Thus they advised that routine PCP prophylaxis for 12 months be continued for 12 months, among patients receiving antirejection treatment. 22nvasive fungal infection (IFIs) frequently complicates post SOT course.Cryptococcosis is a significant opportunistic infection in SOT recipients following aspergillosis and candidiasis.CSF analysis is highly recommended to diagnose underlying CNS disease in suspected cases. 23n Lung and heart transplant, -2% incidence IFI of lung was noted and even dissemination can occur.Cryptococcus can colonize the airways of lung transplant recipients and can cause endobronchial fungal infection.It can present with skin manifestations and Immune reconstitution syndrome as well. 24,25In heart transplant recipients incidence of cryptococcus is 3%, it manifests as sepsis and is associated with high mortality. 26,27In renal transplant recipients incidence of cryptococcus is 2.8% manifests as cryptoccocal necrotizing soft tissue infection. 28In liver transplant recipients the incidence is 2.4 % and liver failure is independently associated with Cryptoccocal meningitis mortality. 29However, with wider employment of antifungal prophylaxis and improvements in transplantation practices, there is a decline in the overall incidence of IFIs. 30,31SOT reciepnts have risk of developing aspergillous particulary in lung trsnplant.A retrospective study involving 362 lung transplant recipients found that 105/335 (31%) patients had evidence of aspergillus infection (colonisation or invasion), 83 (25%) patients had colonisation and 22 (6%) patients had radiographic or histological evidence of invasive disease.Most of the infections occurred within the first 3 months after transplantation.Invasive aspergillosis (IA) was associated with 58% mortality after 2 years, while colonisation was associated with increased mortality after 5 years compared non-colonised patients (p < 0.05). 32Hambrecht et alcompared voriconazole with amphotericin b in their large randomized trial for the treatment of invasive aspergillosis (IA) in immunocompromised patients. 33

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After this trial voriconazole had been considered the preferred agent for IA.In their study they found that at week 12, there were more successful outcomes 52.8% patients in the voriconazole group (complete response 20.8% and partial response in 31.9%)compared to 31.6% in the amphotericin B group (complete response 16.5% partial response in 15%).The survival rate was better at 12 weeks in voriconazole compared to amphotericin B group.(71% vs. 58%) (HR-0.59;95% CI-0.40 to 0.88).After this study several studies were conducted for use of voriconazole for the treatment of IA, especially in patients of solid organ transplant recipient.J. Fortun et al in their case series reported of 100 % complete response in four patients (two liver transplant, one lung transplant and one kidney transplant) of IA after treatment with voriconazole. 34Denning et al in their study showed good response in IA treated with voriconazole; 56 out of 60 patients in voriconazole group were treated successfully. 35eroux et al reported complete response in four kidney transplant patients with IA treated with voriconazole. 36n another report that included 11 SOT recipients with central nervous system aspergillosis treated with voriconazole, the favorable response rate was 36% and survival was 31%. 37Voriconazole was successfully used in heart transplant recipients as first-line and salvage therapy for IA. 38,39Plasma drug level monitoring is important when voriconazole is used as the plasma levels achieved are variable and very often do not reach therapeutic levels in the plasma, requiring dose adjustments. 40The fact that clinical efficacy is dependent on the achievement of therapeutic drug levels has been well established. 41

CMV management
• We recommend IV ganciclovir 5mg/kg twice a day as the initial treatment for (I, A): a. Severe or life-threatening CMV disease b.Patients with high and increasing viral load c.Patients with questionable gastrointestinal absorption • Oral valganciclovir 900 mg once a day is an effective initial therapy for mild to moderate CMV disease (I, A), or as a step down to iv ganciclovir after clinical improvement (II, B) • We recommend against the use of acyclovir and oral ganciclovir for treating CMV disease (UPP, A). • IV gamma globulin or preferably CMV-specific gamma globulin if available in the dose of 1 gm/kg over two days may be considered for patients with life-threatening disease, CMV pneumonitis (II, B). • We recommend a duration of treatment for a minimum of two weeks.It should be continued until viral eradication is achieved either by weekly monitoring for viral load by real-time quantitative PCR (I, A).
• Therapy should be extended beyond two weeks if the clinical resolution is not seen or virus load continues to be high (I, A). • After completion of full-dose antiviral treatment, a 1 to 3 months course of secondary prophylaxis may be considered depending on the clinical situation (II, B). • Cautious reduction in immunosuppression should be considered in SOT patients presenting with CMV disease, especially if the disease is moderate to severe (II, B).

