TMP/SMX, Nitrofurantoin, Fosfomycin Flashcards
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Resistance
1) overproduction of PABA
2) ↓ affinity of enzyme dihydrofolate synthetase for
sulfonamide
3) ↓ affinity of dihydrofolate reductase for trimethoprim
4) ↓ cell permeability (plasmid mediated)
trimethoprim/Sulfamethoxazole
(Cotrimoxazole) (TMP/SMX)
what effect together?
❑ fixed ratio oral or IV results in ideal serum ratio of 1:20
❑ (SS tablet 80mg TMP / 400 mg sulfamethoxazole)
(DS tablet 160mg TMP / 800 mg sulfamethoxazole)
❑ synergistic / bactericidal
❑ reduced risk of resistance
Effect of sum of them together is greater than sum of them alone
TMP/SMX Spectrum
gram postiitve
S. aureus 98% 2020 (99% 2014)
MRSA 94% 2020 (97% 2014)
CoNS 81% 2020 (74% 2014)
S. pneumoniae 86% 2020 (89% 2014), 74% 2011
• not effective against Streptococcal pharyngitis
caused by S. pyogenes
• (Not effective against enterococci)
Not as good as coagulase neg staph
Not as good for pneumoniae but still reasonable
Not good for pyogenes
Not good against group A strep SSTI
TMP/SMX Spectrum
gram neg
❑ H. influenzae 67% 2020 (77% 2012) ❑ E.coli 79% 2020 (78% 2012)* ❑ K. pneumoniae 94% 2020 (96% 2012) ❑ Proteus mirabilis 82% 2020 (71% 2014) ❑ S. marcesens 100% 2020 (100% 2012) ❑ Enterobacter spp (87% 2020, 97% 2012) ❑ Acinetobacter 94% 2019 (UAH) ❑ Citrobacter freundii 90% 2020 ❑ Stenotrophomonas maltophilia 98% 2020 (UAH)
❑ not effective against P. aeruginosa
AMP-C making SPICE-A organisms are treated
TMP/SMX Spectrum
anaerobes?
without cell wall organisms?
fungi?
❑ Active against M. catarrhalis,L. monocytogenes, &
Legionella
❑ Not reliable against M. pneumoniae or Chlamydia
❑ Not active against anaerobes
❑ Active against Pneumocystis jiroveci and Nocardia
TMP/SMX Pharmacokinetics
IV or oral?
metabolized by CYP?
❑ well absorbed orally
❑ well distributed to many tissues, pleural fluids, peritoneal
fluids, and CSF (variable - SMX 25-30%, TMP ~ 40%)
❑ variable protein binding (SMX 70%, TMP 44%)
❑ extensively metabolised in liver (acetylation, glucuronidation)
• both SMX and TMP metabolized by CYP 2C9 and 3A4
❑ Both excreted in urine (metabolites and unchanged) – dosage adjustment required in renal impairment
Good bioavailability
Comp levels to IV
TMP/SMX Adverse Effects
GI
hematologic
❑ GI (nausea, vomiting, diarrhea) jaundice, hepatic necrosis
Hematologic
❑ anemia, agranulocytosis,
❑ thrombocytopenia,
❑ hemolytic anemia (G6PD deficiency)
(hematologic effects may be more severe in elderly and patients with HIV disease)
❑ Teratogenicity in pregnancy (contraindicated in 1
st and 3rd trimesters)
❑ kernicterus, infants (displacement of bilirubin from binding sites)
❑ photosensitivity - protect from sun
TMP/SMX Adverse Effects
which class of rxns more common
❑ Sulfonamide antibacterials can rarely cause
IgE-mediated reactions
❑ More commonly cause maculopapular rashes
❑ Maculopapular rashes occur at a rate of 1-3% in the
non-HIV population, but higher incidence in HIV patients
class 4
❑ Stevens-Johnson syndrome, erythema nodosum,
erythema multiforme
❑ vasculitis
❑ interstitial nephritis, tubular necrosis
hyperkalemia
TMP/SMX
HIV Patients
❑ Hypersensitivity reactions develop in only ~ 1-3 % of
patients not infected with HIV, but 40-50% in HIV
❑ some literature as high as 20 - 80% patients infected with HIV
❑ ? Due to altered drug metabolism, reduced glutathione levels, or both
❑ Graded challenge with sulfamethoxazole may permit its use again (75% in one study)
❑ Patients may tolerate TMP/SMX with rapid induction of tolerance (desensitization)
❑ Patients with HIV more likely to develop anemia
associated with TMP/SMX
TMP/SMX testing for hypersensitibity
❑ Specific determinants of sulfonamide
hypersensitivity not known - no test available
❑ Repeated administration is not recommended after any life-threatening reaction (anaphylaxis, drug-induced
hemolytic anemia, thrombocytopenia, neutropenia,
immune-complex reactions, Stevens-Johnson Syndrome and toxic epidermal necrolysis)
- agents that are used preferentially in certain agents, but there are other agents available and can switch
Sulfonamide Antibiotic
Cross-Reactivity with
Non-Antibiotic Sulfonamide Drugs
(sulfa allergy)
although all sulfonamides contain an NH2
-SO2 moiety, sulfonamide antibiotics also contain an aromatic amine at the N4 position and a substituted ring at the N1 position”
❑ “these groups are believed to be essential for
various types of allergic reactions to sulfonamide
antibiotics”.
