Antibiotics for Tropical infections in ICU
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We often come across tropical infections admitted to ICU in about 20-30% cases coming with critical multi organ dysfunctions and features of sepsis. Detection is often clinical and based on temporal association with certain exposure to bite or seasons, or specific signs and some times non specific and in such situations leading to use of empirical antibiotic coverage for tropical fever, where also great variability exists even after confirmation of diagnosis. And lastly owing to inappropriate and overuse of antibiotics, we have observed growing concern of antibiotic resistance in tropical infections as well.
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Antibiotics for Tropical infections in ICU
- 1. ANTIBIOTICS FOR TROPICAL INFECTIONS IN ICU Dr. Mohd Saif Khan BSc, MD, DNB, Fellowship (CCM), DM (CCM) Specialist SR Homi Bhabha Cancer Hospital, VaranasiMahamana Pandit Madan Mohan Malaviya Cancer Centre, Varanasi
- 2. Do we need this topic for lecture!! • Main differentials (Tropical infections form 20-30% of ICU admissions in tropical countries)*. • Controversies in detection. • Variability of antibiotic practices. • Issues of antibiotic resistance. *J Crit Care. 2018 Aug;46:119-126.
- 3. Pioneer researchers on tropical infections in Indian ICUs
- 4. Defined as infections (Fever) prevalent or unique to tropical and sub-tropical regions due to climatic conditions. Introduction
- 5. Prevalence of tropical infections in India IJCCM 2017 IJCCM 2016 INDICAPS-1
- 6. Fever, malaise, headache Symptomatology Breathlessness Rashes Eschar Abdominal distension Hepatomegaly Splenomegaly Jaundice Signs of organ dysfunction Scrub typhus Leptospirosis Severe Malaria Leptospirosis, Dengue Dengue fever, Typhoid Sepsis Dengue, Typhoid, Leptospirosis, Severe Malaria Scrub typhus, Leptospirosis Nonspecific signs and symptoms
- 7. Scrub Typhus • Eastern + Southern India • Eschar (pathognomonic) • Causes of ICU admission: ARDS, Hepatitis, Encephalitis, Aseptic Meningitis, Myocarditis and DIC • Main diagnostic tests: Weil Felix, IFA (gold standard) & ELISA
- 8. Antibiotic management of scrub typhus • Doxycycline is the first line drug. Inj Doxycycline 100 mg BD IV for a duration of 5 mg/kg body weight/day in two divided doses for children Azithromycin (500 mg OD for five days) is the drug of choice in pregnant women, as doxycycline is contraindicated. DHR-ICMR Guidelines, Indian J Med Res. 2015 Apr; 1 417–422. Rifampin (600 mg-900 mg OD PO) and Azithromycin should be reserved for resistant cases.
- 9. • Rampant in Southern, Eastern and Western India. Seen in Northern India as well! • Peaks during rainy season. • Clinically: – Anicteric – Icteric (Weil’s): Jaundice, Anuria, ARDS and Myocarditis • Serology: ELISA for IgM and PCR. Leptospirosis
- 10. • No FDA-approved drugs for the treatment of leptospirosis. • Antimicrobial therapy is indicated for the severe form of leptospirosis, but its use is controversial for the mild form of leptospirosis. Antibiotic management of Leptospirosis Antibiotics shorten duration of clinical illness by two to four days and also reduces shedding of the organism in the urine Brett‐Major DM, Coldren R. Antibiotics for leptospirosis. Cochrane Database of Systematic Reviews. 2012(2).
- 11. Jarisch-Herxheimer reaction • It occurs following the treatment with antimicrobial therapy for leptospirosis. • An acute inflammatory response to the clearance of spirochetes from the circulation. • Characterized by fever, rigor, and hypotension. • In one series including 262 patients with leptospirosis, a Jarisch-Herxheimer reaction occurred in 21 percent of cases. Guerrier G, Lefèvre P, Chouvin C, D’Ortenzio E. Jarisch-Herxheimer reaction among patients with leptospirosis: incidence and risk factors. Am J Trop Med Hyg. 2017;96:791-794.