Evidence Summary
Drugs used for the treatment of CMV disease are IV Ganciclovir and oral valganciclovir.Oral ganciclovir should not be used due to poor bioavailability.3][44] Asberg et al in a randomized controlled trial compared the outcome of CMV disease after treatment with IV Ganciclovir and oral valganciclovir.Three hundred twenty-one SOT recipients were enrolled and randomized to receive either twice daily intravenous ganciclovir or oral valganciclovir for 21 days followed by once daily valganciclovir until day 49 in all the patients.All patients were followed up for 1 year.The success rate was the same in both the groups with a similar rate of clinical and viral eradication.The clinical recurrence rate was also not statistically different in both the groups. 43In a retrospective study, the response to therapy was assessed using RT-PCR (2262 samples) and antigenemia using pp65 assay (1285 specimens).Both methods had > 90% specificity, but RT-PCR had better sensitivity.The authors concluded that RT-PCR was a more reliable tool to monitor the response to therapy. 45ailure to eradicate DNA-emia was the only independent predictor of recurrence in both the groups.7][48] There is a direct association between viral suppression below the lower limit of quantified test and disease resolution.Rapid resolution of CMV disease is seen with lower pre-treatment viral load (lower than 18,200 IU/mL). 49

PCP Management
• We recommend trimethoprim-sulfamethoxazole (TMP-SMX) as the first-line agent and drug of choice with the Trimethoprim component being 20 mg/kg /day in 3 to 4 divided doses (I, A). • In severe infections, if available, intravenous pentamidine probably remains the second-line agent after TMP-SMX (II, A).
• In patients with hypoxemia (PaO 2 < 70 mmHg on room air), adjunctive corticosteroids should be administered with antimicrobial therapy, ideally within 72 hours of initiating antimicrobial therapy for maximum benefit (II, A).The dose of steroids should be 1 mg/kg/day prednisone (or equivalent) given in two divided doses daily for 5 to 7 days (II, A).Steroids should be tapered over a period of 7 to 14 days (II, B). • Duration of antimicrobial therapy should be for at least 14 days (I, B).

Evidence Summary
TMP-SMX acts by interfering with folate metabolism and remains the drug of choice for treatment of PCP in SOT patients, HIV patients, and non-HIV patients.TMP-SMX has high efficacy and availability in both oral and IV preparation with good oral bioavailability too. 502][53][54][55] However, the use of pentamidine has been largely limited in view of its numerous toxicities in 71% patients leading to withdrawal in around 18 % patients. 52The optimal duration of therapy is usually 14 days which can be extended to 21 days in severe cases with slow clinical improvement. 56djunctive glucocorticoids are recommended for HIVpositive patients with moderate to severe PCP, defined as PaO 2 < 70 mmHg while breathing ambient room air. 57he benefit in survival from corticosteroids begins during the first 72 hours of treatment. 58Bolée et al's study found a trend for longer survival in patients who received adjunctive steroids (p = 0.07). 59In Pareja et al's study, there was no difference in the mortality rates of patients treated with adjunctive high-dose steroids, but they did spend less time on mechanical ventilation compared to patients not managed with steroids. 60

Evidence Statements
• The diagnosis of active TB in transplant recipients requires a high index of suspicion.Although the diagnostic modalities and treatment of TB in SOT patients remains the same as that in immunocompetent hosts, these individuals often require an invasive procedure, such as bronchoscopy with bronchoalveolar lavage or lung biopsy (I, A). • Rifamycins, particularly rifampin, reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, necessary dose adjustments, and therapeutic drug monitoring are warranted to avoid development of rejection (II, A).When rifampin is not used, a longer than usual duration of treatment is required (II, B).

