Table 2.

Empiric therapeutic agents for each infectious disease

Source of infection	Patient background / pathology		Expected causative bacteria	Drug examples (see note k) for VCM dose)	Remarks
Pneumonia^a)	Community-acquired	Other than the reasons listed below	Pneumococcus, Haemophilus influenzae, Klebsiella spp., Mycoplasma pneumoniae, Legionella pneumophila	CTRX 2 g, every 24 h [5] ±AZM 500 mg, every 24 h [5]	See CQ4–3 for Legionella risk.
	Community-acquired	After influenza, necrotizing pneumonia	Above + Staphylococcus aureus (including community-acquired MRSA)	CTRX 2 g, every 24 h [5, 6] ±VCM [5, 6], ^k	See CQ4–3 for MRSA risk.
	Healthcare-associated/ ventilator-related		Streptococcus pneumoniae, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus	“CFPM 2 g, every 8 h, or TAZ/PIPC 4.5 g, every 8 h” ±VCM [5],^k	Option of community-acquired pneumonia is applicable at an early stage or when there is no risk of resistant bacteria. See CQ4–3 for MRSA risk.
	Decreased cell-mediated immunity + no prevention of Pneumocystis jirovecii + bilateral shadows		Pneumocystis jirovecii	ST trimethoprim 240–320 mg, every 8 h or pentamidine 4 mg/kg, every 24 h [5]	ST: trimethoprim 15 mg/kg/day ≒Japanese ST mixture (1 tablet or 1 g of trimethoprim is 80 mg) 3–4 tablets or 3–4 g, every 8 h.
Urinary tract infection^b)	Community-acquired (low risk of ESBL-producing bacteria)		E. coli	CTRX 1–2 g, every 24 h [5]	See CQ4–2 for ESBL-producing bacteria risk.
	Community-acquired (high risk of ESBL-producing bacteria)		E. coli	CMZ 1–2 g, every 8 h [7, 8] or TAZ/PIPC 4.5 g, every 8 h [9] or MEPM 1 g, every 8 h [5]	See CQ4–2 for ESBL-producing bacteria risk.
	Healthcare-associated		E. coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, Enterococcus spp.	“TAZ/PIPC 4.5 g, every 8 h or MEPM 1 g, every 8 h” ±VCM [5],^k	VCM is added when Gram staining shows Streptococcus-like Gram-positive cocci.
Biliary tract / intra-abdominal infection^c)	Community-acquired (low risk of ESBL-producing bacteria)		E. coli, anaerobic bacteria such as Bacteroides spp.	SBT/ABPC 3 g, every 6 h [10] or “CTRX 2 g, every 24 h + MNZ 500 mg, every 8 h” [10]	See CQ4–2 for ESBL-producing bacteria risk. Check antibiogram of facility / region to see if SBT / ABPC can be selected.
	Community-acquired (high risk of ESBL-producing bacteria)		E. coli, anaerobic bacteria such as Bacteroides spp.	CMZ 1–2 g, every 8 h [10] or TAZ/PIPC 4.5 g, every 8 h
	Healthcare-associated		E. coli, anaerobic bacteria such as Bacteroides spp., Enterobacter spp., Pseudomonas aeruginosa, Enterococcus spp. ± Candida spp.	“TAZ/PIPC 4.5 g, every 8 h or (CFPM 2 g, every 8 h + MNZ 500 mg, every 8 h) or MEPM 1 g, every 8 h” [5, 10] ±MCFG 100 mg, every 24 h [5]	See CQ4–3 for Candida risk.
Necrotic soft tissue infection^d)	Monomicrobial infection suspected (Gram-positive cocci or Gram-positive rods)		β-hemolytic Streptococci, Clostridium spp., rarely Staphylococcus aureus (including community-acquired MRSA)	“CTRX 2 g, every 24 h or SBT/ABPC 3 g, every 6 h” ±VCM [5],^k ±CLDM 600 mg, every 8 h [5]	See CQ4–3 for MRSA risk. CLDM is intended for suppressing toxin production in toxic shock syndrome.
	Polymicrobial infection suspected (diabetic, Fournier’s gangrene)		Staphylococcus aureus, E. coli, anerobic bacteria	TAZ/PIPC 4.5 g, every 8 h [5] ±VCM [5],^k
	Exposure to seawater / freshwater		Aeromonas spp., Vibrio vulnificus	CTRX 2 g, every 24 h +MINO 100 mg, every 12 h [5]