- 12. • Hepatitis, ARDS, Renal failure, Myocardiis and Encephalitis • Treatment is only Supportive. • No antibiotics required unless patient develops secondary infections in ICU. Dengue
- 13. Typhoid/Enteric fever • Most prevalent in urban areas, with high incidence in children 15 years of age and younger • Cause of ICU admission: • Intestinal bleeding • Perforation and • MODS (3rd week) • Typhidot (RDT) – Sensitivity 95-97%, Specificity > 90%,
- 14. • The main options are fluoroquinolones, third- generation cephalosporins, and azithromycin. • Fluoroquinolones are more effective than beta-lactams against susceptible organisms. • Ceftriaxone is first line drug – 50 mg/Kg/day for 10-14 days. (risk of relapse with shorter durations) • Carbapenems are reserved for suspected infection with extensively drug-resistant (XDR) strains. Antibiotic management of Typhoid Antimicrob Agents Chemother. 1994;38(8):1716.
- 15. ANTIMICROBIAL RESISTANCE to S. enterica is increasing to ampicillin, trimethoprim- sulfamethoxazole, fluoroquinolones and chloramphenicol.
- 16. • Main species causing severe malaria is Plasmodium falciparum (90 percent), but Plasmodium vivax and recently by Plasmodium knowlesi. • ICU admission: Signs of organ dysfunction+high level of parasitemia • Death can occur within hours of presentation. • Detection is based on P falciparum –specific circulating proteins (HRP & LDH) in the whole blood, using RDT (rapid diagnostic test). • 2 consecutive RDT are required to rule out severe malaria in ICU. Severe malaria
- 17. • Drug of choice: Artesunate • Artemisinin derivatives clear parasitemia faster than quinine and are associated with lower mortality rates in both adults and children. Antibiotic management of severe Malaria Parasite density monitoring q12h for first two to three days to document declining parasite density and confirm adequate response to therapy. 5425 children Artesunate dosing need not be adjusted for hepatic or renal failure Monitor for delayed hemolytic anemia, with repeat hemoglobin testing at 7 and 14 days after treatment Clindamycin is preferred in pregnant women. (Griffith KS et al. JAMA. 2007;297(20):2264. Dosing: Parenteral: Artesunate 2.4 mg/kg IV bolus at admission, 12 h and 24 h; followed by Oral: Artesunate 200 mg OD for three days Plus one of the following: Tab Doxycycline 100 mg PO BD for seven days OR Tab Clindamycin 20 mg base/kg/day orally divided three times daily for seven days
- 18. Leading cause of acute encephalitis Endemic all over India, small outbreaks reported in North India. Sudden onset of convulsions with clenching of teeth and loss of consciousness, mostly in the early morning, with no prodrome or sequelae. Hypoglycemia is a common finding. Mainly supportive. Antibiotic management: Ribavirin no role, Minocycline has neuroprotective and antiinflammatory effect. Japanese encephalitis Presentation Treatment
- 19. • 2009-10: pandemic • High risk groups: elderly people, pregnant female in late stage of pregnancy, postpartum period, obesity (body mass index >30), and presence of chronic underlying medical conditions, including immunosuppression. • Cause for ICU admission: hypoxemic respiratory failure Swine flu (H1N1) Fever and breathlessness MC symptoms N Am J Med Sci. 2012 Sep; 4(9): 394–398.
- 20. Antibiotic management • Start Oseltamivir with in 48 h of onset of influenza symptoms • Dosage: enteral 75 mg twice daily for 5 days • In critically ill, 150 mg twice daily and longer duration of treatment until clinical improvement or sequentially negative results for virus in respiratory tract is achieved. • Zanamivir in case of Oseltamivir resistance. • Two inhalations (5 mg per inhalation for a total dose of 10 mg) 2 times daily (roughly 12 hours apart) 5 days.
