Invasive Nocardiosis: Disease Presentation, Diagnosis and Treatment – Old Questions, New Answers?

Figures & data

Figure 1 Workflow for identification of underlying disease favoring invasive nocardiosis.¹⁷

Figure 2 Radiographic findings in patients with invasive nocardiosis. (A) Chest CT-scan of a sixty-year-old patient with chronic lymphocytic leukemia treated with ibrutinib who developed Nocardia pneumonia. (B and C) Twenty-one-year-old patient with chronic granulomatous disease who developed Nocardia pulmonary abscess with local extension to the ribs (white arrow). (D) Brain MRI of a forty-six-year-old cardiac transplant patient who developed Nocardia brain cerebral abscess (white arrowhead): ring-enhancing multilobulated lesion surrounded by edema causing a mass effect on the anterior ventricles. MRI, axial T1 after gadolinium injection.

Figure 3 Microbiological diagnosis of nocardiosis. (A) Direct examination of a bronchoalveolar lavage (BAL) after Gram staining revealing filamentous Gram-positive bacteria (white arrowhead). (B) Positive culture of the same BAL on blood agar plate.

Table 1 Results of Antibiotic Susceptibility Testing Among Nocardia Isolates According to Their Species^{3,48,49,67–69}

Nocardia Species	Source [Number of Isolates]^REF	Method	Antibiotic, with % of Non-Susceptible^$ Isolates
			AMX	AMC	CRO	CTX	IPM	MEM	AMK	CLR	CIP	MXF	MIN	DOX	LIN	SXT
N. abscessus complex	Schlaberg, R. et al 2014 [n=110]^Citation49	BM		22	2		69†		0	71	100	92	15		0	0
	Valdezate, S. et al 2017 [n=142]^Citation48	E-test		5		5	12		0		84		9		0	3
	Brown-Elliott, B. et al 2016 [n=13]^Citation67*	BM					77	0
	Lebeaux, D. et al 2019 [n=152]^Citation3	DD	24	26	3	3	12†	7	1		87	49	1	5	0	1
	Hamdi, A. et al 2020 [n= 205]^Citation69	BM		39	7		36		0	62	97	87	6	13	0	0
N. nova complex	Schlaberg, R. et al 2014 [n=320]^Citation49	BM		91	53		1		0	3	99	98	88		0	0
	Valdezate, S. et al 2017 [n=168]^Citation48	E-test		68		25	2		0		94		89		1	20
	Brown-Elliott, B. et al 2016 [n=57]^Citation67*	BM					0	6
	Lebeaux, D. et al 2019 [n=145]^Citation3	DD	23	92	29	20	1	4	1		98	64	7	68	0	8
	Hamdi, A. et al 2020 [n= 452]^Citation69	BM		96	86		0		0	3	99	97	81	99	0	0
N. transvalensis complex	Valdezate, S. et al 2017 [n= 27]^Citation48	E-test		0		15	22		49		11		70		0	41
	Brown-Elliott, B. et al 2016 [n=18]^Citation67*	BM					78	17
	Lebeaux, D. et al 2019 [n=49]^Citation3	DD	59	12	4	0	37	17	31		10	6	4	48	0	12
	Hamdi, A. et al 2020 [n= 121]^Citation69	BM		11	36		91		74	98	51	28	69	90	0	12
N. farcinica	Schlaberg, R. et al 2014 [n=204]^Citation49	BM		24	97		67†		0	100	57	21	95		0	0
	Valdezate, S. et al 2017 [n=128]^Citation48	E-test		18		55	2†		2		48		89		3	45
	Brown-Elliott, B. et al 2016 [n=19]^Citation67*	BM					37	67
	Lebeaux, D. et al 2019 [n=149]^Citation3	DD	92	20	81	80	23†	73	1		42	10	13	64	0	4
	Hamdi, A. et al 2020 [n= 319]^Citation69	BM		4	97		17		0	100	51	24	93	98	0	1
N. cyriacigeorgica	Schlaberg, R. et al 2014 [n=264]^Citation49	BM		97	12		57		0	99	100	96	95		0	0
	Valdezate, S. et al 2017 [n=283]^Citation48	E-test		72		3	3		1		98		84		1	4
	Brown-Elliott, B. et al 2016 [n=25]^Citation67*	BM					40	32
	Lebeaux, D. et al 2019 [n=95]^Citation3	DD	87	91	4	7	11	44	11		100	62	19	22	0	3
	Hamdi, A. et al 2020 [n= 352]^Citation69	BM		92	36		1		1	99	100	99	86	89	0	0
N. brasiliensis	Gomez-Flores, A. et al 2004 [n=30]^Citation68	DD	100	3	90	72	90		0		83		7		0	17
	Schlaberg, R. et al 2014 [n=148]^Citation49	BM		5	51		99		0	97	99	1	76		0	0
	Valdezate, S. et al 2017 [n=39]^Citation48	E-test		8		13	56		0		62		59		0	0
	Brown-Elliott, B. et al 2016 [n=8]^Citation67*	BM					100	52
	Lebeaux, D. et al 2019 [n=48]^Citation3	DD	67	8	31	23	85	58	0		90	2	13	67	0	4
	Hamdi, A. et al 2020 [n= 223]^Citation69	BM		1	98		92		0	100	100	60	84	95	0	0

Notes: ^$Non-susceptible isolates were defined as resistant or intermediate; *In this study, susceptible and intermediate isolates were combined; as a consequence, percentages given only represent isolates categorized as “resistant”; ^†BMD may give false-resistant results for imipenem, which therefore need to be confirmed using another method”. The limited stability of imipenem in broth may explain these discrepancies.

