Research letters
Acknowledgements
We thank AstraZeneca Pharmaceuticals for providing avibactam.
Funding
This study was supported by an FP6 European programme (CCE COBRA,
conv 503335) in the framework of which Adriana Fernea was the recipient
of a pre-doctoral fellowship.
Transparency declarations
None to declare.
References
1 Stachyra T, Péchereau MC, Bruneau JM et al. Mechanistic studies of the
inactivation of TEM-1 and P99 by NXL104, a novel non-b-lactam
b-lactamase inhibitor. Antimicrob Agents Chemother 2010; 54: 5132 –8.
2 Ehmann DE, Jahić H, Ross PL et al. Avibactam is a covalent, reversible,
non-b-lactam b-lactamase inhibitor. Proc Natl Acad Sci USA 2012; 109:
11663– 8.
3 Ehmann DE, Jahic H, Ross PL et al. Kinetics of avibactam inhibition
against class A, C, and D b-lactamases. J Biol Chem 2013; 288: 27960–71.
4 Lahiri SD, Giacobbe RA, Johnstone MR et al. Activity of avibactam
against Enterobacter cloacae producing an extended-spectrum class C
b-lactamase enzyme. J Antimicrob Chemother 2014; 69: 2942– 6.
5 Barnaud G, Labia R, Raskine L et al. Extension of resistance to cefepime
and cefpirome associated to a six amino acid deletion in the H-10 helix of
the cephalosporinase of an Enterobacter cloacae clinical isolate. FEMS
Microbiol Lett 2001; 195: 185– 90.
6 De Meester F, Joris B, Reckinger G et al. Automated analysis of enzyme
inactivation phenomena. Application to b-lactamases and DD-peptidases.
Biochem Pharmacol 1987; 36: 2393 –403.
7 Porres-Osante N, Dupont H, Torres C et al. Avibactam activity against
extended-spectrum AmpC b-lactamases. J Antimicrob Chemother
2014; 69: 1715– 6.
J Antimicrob Chemother 2015
doi:10.1093/jac/dku464
Advance Access publication 23 November 2014
Ceftaroline CSF concentrations
in a patient with ventriculoperitoneal
shunt-related meningitis
Safia S. Kuriakose1*, Mohamed Rabbat2
and Jason C. Gallagher3
1
Department of Pharmacy, St Joseph’s Regional Medical Center,
703 Main Street, Paterson, NJ 07503, USA; 2Department of
Infectious Diseases, St Joseph’s Regional Medical Center, 703 Main
Street, Paterson, NJ 07503, USA; 3Temple University School of
Pharmacy, 3307 N. Broad Street, Philadelphia, PA 19140, USA
*Corresponding author. Tel: +1-973-754-3526; Fax: +1-973-754-4908;
E-mail: safia.kuriakose@yahoo.com
JAC
Keywords: cephalosporins, CNS, MRSA
Sir,
Ceftaroline is a cephalosporin antibiotic indicated for the treat-
ment of acute bacterial skin and skin structure infections and
community-acquired bacterial pneumonia.1 Ceftaroline has
been used for non-FDA-approved indications, including osteomye-
litis, endocarditis, bacteraemia and epidural abscesses.2 – 5 Data
on use for meningitis are limited to two rabbit models, showing
penetration into CSF of 14% – 15% in inflamed meninges and
3% in uninflammed meninges.6,7 The distribution of drugs into
the CSF is dependent upon multiple factors, including their lipophi-
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licity, plasma protein binding and molecular size, and the affinity
of active transport mechanisms to remove them from the CNS.8
Ceftaroline has low protein binding, is hydrophilic and has a similar
volume of distribution to other cephalosporins.1 Cephalosporins
distribute into the CSF relatively poorly, averaging AUCCSF/AUCserum
ratios of 0.007–0.1 for uninflamed or mildly inflamed meninges
and 0.15 for strongly inflamed meninges. However, due to their
potency, many cephalosporins achieve therapeutic CSF concen-
trations.8 We report a case of ceftaroline for the treatment of
MRSA meningitis related to an infected ventriculoperitoneal (VP)
shunt. This case report was reviewed and approved by our
Institutional Review Board.