HCTZ, furosemide, COX2 inhibitors are diff from sulfamethoxazole
Cross-reactivity with
Sulfonamide Antibacterials and
Sulfonamide Non-antibacterials
is there evidence to suggest cross-reactivity b/w sulfonamide abx and non-sulfonamide abx?
“ There is an association betweenhypersensitivity after the receipt of sulfonamide antibiotics and a subsequent allergic reaction after the receipt of a sulfonamide non-antibiotic, but, this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.”
“ There is no evidence to suggest allergic cross-reactivity between sulfonamide antibiotics and non-antibiotic sulfonamides”
confirm speciifc sulfa drug pt was allergic to
By comparison the OR for an allergic reaction after the receipt of a Rx for penicillin in those with a prior rxn to sulfonamides
compared to those without such a reaction was 7.8
These results suggest subsequent reaction
to nonantibiotic sulfonamides is probably a
predispostion to allergic reactions in general”
Testing for IgE Mediated Allergy
in Non-β-lactams
❑ Any non-β-lactam antibiotic has the potential of
causing an IgE-mediated reaction, but these appear
to occur less commonly than with β-lactam antibiotics
❑ There are no validated diagnostic tests for
evaluation of IgE-mediated reactions to non-βlactam antibiotics
❑ Evaluation of possible allergy should be limited to
situations when treatment with the drug is anticipated
(rather than electively as for penicillin)
Skin testing with nonirritating concentrations
of non-β-lactams antibiotics is not standardized
A negative test does not rule out the possibility of
an IgE immediate-type reaction
A positive test suggests drug specific IgE antibodies by the predictive value is unknown
Patient with a history of reactions to non-β-lactams antibiotics consistent with an IgE mediated mechanism should only receive them if an alternative is not available and only with rapid induction of drug tolerance
Drug Interactions
TMP/SMX
Inhibitor of CYP2C9
❑ May substantially increase S-warfarin levels (increasing INR)
❑ (S enantiomer 2-5 x more potent than R)
❑ Either use alternative antibacterial; or
❑ Monitor and adjust dose if no other choice
❑ Zidovudine increases risk of hematologic effects.
❑ May increase levels of phenytoin
❑ possible hypoglycemia with sulfonylureas
Nitrofurantoin
Macrodantin, Macrobid
Mechanism
❑ Reduced by bacterial flavoproteins to reactive
intermediates which alter bacterial ribosomal
proteins or other macromolecules
❑ Remarkably stable to the development of
resistance
doesnt conc much in tissues, absorbed and very little affects the gut bacteria
Nitrofurantoin
kinetics
dose
Kinetics
❑ well absorbed, 2/3 rapidly metabolized in tissues, 1/3
unchanged in urine
❑ low serum levels, levels only effective for UTIs
❑ may be insufficient drug in urine if CrCl < 30-60 mL/min
Dose
❑ Macrodantin 50 - 100 mg qid
❑ Macrobid 100 mg bid (25% macrocrystals, 75% powde
Nitrofurantoin spectrum
❑ S. aureus 99% ❑ E. faecalis 98% ❑ E. faecium 14% ❑ E. coli 96% (84% of ESBL producers) ❑ K. pneumoniae 32% ❑ P. mirabilis - R
Nitrofurantoin AE
GI
hematologic
GI
❑ most common (take with food or milk)
❑ macrocrystals designed to ↓ peak ↓ nausea
Hepatotoxicity - rare
Hypersensitivity - rare
❑ Skin rash, anaphylaxis, drug fever, asthma
❑ pneumonitis (reversible)
❑ Chronic interstitial pulmonary fibrosis occasionally
(may be irreversible)
Hematologic
❑ hemolytic anemia with G6PD deficiency
❑ (not recommended in neonates < 1 month due to immature enzyme systems, at term in pregnancy, & women nursing infants < 1 month)
❑ Risk Factor B in pregnancy, except at term
❑ leukopenia, granulocytopenia, eosinophilia (rare)
Nitrofurantoin AE
neurologic
urine
Neurologic ❑ ascending polyneuropathy with prolonged therapy or if renal failure Urine discolouration ❑ may be brown or rust-yellow
Nitrofurantoin Drug Interactions
Uricosuric Agents (Sulfinpyrazone, Probenecid) ❑ decrease excretion ❑ decrease effectiveness in UTI ❑ increase toxicity
Fosfomycin Tromethamine
(Monurol®)
mechanism?
Inhibits peptidoglycan cell wall synthesis at a
very early stage
Fosfomycin Spectrum of Activity
S. aureus, ? S. saprophyticus, Enterococci
E. coli, Klebsiella, Serratia, Enterobacter,
Citrobacter
Fosfomycin Resistance
Develops frequently with multiple doses but not
as frequently with single doses
Chromosomal
decreased uptake into bacterial cell
Plasmid Mediated
Catalytic conjugation with glutathione
Little cross resistance with other antibacterials
some resetriction to ESBL prod E coli
Fosfomycin Bioavail
Bioavailability 34 - 65% (OK with food, but best without food if tolerated)
No proteinbinding
Large volume of distribution
Excreted unchanged inurine
Minor (0.5%) biliary excretion
Peak urinary concentrations up to 4415mg/L
Break point >128 mg/L
Fosfomycin AE
Well tolerated (only 3.1% adverseeffects)
Mild, transient 1 - 2 days
GI - diarrhea1.8%
Hypernatremia with IV formulation (dosed several times a day
Other - dizziness, headache
Rarely
Angioedema, asthma, aplastic anemia,
cholestatic jaundice, hepatic necrosis, toxic
megacolon
Pregnancy category B