Vertebral osteomyelitis (spondylitis)^e	Community-acquired		MSSA, Streptococcus spp., rarely Streptococcus pneumoniae, Gram-negative bacilli	CEZ 2 g, every 8 h [5] or CTRX 2 g, every 24 h [5]	See CQ4–3 for MRSA risk.
Vertebral osteomyelitis (spondylitis)^e	Healthcare-associated		Staphylococcus aureus, Gram-negative bacillus	CFPM 2 g, every 12 h +VCM [5],^k	See CQ4–3 for MRSA risk.
Endocarditis^f	Native valve: without MRSA risk		MSSA, Streptococcus spp., Enterococcus spp.	SBT/ABPC 3 g, every 6 h [5] or “CTRX 2 g, every 24 h +ABPC 2 g, every 4 h” [5, 11]	Select “CTRX+ABPC” when there is a high possibility of enterococcus. Select CTRX 2 g every 12 h if there is an intracranial disseminated lesion.
	Native-valve: with MRSA risk		Above+MRSA	CTRX 2 g, every 24 h +VCM [5, 11],^k	Select CTRX 2 g every 12 h if there is an intracranial disseminated lesion. See CQ4–3 for MRSA risk.
	Prosthetic valve or pacemaker		Above+Staphylococcus epidermidis, Gram-negative bacilli	“CTRX 2 g, every 24 h or CFPM 2 g, every 12 h” +VCM [5, 11],^k
Mycotic aneurysm^g	Community-acquired/native arteries		Staphylococcus aureus, Salmonella spp., Gram-negative bacilli	“CFPM 2 g, every 12 h or TAZ/PIPC 4.5 g, every 8 h” ±VCM^k	See CQ4–3 for MRSA risk.
Mycotic aneurysm^g	Prosthetic vascular graft infections		Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa	“CFPM 1 g, every 8 h or TAZ/PIPC 4.5 g, every 8 h or MEPM 1 g, every 8 h” +VCM^k
Catheter-related bloodstream infections^h	Intravascular catheter		Staphylococcus epidermidis, Staphylococcus aureus (including MRSA), E. coli, Pseudomonas aeruginosa, ±Candida	VCM^k +CFPM 2 g, every 8–12 h ±MCFG 100 mg, every 24 h [5]	See CQ4–3 for Candida risk
Meningitisⁱ	Community-acquired (in a patient younger than 50 years)		Streptococcus pneumoniae, Neisseria meningitidis	CTRX 2 g, every 12 h +VCM [5, 12] ^,k
	Community-acquired (patient older than 50 years, cell-mediated immunodeficiency)		Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes	ABPC 2 g, every 4 h +CTRX 2 g, every 12 h +VCM [5, 12] ^,k
	Post-neurosurgery or shunt-related meningitis		MRSA, Pseudomonas aeruginosa	“CAZ or CFPM or MEPM (2 g, every 8 h)” +VCM [5, 12], ^k
Unknown or systemic source^j	Community-acquired (not any of the items listed below)		Streptococcus pneumoniae, Neisseria meningitidis,β-hemolytic streptococcus, E. coli	CTRX 2 g, every 24 h [5]	See section on meningitis if there is a possibility of meningitis
	Healthcare-associated (not any of the items listed below)		Pseudomonas aeruginosa, MRSA	“CFPM 2 g, every 8 h or TAZ/PIPC 4.5 g, every 8 h or MEPM 2 g, every 8 h” +VCM^k
	Toxic shock syndrome		Staphylococcus aureus, β-hemolytic streptococcus, Clostridium spp.	“CTRX 2 g, every 24 h or SBT/ABPC 3 g, every 6 h” +CLDM 600 mg, every 8 h ±VCM^k	See CQ4–3 for MRSA risk
	Rickettsia endemic areas		Japanese spotted fever, scrub typhus	MINO 100 mg, every 12 h [13]
	Febrile neutropenia		Pseudomonas aeruginosa, MRSA	CFPM 2 g, every 12 h +VCM [5],^k	See CQ4–2 for anti-Pseudomonal drugs
	After splenectomy		Pneumococcus, Neisseria meningitidis, Haemophilus influenzae, Capnocytophaga spp.	When there is no possibility of meningitis: CTRX 2 g, every 24 h [5]	See section on meningitis if there is a possibility of meningitis
	Shock +rash		Purpura fulminans (meningococcus, pneumococcus), Rickettsia spp.	CTRX 2 g, every 12 h +VCM [5] +MINO 100 mg, every 12 h [13, 14]	See section on endocarditis if there is a possibility of endocarditis