Evidence Summary
Given that tuberculosis is an immunological disease and with the high prevalence of TB in India, the incidence of active tuberculosis infection is higher among SOT recipients as compared to the general population. 61,62he diagnosis of TB in SOT recipients presents challenges that may lead to treatment delay.4][65] One-third to one-half of cases of tuberculosis after transplant are disseminated or extrapulmonary.Lung transplant recipients are most likely to develop pulmonary manifestations of TB. [65]

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• We suggest consideration for surgical intervention in cases of complicated CDI.(II, B). • In cases of multiple recurrences of CDI, we recommend prolonged courses of oral vancomycin, either in a tapering or pulse dose schedule (II, A).Fidaxomicin can be used if available (II, B)

Evidence Summary
Due to frequent exposure to antibiotics and repeated hospitalizations SOT patients are a risk of developing intra-abdominal infections (IAI).IAI is commonly seen as a complication in post-liver, pancreas, multivisceral transplantation and superinfection with MDR pathogens occur frequently causing tertiary peritonitis. 66Common causes of diarrhea are as mentioned in Table 3.The treatment of choice for CDI had been oral vancomycin.
Vancomycin has been shown to have much better efficacy compared to metronidazole in many studies.Zar et al in their randomized controlled trial in 150 patients found that both metronidazole and vancomycin were equally effective in treating mild CDI, but Vancomycin was much more effective in treating severe CDI. 67The clinical cure rate in mild CDI was 90% and 98% with metronidazole and vancomycin respectively (p = 0.36).In severe CDI the cure rates were 76% and 97% respectively (p = 0.02).
Recurrence rates were also comparable in both the groups.Fekety et al in their randomized controlled trial compared two doses regimen of vancomycin in 46 patients viz.125 mg four times a day vs. 500 mg four times a day. 68They found no difference in measurable responses to the two regimens.Since 125 mg four times a day is more costeffective 125 mg dose is recommended.Even 125 mg-dose produces stool concentration of vancomycin of around 100 times more than the minimal inhibitory concentration (MIC) for C. difficile. 69The usual dose of oral vancomycin for children is 40mg/kg daily given in three or four divided doses.Fecal microbiota transplantation (FMT) in the management of refractory CDI has gained popularity recently, although in SOT recipients it has theoretical safety concerns.A series of cases (75 adults and 5 pediatric patients) treated with FMT for recurrent, refractory, and severe and/or overlap of recurrent/refractory and severe CDI had 78% cure rate after first FMT. 70There were no related infectious complications or adverse events in these high-risk patients.

CNS Infections
Evidence Statements

Evidence Summary
SOT patients with altered sensorium should be evaluated with detailed workup.Multifactorial etiologies coexist which are often obscured in these group of patients. 71ommon pathogens causing CNS infections in SOT recipients are mentioned in Table 4.Although each imaging modality has unique insight to diagnose pathophysiology, but magnetic resonance imaging (MRI) is the preferred modality.It can diagnose infectious as well as non-infectious etiologies like drug toxicities, metabolic disorders as well as the progression of the disease and response to the therapy. 72,73Empiric broad-spectrum antimicrobial therapy including viral and fungal infections are preferred.It is preferred to use empirical bactericidal or fungicidal agents having CNS penetration until a diagnosis is achieved. 71There has been always a risk of donor-derived infections in SOT recipients thus donors should be screened with standard screening tests. 74,75