A patient presented with altered mental status and lethargy for
24 h. The patient had a history of hydrocephalus with chronic VP
shunt placement and 1 month prior had undergone shunt replace-
ment due to infection with methicillin-resistant Staphylococcus
epidermidis, which was treated with vancomycin.
On presentation, vitals were stable. However, the patient sud-
denly desaturated to 40% oxygen on room air and was intubated.
The white blood cell count was 23.6/mm3 with 93% segmented
neutrophils and 4% bands. Arterial blood gas results were
pH 7.55, pCO2 29 mmHg, pO2 216 mmHg and HCO3 25.4 mmol/L.
Serum creatinine was 0.5 mg/dL, which remained stable with an
estimated creatinine clearance of .100 mL/min throughout
admission. A CT scan showed new prominent dilatation of the
lateral ventricles. The patient was diagnosed with obstructive
hydrocephalus and taken to the operating room. Cefazolin was
administered for surgical prophylaxis and a proximal shunt mal-
function was addressed with insertion of a new proximal catheter.
CSF was drawn from the shunt and sent for culture. The patient
was transferred to the ICU.
On day 1 of admission, the CSF Gram stain report showed
Gram-positive cocci in pairs and clusters. Fluid count was not com-
pleted. Infectious diseases consultation was requested for menin-
gitis. On day 2, the patient became febrile at 39.18C and was taken
to the operating room for removal of the shunt and placement of
an external ventricular drain. A repeat CSF culture and the VP shunt
tip were sent for analysis. The patient was started on linezolid, cef-
triaxone and nafcillin and then switched to 600 mg of ceftaroline
intravenously every 8 h on day 3. Vancomycin was avoided given
recent use and concern for treatment failure. The CSF culture from
day 1 was finalized as MRSA with a ceftaroline MIC¼ 1.0 mg/L by
Etestw. The CSF culture from day 2 was finalized as negative, while
the shunt tip grew MRSA. By the time of finalization, the patient
had been started on ceftaroline and had additional repeat CSF cul-
tures that were negative so ceftaroline was continued. Due to the
lack of data on the use of ceftaroline for meningitis, samples of
953
Research letters
Table 1. Ceftaroline concentrations in the plasma and CSF
Ceftaroline doses prior to sample collection (no.) Timing of sample collection
15 1.5 h after end of infusion of previous dose
17 0.5 h before next scheduled dose
CSF from the external ventricular drain and blood were sent for
analysis. CSF samples were cultured an additional seven times
during the admission and were negative. On day 14, the patient
developed Serratia marcescens line-related bacteraemia with a
ceftaroline MIC ¼ 1.5 mg/L by Etestw. Gentamicin and merope-
nem were started empirically and streamlined to ciprofloxacin
after final susceptibilities were reported. Repeat blood cultures
were negative. On day 23 a new VP shunt was placed. The patient
received ceftaroline and ciprofloxacin until discharge on day 27, at
which point oral linezolid and ciprofloxacin were prescribed for an
additional 7 days.
Simultaneous ceftaroline blood and CSF samples were
collected 6 and 7 days into therapy. The blood samples were
centrifuged and CSF and blood samples were frozen at 2708C.
The samples were mailed on dry ice to Keystone Bioanalyticals,
which analysed them by liquid chromatography– MS. All storage
and handling instructions were strictly followed. Results are
shown in Table 1.