- 21. What will you do
- 22. Antibiotic management of acute undifferentiated fever with MOF and hypotension CEFTRIAXONE+DOXYCYCLINE/AZITHROMYCIN Send serology (IgM ELISA, PCR), Peripheral smear and blood culture Initiate empirical coverage with De escalate once diagnosis is made. J Crit Care. 2018 Aug;46:119-126. Resuscitation
- 23. Take home message • Initial antibiotics for tropical sepsis are mostly empirical. • Aware of local resistance pattern of particular antibiotic. • Always de escalate • Avoid under or over treatment • Take help from ID specialist if available
- 24. Thank You
Editor's Notes
- That, Do we need this topic for lecture!! And answer is yes as we often come across tropical infections admitted to ICU in about 20-30% cases coming with critical multi organ dysfunctions and features of sepsis. Detection is often clinical and based on temporal association with certain exposure to bite or seasons, or specific signs and some times non specific and in such situations leading to use of empirical antibiotic coverage for tropical fever, where also great variability exists even after confirmation of diagnosis. And lastly owing to inappropriate and overuse of antibiotics, we have observed growing concern of antibiotic resistance in tropical infections as well which, I would like to present in coming slides.
- Now, we should not forget the role of few pioneer clinical scientists who have contributed to research on tropical infections in our countries. Dr. sunit Singhi from PGI chandigarh, Dr. George M Verghes, Dr Dhruva Chaudhary, Dr Bhalla, Dr JV Peter from CMC Vellore and Dr Prakash Shastri from GangaRam Hospital , new Delhi.
- The tropics are the regions of the Earth surrounding the Equator. These regions have ideal conditions for breeding of insects. Such as warmer climate, greater humidity and higher rainfall, and lush vegetation.
- According to latest INDICAPS study-1 which was a 4-day point prevalence study performed between 2010 and 2011 in 4209 patients from 124 Indian ICUs, tropical infections constituted about 20% of all infections. According to another multicenter study done in our country, Dengue, Scrub typhus and Meningoencephalitis constituted most of the tropical infection diagnosis. However, unfortunately,in about 20% of cases, no specific diagnosis could be attained.
- Tropical infections usually present with non specific symptomatology, most common of which are Fever, malaise and headache. However, there has been also a syndromic approach applied to make a set of differential diagnoses. You should be aware that most of the patients who present late in the course of disease often develop sepsis, which makes diagnosis clinically challenging. Now we will move on to discuss each of the specific tropical infections and their antibiotic management.
- Eschar is a pathognomonic sign and an early clinical manifestation of scrub typhus.
- Without waiting for laboratory confirmation of the rickettsial infection, antibiotic therapy should be instituted when rickettsial disease is suspected. It should be suspected in fever cases of duration of five days or more where malaria, dengue and typhoid have been ruled out. Scrub typhus may cause spontaneous abortions in pregnant women.
- You all will be familiar with leptospirosis which is quite rampant in mostly south, western India. Outbreaks are mainly reported during rainy season. Fortunately most of the cases are nonfatal anicteric and self-limited, flulike illness. This is Icteric phase, also k/s Weil’s disease which is severe illness characterized by multiorgan involvement or even failure. Laboratory Diagnosis is most commonly based on IgM ELISA, however, main limitation is that antibodies are lacking at the acute phase of the disease. The only sensitive and specific test accurate at the acute phase of the disease is polymerase chain reaction (PCR), which is not available. MAT detects both class M and class G antibodies, and cannot differentiate between current, recent, or past infections.
- There is no FDA-approved drugs, and their use is controversial for the mild form of leptospirosis. Antimicrobial therapy should be used for the severe form of leptospirosis, i.e., patients who are icteric and having signs of organ dysfunction. A list of antibiotics have been given in various literature, of which third-generation cephalosporins cefotaxime and ceftriaxone have been widely used. Intravenous penicillin G has long been the drug of choice. In case where there is doubt in differentiating between leptospirosis from rickettsial disease, Doxycycline should be considered, which covers both effectively.
- You may observe in about one in five patients, an acute inflammatory response following the treatment with antimicrobial therapy for leptospirosis, which is called as Jarisch-Herxheimer reaction, characterized by fever, rigor, and hypotension.
- Dengue is a capillary leak syndrome characterized by multisystem involevement in third phase. Treatment is mainly supportive and no antibiotics should be administered unless patient develops secondary infections in ICU.
- Enteric fever is prevalent in urban areas , where sanitary conditions remain poor. Diagnosis is based on rapid card test -Typhidot (RDT) – Sensitivity 95-97%, Specificity > 89%,
- Main antibiotic options are fluoroquinolones, third-generation cephalosporins, and azithromycin. Fluoroquinolones are more effective than betalactams, but due to increasing resistance to quinolones, Ceftriaxone has been recommended as first line drug (by ISCCM 2014 guidelines), which requires to be given atleast for 10-14 days as relapse may result with shorter durations.