[Precautions] This table is a list of infectious diseases related to sepsis based on guidelines for various infectious diseases and those published by the Japanese Association for Infectious Diseases and the Japanese Society of Chemotherapy, with the following information added. Typical options are shown to make the table practical for use

Given their very nature, empiric therapeutic agents are difficult to present as the only absolute option, and they are often presented in various guidelines as evidence and expert opinion suggestions. However, this also depends on the age and region of the antibiograms produced, and the types of antimicrobial agents available at each facility. This table can be used as a reference for experts in the septic/antimicrobial stewardship teams of each facility when developing antimicrobial guidelines for each facility

Abbreviations: ABPC ampicillin, AZM azithromycin, CAZ ceftazidime, CFPM cefepime, CLDM clindamycin, CMZ cefmetazole, CTRX ceftriaxone, GM gentamycin, MCFG micafungin, MEPM meropenem, MINO minocycline, MNZ metronidazole, SBT/ABPC sulbactam/ampicillin, ST sulfamethoxazole/trimethoprim, TAZ/PIPC tazobactam/piperacillin, VCM vancomycin (abbreviations of antimicrobial agents are based on JAID/JSC infectious disease treatment guidelines)

^aPneumonia: Staphylococcus aureus (including MRSA) can be a causative bacterium in addition to the usual causes of community-acquired pneumonia following influenza virus infection or necrotizing pneumonia; thus, a separate section has been created

^bUrinary tract infection: Presented based on reports of epidemiology and treatment of ESBL-producing bacteria in Japan

^cBiliary tract/intra-abdominal infection: Presented based on reports of epidemiology and treatment of ESBL-producing bacteria in Japan

^dNecrotic soft tissue infection: Three types are presented as options when the causative bacteria can be estimated from the patient background (exposure history, underlying disease) and clinical course (rapid inspection results of the test incision sample are also taken into consideration)

^eVertebral osteomyelitis (spondylitis): Refraining from empiric therapeutic drugs is recommended for hemodynamically and neurologically stable spondylitis; however, empiric treatment is indicated when complications of sepsis are present [15]. The regimen of empiric treatment is not established, but options were selected based on the JAID/JSC infectious disease treatment guidelines [5]

^fEndocarditis: Concomitant use of GM in native valve endocarditis was previously recommended for Staphylococcus aureus [5], but this is no longer recommended in recent years [16]. A combination regimen of CTRX and ABPC was indicated in place of GM for enterococci. In addition, a regimen without the concomitant use of GM was shown as an empiric treatment [16]. There was also no description in the JAID/JSC infectious disease treatment guideline in cases of endocarditis with a high rate of intracranial dissemination; however, this table presents this considering cerebrospinal fluid penetration. We presented an option for endocarditis of the prosthetic valve that does not include GM as an empiric treatment when the causative organism is uncertain, considering the nephrotoxicity of GM

^gMycotic aneurysm: There is no description in the JAID/JSC infectious disease treatment guidelines and no established recommendation exists [5, 17], but this was presented as an option

^hCatheter-related bloodstream infections: options were presented based on the JAID/JSC infectious disease treatment guidelines [5]

ⁱMeningitis: options were presented based on the JAID/JSC infectious disease treatment guidelines [5, 12]

^jUnknown or systemic sources: There is no description in the JAID/JSC infectious disease treatment guidelines, but the source of infection is occasionally unknown in sepsis, so options for each possible pathology were presented

^k Please refer to the description of the TDM guideline 2016 (initial loading dose: 25–30 mg/kg intravenous injection, subsequent maintenance doses (normal renal function):15–20 mg/kg intravenous injection, every 12 h) for the VCM dose [18]