Evidence Summary
SOT recipients are at risk of developing nocardia infection which is an opportunistic event. 76The risk of developing nocardiosis after SOT varies with the type of organ transplanted, e.g., the highest incidence in recipients of a lung transplant.A review of 5126 organ transplant recipients has demonstrated that highest nocardial infection rate among lung transplant recipients (3.5%). 77TMP-SMX is the treatment of choice for nocardial infections as it has demonstrated clinical efficacy and achieves high tissue concentrations in lung, brain, skin, and bone.Combination therapy is recommended in critically ill patients with pulmonary nocardia, cerebral nocardia, and disseminated nocardia. 78Linezolid has shown good activity against all species of nocardia. 79

IJCCM PART 3. THE HUMAN IMMUNODEFICIENCY VI-RUS (HIV) POSITIVE PATIENT IN THE INTENSIVE CARE UNIT
These guidelines are applicable to a patient who is known to be infected with the human immunodeficiency virus (HIV) or presents for the first time to ICU with AIDSdefining conditions.
With the advent of highly active anti retroviral therapy (HAART) era and the Test and Treat policy in HIV (where anyone testing positive receives HAART irrespective of CD4 cell counts).The incidence of ICU admissions for an HIV related illness is decreasing.Although HIV infected patients may still seek intensive care for reasons related directly to HIV infection, more and more seek care for other conditions that are unrelated to HIV such as trauma, infections, and other chronic diseases.Except for some special conditions such as opportunistic infections or HIV related treatment complications, HIV-infected patients are managed similarly to other patients without HIV infection.The treating physician should be aware of drug interactions, infectious and noninfectious conditions as a cause of the clinical presentation.• We suggest the addition of clindamycin (to vancomycin, but not to linezolid) in cases of severe necrotizing pneumonia to minimize bacterial toxin production (III, B). • When the etiology of pneumonia has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be de-escalated (II, A). • A switch to oral therapy should be considered in patients with community acquired pneumonia (CAP) on IV antibiotic therapy who have improved clinically, can swallow and tolerate oral medications, and have intact gastrointestinal function (II, A).

Evidence Summary
Respiratory failure is the most important cause of ICU admission among HIV patients.However, the specific microbiology data on etiology among HIV positive patients in the ICU is lacking from the Indian sub-continent.After going through the available literature, the most common pathogens seem to be viral infections, Pneumocystis Jirovecii, Streptococcal pneumoniae, H. Influenzae, M. tuberculosis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli 2 (Table 1).These patients are highly susceptible to infections with Mycobacterium tuberculosis (MTB).Hence MTB should be actively searched and ruled out in this population, and this may often require invasive interventions like bronchoscopy to get a bronchoalveolar sample.Appropriate sample collection may be taken for staining and cultures (sputum/bronchoscopic lavage or non-directed BAL in intubated patients Table 2).Sample collection should be done as early as possible, preferably within 1 hour and a broad spectrum antibiotic to cover gram-negative organisms may be added empirically.In case there is a delay of collecting the sample, the antibiotics should be administered as fast as possible.Sputum samples should be sent for gram staining, culture, and also special stains for pneumocystis.Cartridge based nucleic acid amplification test (CBNAAT) of samples is beneficial in the early and rapid diagnosis of MTB and multi-drug resistant tuberculosis (MDRTB).In con-cordance with the surviving sepsis guidelines, we also recommend measuring lactate at baseline.The recommendations regarding antibiotic therapy in HIV are based on studies in both ICU and Non-ICU patients admitted with community-acquired pneumonia (Table 4).In a Dutch trial-CAP-START, among patients admitted to inpatient wards for CAP, b-lactam, and macrolide combination therapy was associated with increased mortality -as compared with fluoroquinolone monotherapy.However, the cohort group had a very low incidence of atypical infections.Studies from Switzerland that compared b-lactam monotherapy to combination therapy with a b-lactam plus a macrolide found a nonsignificant trend of clinical stability in the combination group.A meta-analysis of b-lactam-macrolide combination therapy suggested that the combination was associated with reduced mortality compared with beta-lactam monotherapy.In view of the paucity of literature and