- MDR S typhi is emerging as a threat hence antibiotic stewardship should help here where culture should be obtained before antibiotics, and antibiotics should be de escalated as soon as possible.
- Severe malaria usually caused by Plasmodium falciparum (90 percent), but Plasmodium vivax and Plasmodium knowlesi. Patients usually presents with signs of organ dysfunction and high level of parasitemia. Detection is based on P falciparum –specific circulating proteins (HRP & LDH) in the whole blood, using RDT (rapid diagnostic test). 2 consecutive RDT are required to rule out severe malaria in ICU.
- WHO recommends Artesunate which clears parasitemia faster than quinine and also associated with lower mortality as has been observed in AQUAMAT trial conducted in about 5000 children. Unlike artemisinin derivatives, quinine has a narrow therapeutic window. First dose should be parenteral Artesunate 2.4 mg/kg i.v. bolus at admission, 12 h and 24 h followed by oral therapy with Artesunate 200 mg OD for three days. Plus either doxycycline or clindamycin tablets for 7 days. Clindamycin is preferred in pregnant women. Unlike artemisinin derivatives, quinine has a narrow therapeutic window. Artesunate dosing need not be adjusted for hepatic or renal failure. Parasite density monitoring q12h for first two to three days. One should also monitor for delayed hemolytic anemia, with repeat hemoglobin testing at 7 and 14 days after treatment.
- Acute encephalopathy syndrome make about 10% of cases of tropical fever. JE is the Leading cause of acute encephalitis specially in pediatric age group. Endemic all over India, small outbreaks reported in North India. The most devastating outbreak was in Gorakhpur district in 2005 affecting 6061 cases with 1500 deaths. (25% mortality). Children usually present with Sudden onset of convulsions with clenching of teeth and loss of consciousness, mostly in the early morning, with no prodrome or sequelae. A common finding is hypoglycemia(<70 mg/dl) on admission. Treatment of JE is mainly supportive care with emphasis on control of intracranial pressure, maintenance of adequate cerebral perfusion pressure, seizure control, and prevention of secondary complications. Ribavirin no role, Minocycline has neuroprotective and antiinflammatory effect.
- Viral pandemic which has drawn wide attention in our country is H1N1 infection or swine flu which is presented as respiratory distress and fever after few days of prodromal symtoms in high risk groups. Usual cause of ICU admission is ARDS which has high mortality rate
- Main Antiviral which is quite effective in confirmed case of oseltamivir which needs to be started within 48 h of onset of influenza symptoms for maximum efficacy. In ICU patients, higher dose is recommended for duration until clinical improvement or sequentially negative results for virus in respiratory tract is achieved. In places where oseltamivir resistance is documented Zanamivir in inhalation form is good option.
- Okay…SO Now tell me, What will you do regarding antibiotic choice for a suspected tropical sepsis patient in ICU setting? Here I have a flowchart prepared for you to guide
- When ever a patient presents with acute undifferentiated fever with MOF and hypotension, first thing you must do is to RESUSCITATE and STABLIZE following which Send serology (IgM ELISA, PCR), Peripheral smear and blood culture. Then without wasting any time, Initiate empirical coverage with CEFTRIAXONE+DOXYCYCLINE/AZITHROMYCIN It appears to be reasonable to initiate ceftriaxone and doxycycline as empirical antimicrobials as they would adequately cover common diagnoses including scrub typhus, enteric fever, leptospirosis, meningitis, and most cases of bacterial sepsis. Please do not start artesunate empirically. There is limited role for empiric artesunate in patients presenting with fever even from endemic areas. Therefore do atleast two RDT to rule out malaria. In case where you suspect viral encephalitis, acyclovir may be given. In a patient with H1N1 specially in high risk group start on Oseltamivir <48h of symptom onset. Do not forget to de escalate the antibiotics when diagnosis is confirmed.
- This concludes my presentation. The take home messages are Initial antibiotics for tropical sepsis are mostly empirical. Aware of local resistance pattern of particular antibiotic. Always de escalate Avoid under or over treatment Take help from ID specialist if available