By the time of CSF analysis, the patient’s symptoms of
infection had abated and it is likely that little-to-no meningeal
inflammation remained. Thus, the CSF:plasma ratios of 0.035
and 0.041 are consistent with those of other b-lactams in this
clinical situation.8 Although the patient’s clinical picture resolved
while receiving ceftaroline, we cannot be sure that ceftaroline
was the reason since the patient’s CSF cultures cleared before it
was initiated. While the drug levels from this patient help assess
ceftaroline CSF penetration, we believe that ceftaroline levels col-
lected during acute meningitis should be measured to determine
the likely role of ceftaroline in the treatment of CNS infections.
Funding
This study was carried out as part of our routine work.
Transparency declarations
J. C. G. is a speaker for Forest, Cubist and Astellas, he is a consultant for
Forest and Pfizer, and he has received grant funding from
Merck. S. S. K. and M. R.: none to declare.
References
1 Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin
with activity against methicillin-resistant Staphylococcus aureus. Clin
Infect Dis 2011; 52: 1156– 63.
2 Polenakovik HM, Pleiman CM. Ceftaroline for meticillin-resistant
Staphylococcus aureus bacteraemia: case series and review of the litera-
ture. Int J Antimicrob Agents 2013; 42: 450–5.
3 Ho TT, Cadena J, Childs LM et al. Methicillin-resistant Staphylococcus
aureus bacteraemia and endocarditis treated with ceftaroline salvage
therapy. J Antimicrob Chemother 2012; 67: 1267– 70.
954
CSF (mg/L) Plasma (mg/L) CSF:plasma ratio
0.461 11.323 0.041
0.190 5.428 0.035
4 Jongsma K, Joson J, Heidari A. Ceftaroline in the treatment of concomi-
tant methicillin-resistant and daptomycin-non-susceptible Staphylococcus
aureus infective endocarditis and osteomyelitis: case report. J Antimicrob
Chemother 2013; 68: 1444–5.
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5 Bucheit J, Collins R, Joshi P. Methicillin-resistant Staphylococcus aureus
epidural abscess treated with ceftaroline fosamil salvage therapy. Am J
Health Syst Pharm 2014; 71: 110–3.
6 Cottagnoud P, Cottagnoud M, Acosta F et al. Efficacy of ceftaroline fosa-
mil against penicillin-sensitive and -resistant Streptococcus pneumoniae in
an experimental rabbit meningitis model. Antimicrob Agents Chemother
2013; 57: 4653– 5.
7 Stucki A, Acosta F, Cottagnoud M et al. Efficacy of ceftaroline
fosamil against Escherichia coli and Klebsiella pneumoniae strains in a
rabbit meningitis model. Antimicrob Agents Chemother 2013; 57:
5808– 10.
8 Nau R, Sorgel F, Eiffert H. Penetration of drugs through the blood-
cerebrospinal fluid/blood-brain barrier for treatment of central nervous
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J Antimicrob Chemother 2015
doi:10.1093/jac/dku428
Advance Access publication 23 October 2014
SAMHD1 expression in blood cells of
HIV-1 elite suppressors and viraemic
progressors
Erin L. Buchanan†, Melissa A. McAlexander† and
Kenneth W. Witwer*
Department of Molecular and Comparative Pathobiology, The Johns
Hopkins University School of Medicine, Baltimore, MD, USA
*Corresponding author. Tel: +1-410-955-9770; Fax: +1-410-955-9823;
E-mail: kwitwer1@jhmi.edu
†These authors contributed equally.
Keywords: elite controllers, PBMCs, interferon, IFN
Sir,
Riveira-Muñoz et al.1 recently reported that HIV-1 elite suppres-
sors (ES), who maintain low viral loads without pharmacological
intervention,2 also maintain higher levels of restriction factor
SAMHD1 transcript than either healthy donors (HD) or viraemic
progressors (VP) in PBMCs. This compelling finding applied to indi-
viduals with and without protective HLA-B alleles. As the authors
astutely stated, however, increased SAMHD1 ‘may not be a cause
but the consequence’ of suppression.1 Beyond this caveat, it is