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unknown efficacy of monotherapy, the expert committee felt that these patients should receive broad-spectrum combination therapy rather than monotherapy.
After starting on initial broad-spectrum antibiotics, once the culture reports are available, the antibiotic therapy should be de-escalated as quickly as possible.Antibiotic de-escalation reduces the possibility of adverse drug effects, treatment costs and reduces the incidence of drug resistance.Parenteral antibiotics can be changed to oral route once clinical stability is attained.Suggested criteria for clinical stability include oral temperature < 37.8° C, heart rate < 100 beats/minute, respiratory rate < 24 breaths/minute, systolic blood pressure ≥ 90 mm Hg, and room air oxygen saturation > 90% or partial pressure of oxygen in arterial blood (PaO 2 ) > 60 mm Hg.3][14] Antibiotics need to be given for a minimum of 5 days of treatment and may be stopped in case patients remain afebrile for 48 to 72 hours and are clinically stable.A longer duration of treatment might be required in case of metastatic foci of infection, or infection with drug-resistant bacteria such as MRSA or drug-resistant gram-negative bacteria. 15,16

HIV Positive Patients Presenting with Suspected Bloodstream Infections or Sepsis of Unknown Origin Evidence Statements
• In the presence of sepsis or septic shock, we recommend following the surviving sepsis guidelines similar to the management of other patients with sepsis (UPP, A). • In the absence of septic shock or absence of risk factors for Pseudomonas a monotherapy with a third-generation cephalosporin or a cephalosporin, the b-lactamase inhibitor is sufficient (II, A) • In more severe disease states, such as in the presence of organ dysfunction or septic shock-a combination of broad-spectrum antibiotics may be used for initial empiric therapy (III, A). • Combination therapy is discouraged in the absence of ongoing shock (I, B) • Empiric gram-positive coverage is suggested for those who have risk factors for MRSA (UPP, A) • Anti-fungal agents may be considered only if there is no clinical improvement or there is clinical deterioration even after 72 hours of appropriate empirical antibiotics therapy and CD4 counts < 200/mm 3 (II, A). • We recommend against the use of empirical antifungal therapy (II, A) • Those with CD4 < 100/mm 3 are at high risk for disseminated tuberculosis and hence, need to be worked up for tuberculosis -including blood cultures for tuberculosis (I, B). • We recommend against empirical anti-tubercular therapy (ATT).In cases of proven mycobacteremia, ATT may be started as per national guidelines or in consult with the ID specialist (I, A). • Lateral Flow urine LipoArabinomannan Assay (LF-LAM) may be used to assist in the diagnosis of TB only in HIV positive adult in-patients with signs and symptoms of TB (pulmonary and/or extrapulmonary) who have a CD4 cell count < 100 cells/mm 3 , or HIV positive patients who are seriously ill regardless of CD4 count or with unknown CD4 count (II, B). • LF-LAM should not be used as a screening test for TB (III, A).

Evidence Summary
Bloodstream infections are common in AIDS patients.As with respiratory failure cases, most of the data is from western countries (   , B).
• Secondary prophylaxis should be reinitiated if the CD4 count decreases again to < 100 cells/mm 3 (III, A) • Corticosteroids and mannitol have been shown to be ineffective in managing ICP, and we recommend against the routine use of these agents in cryptococcal meningitis (III, A).In the case of IRIS, corticosteroids should be administered to manage severe central nervous system immune reconstitution inflammatory syndromes.(I, A) Immediate ART in the setting of Cryptococcal meningitis may increase the risk of serious IRIS, a short delay (4-8 weeks) before initiating ART may be necessary. 29,30