Abbreviations: AMC, amoxicillin/clavulanic acid; AMK, amikacin; AMX, amoxicillin; BM, broth microdilution; CIP, ciprofloxacin; CLR, clarithromycin; CRO, ceftriaxone; CTX, cefotaxime; DD, disk diffusion; DOX, doxycycline; IMP, imipenem; LIN, linezolid; MIN, minocycline; MXF, moxifloxacin; SXT, trimethoprim-sulfamethoxazole.

Table 2 Main Characteristics of Antibiotics That Can Be Used Before Obtaining the Results of Antibiotic Susceptibility Testing, ie, for the Initial Antibiotic Treatment^2,62,70

Characteristics	Cotrimoxazole	Linezolid	Parenteral Cephalosporins		Imipenem^a	Amikacin
			Cefotaxime	Ceftriaxone
Total daily dose^b	10–20 (15) mg TMP/kg/d ^c	1200 mg/d	6–12 g/d	2 g/d	2–3 g/d	20–30 mg/kg/d
Route of administration	PO or IV	PO or IV	IV	IV	IV	IV
Number of daily doses	3 or 4	2	3	1	3 or 4	1
Oral bioavailability	80%	100%	NA	NA	NA	NA
Drug concentration ratio CSF/C serum	50%	80%	10–50%	10%	10%	10%
Interference with immunosuppressive agents	↑Cyclosporine/tacrolimus-related nephrotoxicity. Contraindication with methotrexate^c					↑Cyclosporine/tacrolimus-related nephrotoxicity
Main adverse events^d	Myelosuppression, serum creatinine increase	Myelosuppression, peripheral neuropathy			Seizures	Nephrotoxicity, ototoxicity
Management/prevention of adverse events	- Consider “false” nephrotoxicity before stopping cotrimoxazole^e - Adjunction of folinic acid if progressive ↓ of blood cells - Switch to another antibiotic	- Obtain blood concentration (trough target 2–6mg/L) ± dose reduction. - Possibility of myelosuppression-sparing antibiotic with tedizolid^f. - Switch to another antibiotic.	- Obtain blood concentration ± dose reduction. - Switch to another antibiotic		- Consider switch to meropenem.^a - Switch to another antibiotic	- Obtain undetectable amikacin level before next injection. - Switch to another antibiotic

Notes: ^aMeropenem (3–6 g/d) may be an alternative agent depending on species and only with the results of antibiotic susceptibility testing. Ertapenem is not recommended; ^bAll these antibiotics must be adapted to renal function. Therapeutic drug monitoring may be required. 8 mg/kg/d in case of primary cutaneous nocardiosis; ^cMajor drug interaction between methotrexate and cotrimoxazole, which increases the risk of methotrexate-related toxicity, like severe pancytopenia. Prophylactic dose of cotrimoxazole is possible with methotrexate; ^dAll these antibiotics may induce skin rashes, anaphylaxis, and digestive symptoms including Clostridioides difficile infections; ^eSystematic increase in creatinine concentration can occur when taking trimethoprim/sulfamethoxazole due to its inhibitory effects on tubular creatinine secretion, with no modification of the measured GFR. A moderate (≈20–30%) increase in creatinine concentration, with no other AE should not prompt SXT interruption but rather encourage close monitoring and possibly the use of non-creatinine-based equations (eg, cystatin C) to assess renal function; ^fTedizolid, a more recent agent from the oxazolidinone class of antibiotics, may be a therapeutic option as suggested by a recent case report.

Abbreviation: CSF, cerebrospinal fluid.

Table 3 Proposed Initial Treatment and Antibiotic Duration for Invasive Nocardiosis, Based on Clinical Presentation, Before Obtaining Species Identification and/or Antibiotic Susceptibility Testing

Clinical Presentation	Initial Antibiotic Treatment, Antibiotic Duration
Skin*	Monotherapy: cotrimoxazole OR linezolid Antibiotic duration: 3 months. Initial oral treatment is possible.
Pulmonary, non-severe*	Monotherapy: cotrimoxazole OR linezolid Antibiotic duration: 4 to 6 months. Initial oral treatment is possible.
Pulmonary, severe*	Multi-drug regimen: 2 drugs among the 5 first-line agents. Possible combinations include: - [Imipenem OR cefotaxime OR ceftriaxone] + [amikacin OR cotrimoxazole OR linezolid] Antibiotic duration: 4 to 6 months. 2–3 weeks of intravenous therapy.
Central nervous system*	Multi-drug regimen: 2 to 3 drugs among the first-line agents. Possible combinations include: - [Imipenem OR cefotaxime OR ceftriaxone] + amikacin + cotrimoxazole - [Imipenem OR cefotaxime OR ceftriaxone] + [cotrimoxazole OR linezolid] Antibiotic duration: 12 months. 3–6 weeks of intravenous therapy.

Notes: Associated measures: In case of abscess, surgical treatment or radiologic aspiration should be considered. *Based on animal studies and numerous case series; No controlled trials available.

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