Empiric therapy for suspected CNS toxoplasmosis
Evidence Statements

Management of Tuberculous meningitis or CNS Tuberculoma
• The management remains the same as in CNS tuberculosis in an immunocompetent individual with 2 months of an intensive regimen with four drugs and 7 to 9 months of continuation phase (total 9-11 months) (I, A) • If not already on ART, ART should be initiated after 8 weeks of intensive phase, regardless of CD4 count (I, A).
Drug interactions need to be considered when starting treatment of an HIV patient already on HAART with drugs such rifampicin and clarithromycin.Drug resistance is an important factor that has to be considered in these patients hence whenever possible, the expert committee feels that treatment of suspected TB should be initiated only after a microbiological diagnosis and in liaison with an infectious disease expert.
• Systemic corticosteroids are indicated to prevent/ manage IRIS.Initiate 0.5 to 1 mg/kg of prednisone daily, and then taper the dose over two to six weeks.(I, A) A good alternative is to administer dexamethasone, tapered over 2 to 6 weeks.(I, A) • We suggest initiation of antituberculous therapy on the basis of strong clinical suspicion of CNS tuberculosis.Treatment should not be delayed until proof of infection has been obtained (I, B).

Evidence Summary
Management of treatment-naïve HIV-infected patients with TB is especially challenging in areas with high rates of coinfection.Initiation of antiretroviral therapy may be complicated by the immune reconstitution inflammatory syndrome (IRIS), which can manifest as reactivation of latent TB, the progression of active TB disease, or clinical deterioration in patients previously improving on antituberculous therapy.
The most important factor in determining the differential diagnosis is the degree of immunosuppression in the patient.
In patients with CD4 cell counts > 500/mm 3 , benign and malignant brain tumors and metastases predominate, as in immunocompetent hosts.
In moderately immunosuppressed patients with CD4 cell counts from 200 to 500/mm 3 , HIV-associated cognitive and motor disorders are common but usually, do not present with focal lesions.
In severely immunosuppressed patients with CD4 cell counts < 200/ mm 3 , CNS mass lesions are most common.The most likely diagnostic considerations include opportunistic infections (Toxoplasma encephalitis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, HIV encephalopathy, and CMV encephalitis) and AIDS-associated tumors, such as primary central nervous system lymphoma.
][33] Patients who are not under medical supervision, or those who are not aware of their HIV status, may present with their first opportunistic infection in the central nervous system.The clinical manifestations and the diagnostic possibilities are similar to those seen in before the introduction of potent antiretroviral therapy (ART) era.5] In a patient presenting with CNS symptoms/ altered mentation, noninfectious and infectious causes need to be ruled out.A practical approach is shown in the flowchart.

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7][8][9] Patients with sickle cell anemia, thalassemia major or malignancies such as Hodgkin's lymphomas and non-Hodgkin's lymphomas have a higher risk for OPSI.Asplenic patients have a higher incidence of parasitemia, a delayed clearance of parasites after treatment or a severe or even fatal infection due to malaria.These patients are also at high risk for Babesiosis, and this might be confused with Plasmodium falciparum. 2 These patients are at an increased risk of OPSI with Capnocytophaga canimorsus, if bitten by dogs and other animals and should receive adequate antibiotic coverage following such bites. 10Otherwise rare, Ehrlichiosis is also more severe in patients with asplenia/hyposplenia. 2 OPSI should be considered as a medical emergency and mandates early recognition and aggressive management.These patients should be managed aggressively including immediate cultures and administration of a combination of antibiotics to cover all possible etiological agents.In areas where penicillin-resistant pneumococci are prevalent, other agents such as vancomycin, teicoplanin or rifampicin should be added to ceftriaxone as the initial empiric therapy.Gram stain of the peripheral blood or buffy coat will give an idea regarding the presence or absence of intraleukocytic bacteria.Antipseudomonal coverage should be added in case of high risk for Pseudomonas infection or peripheral blood growing GNB.The presence of intracellular bacteria within leukocytes should alert the clinician towards ehrlichiosis while the presence of parasites in RBC should alert for malaria or babesiosis.Once the blood cultures are positive antibiotics can be modified accordingly.

Evidence Summary
Patients with PID commonly present with recurrent infections and invasive infections, atypical pathogens, partial response to antibiotics, failure to thrive, chronic diarrhea, fungal infections, unexplained skin rash, and family history.Infections such as Pneumonia and bronchiolitis, acute gastroenteritis, otitis media, and bacteremia in patients with an antibody, combined, and cellular deficiencies.Whereas viral infections meningitis, osteomyelitis, gastroenteritis is commonly seen in CVID.Children tend to have bacterial or fungal infections with unusual organisms or unusually severe and recurrent infections with common organisms.A family history of primary immunodeficiency disease is the strongest predictor of a person having this type of disease. 5he typical presentations of various PIDs by age of presentation and spectrum of infections.

( 4 .
9%) and Citrobacter freundii (4.5%) whereas polymicrobial infections occurred in 8.1% of cases.The incidence of GNB infections shows a declining trend to fall to 25.7 (95% CI: 20.1-32.1)from 2 to 12 months.It further declines to 8.2 (95% CI: 6.7-10.0)after 12 months per 1000 personyears following SOT.1,2 Statements • We recommend empiric management of GI infections with ceftriaxone iv + ganciclovir 5g/kg BD IV and vancomycin 125 mg PO QID (if the patient is already on antibiotics to cover CDI) till definitive diagnosis is made (I, A). • If the patient is in septic shock, based on local resistance pattern, and previous drug history of patient consider carbapenems (UPP, A). • We recommend cessation of the inciting antimicrobial agent whenever possible (II, A). • We recommend NAAT for the diagnosis of CDI (I, A). • For mild-to-moderate CDI we recommend oral metronidazole (I, A).Dose of metronidazole 500 mg TID for adults.• We recommend oral vancomycin for the treatment of severe CDI (IA).The accepted dose of vancomycin is 125 mg qid for adults and 40 to 50 mg/kg/day divided QID for pediatric patients (not to exceed adult dosing).• In severe CDI with complications, a dose of oral vancomycin may be increased up to 500 mg orally QID.• Vancomycin may be administered by retention enema (IIB), and intravenous metronidazole may be added (IIC).• Feacal transplant may be considered in recurrent or relapsing CDI (II, B).

•
Appropriate samples should be collected for staining and cultures-including sputum/induced sputum and bronchoscopic lavage-if indicated.(UPP, A) • Patients with severe pneumonia who require intensive care and without risk of Pseudomonas aeruginosa should be empirically treated with an IV b-lactam plus IV macrolide (II, A).Preferred b-lactams are ceftriaxone, cefotaxime, or amoxicillin-clavulanic acid.In patients who are allergic to penicillin, aztreonam plus azithromycin should be used (III, B). • Those with CD4 counts < 200/mm 3 and without signs of focal consolidation may be suspected to have PCP and should receive Trimethoprim-sulphamethoxazole (Co-trimoxazole) in therapeutic dose (TMP 15-20 mg/ kg/day plus SMX 75 to 100 mg/kg/day given q6h or q8h).(I, A) • Patients with documented or suspected Pneumocystis Jerovecii pneumonia (PCP) pneumonia and moderateto-severe disease, defined by room air PO 2 < 70 mm Hg or Alveolar-arterial O 2 gradient ≥ 35 mmHg, should receive adjunctive corticosteroids as early as possible and certainly within 72 hours after starting specific PCP therapy (I, A) • If patients with HIV/AIDS develop acute respiratory failure and they have any of the risk factors for Pseu-domonas infection we recommend dual antipseudomonal coverage such as anti-pseudomonal b-lactam plus aminoglycoside (examples of anti-pseudomonal b-lactams include ceftazidime, cefoperazone, cefoperazone-sulbactam, piperacillin-tazobactam, imipenemcilastatin, or meropenem (III, A).In patients who are allergic to penicillin, aztreonam can be used in place of the b-lactam.Combination therapy may be considered with the addition of aminoglycosides or antipseudomonal fluoroquinolones (e.g., levofloxacin, ciprofloxacin) (III, B). • We recommend continuing Azithromycin along with anti-pseudomonal therapy for coverage of atypical pathogens (II, B). • We recommend against using fluoroquinolones empirically to avoid development of drug-resistant TB.Patients should also undergo sputum testing for acid-fast bacilli simultaneously if fluoroquinolones are being used.Fluoroquinolones may be continued only if tuberculosis is not a diagnostic consideration at admission (I, A). • In patients who have risk factors for methicillin-resistant Staphylococcus aureus (MRSA) infection-empiric treatment should include vancomycin or linezolid (III, B).

Table 2 :
Isolates from the blood of febrile neutropenic patients in Indian ICUs.

Table 3 :
Incidence of resistance among common gramnegative bacterial isolates in India (ICMR data)17

•
Micafungin: 100 mg daily.No dose adjustment in the liver or renal failure.•Anidulafungin:loading dose of 200 mg, followed by 100 mg daily.No dose adjustment is required in the liver or renal failure.Limitations of echinocandin therapy should be kept in mind.Echinocandins have poor penetration in eye, CNS, and urine.Intuitively they should not be used for the treatment of fungal meningitis, endophthalmitis, and urinary tract infection.Echinocandins are not active against Zygomycosis.31

Role of Source Control in the Treatment of a Febrile Neutropenic Patient Evidence Statements •
We recommend that in patients with febrile neutropenia with a clinically documented source of infection; immediate intervention should be undertaken for source control (III, A) • We recommend that Non-tunnelled (short term) central venous catheter (CVC) should be promptly removed in following cases (III, A).52a.CVC is an obvious source of infection.b.Patient not improving/deteriorating in spite of 24 hours of antibiotics and resuscitation with no other source of infection evident • We recommend that long term central venous catheter should be promptly removed in presence of any of the following (III, A).
52 a. Documented line/blood infection with S. aureus, or Candida species b.Tunnel infection or port abscess c.Septic thrombosis, endocarditis or osteomyelitis • We suggest considering the removal of long term central venous catheter in the absence of abovementioned features if there is deterioration or no improvement in patients condition and no other obvious source of infection is evident (UPP, B) Infectious complications in solid organ transplant (SOT) recipients pose unique challenges when such patients require intensive care unit (ICU) care.The net immunological state of these patients is a measure of an individual's unique susceptibility to infection and incorporates an assessment of several important contributing factors.• Pretransplant diagnosis or treatment • Nature of organ transplant received (e.g., lung vs. liver organ transplant) • Dose, duration, and choice of maintenance immunosuppression • Comorbidities (e.g., viral coinfection [hepatitis C virus (HCV), cytomegalovirus (CMV)], malnutrition, end-organ failure [cirrhosis, chronic kidney disease]) • Breaches of the mucocutaneous barrier: Indwelling devices, mucositis Detection of infection in SOT recipients is difficult and requires a high index of suspicion, as fever and localizing signs are usually absent in the majority of the patients.Detection of infections should include an assessment of risk factors, detailed history, and physical examination.The infections in SOT patients can be categorized as follows S73IJCCM2.SOLID ORGAN TRANSPLANT (SOT) RECIPI-ENT IN THE INTENSIVE CARE UNIT (ICU)

Table 1 :
Timeline of infections after a solid organ transplant

Table 2 :
Common infections in SOT recipients in the period 30 to 180 days 1-41

Table 3 :
Common causes of diarrhea in SOT patients

Table 4 :
Common pathogens causing CNS Infections in SOT

Table 3 :
Risk factors for Pseudomonas and Staphylococcal

Table 1 :
Etiology of acute respiratory failure in patients with HIV

Table 4 :
Results of comparison of various antibiotic regimen in Community Acquired Pneumonia.

Table 2 :
The types of clinical patterns of presentation and infections in PIDs

Table 1 :
Absolute Lymphocyte count (ALC) nomogram Any value below the reference range should raise suspicion of PID